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Ghayal NB, Roemer SF, Tipton PW, Jiang P, Selner EM, Peck DS, Murakami A, Oglesbee D, Graff-Radford NR, Dickson DW. Clinical Heterogeneity of Neuronal Ceroid Lipofuscinosis Type 13: A Case Report and Systematic Review of Literature. Neurol Genet 2025; 11:e200227. [PMID: 39720560 PMCID: PMC11668517 DOI: 10.1212/nxg.0000000000200227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/08/2024] [Indexed: 12/26/2024]
Abstract
Objectives In this study, we describe a 54-year-old Indian woman who presented with clinical features of Kufs syndrome A (KSA) and Kufs syndrome B (KSB), as well as neuropathologic and genetic findings consistent with neuronal ceroid lipofuscinosis type 13 (CLN13). Subsequently, we review the clinicopathologic features of 20 patients with CLN13 reported in the literature. Methods Data and imaging were obtained from the patient's medical records. The patient was examined neuropathologically, and next-generation sequencing was performed. Results Clinical radiologic scans revealed bilateral cortical atrophy, ventriculomegaly, a thin corpus callosum, and cerebellar vermian atrophy. Pathologic examination was remarkable for NCL. Postmortem genetic testing revealed a homozygous cathepsin F (CTSF) indel variant. A review of 20 reported CLN13 patients revealed novel clinical subtypes, including KSB type I (KSB-I), KSB type II (KSB-II), and Kufs syndrome C (KSC). Discussion CLN13 was clinically heterogeneous. Most patients with CLN13 (14/20) did not present with classic KSB (KSB-I). Instead, 6 patients presented with KSB-II, 4 patients presented with KSC (including the present patient), and 3 patients presented with dementia. Our results expand the CLN13 clinical spectrum and emphasize the importance of screening CTSF variants in clinical dementia and movement disorder cohorts.
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Affiliation(s)
| | - Shanu F Roemer
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL
| | | | - Peizhou Jiang
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL
| | - Elizabeth M Selner
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; and
| | - Dawn S Peck
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; and
| | - Aya Murakami
- Department of Neurology, Kansai Medical University, Osaka, Japan
| | - Devin Oglesbee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; and
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2
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Huang H, Liao Y, Yu Y, Qin H, Wei YZ, Cao L. Adult-onset neuronal ceroid lipofuscinosis misdiagnosed as autoimmune encephalitis and normal-pressure hydrocephalus: A 10-year case report and case-based review. Medicine (Baltimore) 2024; 103:e40248. [PMID: 39470529 PMCID: PMC11520998 DOI: 10.1097/md.0000000000040248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/01/2024] [Accepted: 10/08/2024] [Indexed: 10/30/2024] Open
Abstract
RATIONALE Neuronal ceroid lipofuscinoses (NCLs) are rare, fatal, inherited neurodegenerative disorders characterized by myoclonic epilepsy, cognitive decline, brain atrophy, and retinopathy. The pathogenesis and clinical manifestations of NCL are not well understood and frequently result in misdiagnosis and overtreatment. The aim of this case report and review is to improve our understanding of the clinical features and management of NCL. PATIENT CONCERNS A 36-year-old woman initially presented with refractory epilepsy. DIAGNOSES Initially diagnosed with autoimmune encephalitis, the patient was later diagnosed with normal-pressure hydrocephalus. A definitive diagnosis of adult-onset neuronal ceroid lipofuscinosis (ANCL) was established after 10 years of observation, utilizing biopsy and genetic testing. INTERVENTIONS High-dose intravenous immunoglobulin and methylprednisolone were administered, along with the insertion of a ventriculoperitoneal shunt. OUTCOMES Despite various treatments, the patient's condition did not improve. LESSONS ANCL typically presents with the clinical triad of refractory seizures, progressive cognitive decline, and movement disorders. Neuroimaging often reveals progressive brain atrophy on magnetic resonance imaging, while electroencephalograms frequently show epileptiform discharges. The prognosis is generally poor. Improved understanding of ANCL from both clinical and radiological perspectives, coupled with early consideration of differential diagnoses, could minimize unnecessary interventions and optimize patient care.
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Affiliation(s)
- Huasheng Huang
- Department of Neurology, Liuzhou People’s Hospital, Liuzhou, Guangxi Zhuang Autonomous Region, China
| | - Yuqi Liao
- School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Yanni Yu
- School of Medicine, Shenzhen University, Shenzhen, Guangdong Province, China
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - HuiHui Qin
- Department of Neurology, Liuzhou People’s Hospital, Liuzhou, Guangxi Zhuang Autonomous Region, China
| | - Yi Zhi Wei
- Department of Neurology, Liuzhou People’s Hospital, Liuzhou, Guangxi Zhuang Autonomous Region, China
| | - Liming Cao
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan Province, China
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3
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Chen B, Liu Y, Cai N, Wang N, Yang K. A novel homozygous CLN6 Tyr142Cys variant in a nonconsanguineous family with Kufs disease. Neurol Sci 2024; 45:4597-4600. [PMID: 38771523 DOI: 10.1007/s10072-024-07579-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/03/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it's rare and challenging to diagnose. CASE DESCRIPTION The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic-clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband's younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G. CONCLUSION Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene.
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Affiliation(s)
- Boli Chen
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China
| | - Yue Liu
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China
| | - Naiqing Cai
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China
| | - Ning Wang
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China
| | - Kang Yang
- Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China.
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4
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Cameron JM, Ellis CA, Berkovic SF. ILAE Genetics Literacy series: Progressive myoclonus epilepsies. Epileptic Disord 2023; 25:670-680. [PMID: 37616028 PMCID: PMC10947580 DOI: 10.1002/epd2.20152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/21/2023] [Accepted: 08/19/2023] [Indexed: 08/25/2023]
Abstract
Progressive Myoclonus Epilepsy (PME) is a rare epilepsy syndrome characterized by the development of progressively worsening myoclonus, ataxia, and seizures. A molecular diagnosis can now be established in approximately 80% of individuals with PME. Almost fifty genetic causes of PME have now been established, although some remain extremely rare. Herein, we provide a review of clinical phenotypes and genotypes of the more commonly encountered PMEs. Using an illustrative case example, we describe appropriate clinical investigation and therapeutic strategies to guide the management of this often relentlessly progressive and devastating epilepsy syndrome. This manuscript in the Genetic Literacy series maps to Learning Objective 1.2 of the ILAE Curriculum for Epileptology (Epileptic Disord. 2019;21:129).
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Affiliation(s)
- Jillian M. Cameron
- Epilepsy Research Centre, Department of MedicineUniversity of MelbourneAustin HealthMelbourneVictoriaAustralia
| | - Colin A. Ellis
- Department of NeurologyUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvaniaUSA
| | - Samuel F. Berkovic
- Epilepsy Research Centre, Department of MedicineUniversity of MelbourneAustin HealthMelbourneVictoriaAustralia
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5
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Wang XQ, Chen CB, Zhao WJ, Fu GB, Zhai Y. Rare adult neuronal ceroid lipofuscinosis associated with CLN6 gene mutations: A case report. World J Clin Cases 2023; 11:3533-3541. [PMID: 37383919 PMCID: PMC10294197 DOI: 10.12998/wjcc.v11.i15.3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/06/2023] [Accepted: 04/13/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Adult neuronal ceroid lipofuscinosis (ANCL) can be caused by compound heterozygous recessive mutations in CLN6. The main clinical features of the disease are neurodegeneration, progressive motor dysfunction, seizures, cognitive decline, ataxia, vision loss and premature death.
CASE SUMMARY A 37-year-old female presented to our clinic with a 3-year history of limb weakness and gradually experiencing unstable walking. The patient was diagnosed with CLN6 type ANCL after the identification of mutations in the CLN6 gene. The patient was treated with antiepileptic drugs. The patient is under ongoing follow-up. Unfortunately, the patient’s condition has deteriorated, and she is currently unable to care for herself.
CONCLUSION There is presently no effective treatment for ANCL. However, early diagnosis and symptomatic treatment are possible.
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Affiliation(s)
- Xue-Qiang Wang
- Department of Neurology, Sanya People’s Hospital, West China (Sanya) Hospital, Sichuan University, Sanya 572000, Hainan Province, China
| | - Chuan-Bi Chen
- Department of Pediatrics, Sanya Women and Children’s Hospital Managed by Shanghai Children's Medical Center, Sanya 572000, Hainan Province, China
| | - Wen-Jie Zhao
- Department of Neurology, The First Affiliated Hospital of Hainan Medical College, Haikou 570100, Hainan Province, China
| | - Guang-Bin Fu
- Department of Neurology, Hainan Western Central Hospital, Danzhou 571799, Hainan Province, China
| | - Yu Zhai
- Department of Neurology, Hainan Western Central Hospital, Danzhou 571799, Hainan Province, China
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6
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Progressive myoclonic epilepsies—English Version. ZEITSCHRIFT FÜR EPILEPTOLOGIE 2022. [DOI: 10.1007/s10309-022-00546-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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7
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Riney K, Bogacz A, Somerville E, Hirsch E, Nabbout R, Scheffer IE, Zuberi SM, Alsaadi T, Jain S, French J, Specchio N, Trinka E, Wiebe S, Auvin S, Cabral-Lim L, Naidoo A, Perucca E, Moshé SL, Wirrell EC, Tinuper P. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022; 63:1443-1474. [PMID: 35503725 DOI: 10.1111/epi.17240] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 03/12/2022] [Accepted: 03/16/2022] [Indexed: 01/15/2023]
Abstract
The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.
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Affiliation(s)
- Kate Riney
- Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, South Brisbane, Queensland, Australia
| | - Alicia Bogacz
- Institute of Neurology, University of the Republic, Montevideo, Uruguay
| | - Ernest Somerville
- Prince of Wales Hospital, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
| | - Edouard Hirsch
- Francis Rohmer Epilepsy Unit, Hautepierre Hospital, Strasbourg, France.,National Institute of Health and Medical Research 1258, Strasbourg, France.,Federation of Translational Medicine of Strasbourg, University of Strasbourg, Strasbourg, France
| | - Rima Nabbout
- Reference Centre for Rare Epilepsies, Assistance Publique - Hôpitaux de Paris, Department of Pediatric Neurology, Necker-Enfants Malades Hospital, Member of Epicare, Paris, France.,Imagine Institute, National Institute of Health and Medical Research Mixed Unit of Research 1163, Paris, France.,University City University, Paris, France
| | - Ingrid E Scheffer
- Austin Health, Royal Children's Hospital, Florey Institute and Murdoch Children's Research Institute, University of Melbourne, Melbourne, Victoria, Australia
| | - Sameer M Zuberi
- University City University, Paris, France.,Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.,Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK
| | - Taoufik Alsaadi
- Department of Neurology, American Center for Psychiatry and Neurology, Abu Dhabi, United Arab Emirates
| | | | - Jacqueline French
- New York University Grossman School of Medicine and NYU Langone Health, New York, New York, USA
| | - Nicola Specchio
- Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Scientific Institute for Research and Health Care, member of EpiCARE, Rome, Italy
| | - Eugen Trinka
- Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Center for Cognitive Neuroscience, member of EpiCARE, Salzburg, Austria.,Neuroscience Institute, Christian Doppler University Hospital, Center for Cognitive Neuroscience, Salzburg, Austria.,Department of Public Health, Health Services Research and Health Technology Assessment, University for Health Sciences, Medical Informatics, and Technology, Hall in Tirol, Austria
| | - Samuel Wiebe
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Stéphane Auvin
- Institut Universitaire de France, Paris, France.,Paediatric Neurology, Assistance Publique - Hôpitaux de Paris, Robert-Debré Hospital, Paris, France.,University of Paris, Paris, France
| | - Leonor Cabral-Lim
- Department of Neurosciences, College of Medicine and Philippine General Hospital, Health Sciences Center, University of the Philippines Manila, Manila, the Philippines
| | - Ansuya Naidoo
- Neurology Unit, Greys Hospital, Pietermaritzburg, South Africa.,Department of Neurology, University of KwaZulu Natal, KwaZulu Natal, South Africa
| | - Emilio Perucca
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.,Department of Neuroscience, Monash University, Melbourne, Victoria, Australia
| | - Solomon L Moshé
- Isabelle Rapin Division of Child Neurology, Saul R. Korey Department of Neurology and Departments of Neuroscience and Pediatrics, Albert Einstein College of Medicine, New York, New York, USA.,Montefiore Medical Center, Bronx, New York, USA
| | - Elaine C Wirrell
- Divisions of Child and Adolescent Neurology and Epilepsy, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | - Paolo Tinuper
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.,Reference Centre for Rare and Complex Epilepsies, IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy
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8
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Simonati A, Williams RE. Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview. Front Neurol 2022; 13:811686. [PMID: 35359645 PMCID: PMC8961688 DOI: 10.3389/fneur.2022.811686] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/11/2022] [Indexed: 01/04/2023] Open
Abstract
The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.
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Affiliation(s)
- Alessandro Simonati
- Departments of Surgery, Dentistry, Paediatrics, and Gynaecology, School of Medicine, University of Verona, Verona, Italy
- Department of Clinical Neuroscience, AOUI-VR, Verona, Italy
- *Correspondence: Alessandro Simonati
| | - Ruth E. Williams
- Department of Children's Neuroscience, Evelina London Children's Hospital, London, United Kingdom
- Ruth E. Williams
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Smirnov VM, Nassisi M, Solis Hernandez C, Méjécase C, El Shamieh S, Condroyer C, Antonio A, Meunier I, Andrieu C, Defoort-Dhellemmes S, Mohand-Said S, Sahel JA, Audo I, Zeitz C. Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort. JAMA Ophthalmol 2021; 139:278-291. [PMID: 33507216 DOI: 10.1001/jamaophthalmol.2020.6089] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Importance Biallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions. Objective To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect. Design, Setting, and Participants This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020. Main Outcome and Measures Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis. Results Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background. Conclusions and Relevance These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.
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Affiliation(s)
- Vasily M Smirnov
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.,Université de Lille, Faculté de Médecine, Lille, France.,Exploration de la Vision et Neuro-Ophtalmologie, CHU de Lille, Lille, France
| | - Marco Nassisi
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France
| | - Cyntia Solis Hernandez
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France
| | - Cécile Méjécase
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.,Institute of Ophthalmology, University College London, London, United Kingdom
| | - Said El Shamieh
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.,Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon
| | - Christel Condroyer
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France
| | - Aline Antonio
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France
| | - Isabelle Meunier
- Institute for Neurosciences Montpellier, INSERM U1051, University of Monpellier, Montpellier, France.,National Center for Rare Genetic Retinal Dystrophies, Hôpital Guy de Chauliac, Montpellier, France
| | - Camille Andrieu
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France
| | | | - Saddek Mohand-Said
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France
| | - José-Alain Sahel
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.,Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France.,Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.,Académie des Sciences, Institut de France, Paris, France.,Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Isabelle Audo
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.,Institute of Ophthalmology, University College London, London, United Kingdom.,Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France
| | - Christina Zeitz
- Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France
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10
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Singh RB, Gupta P, Kartik A, Farooqui N, Singhal S, Shergill S, Singh KP, Agarwal A. Ocular Manifestations of Neuronal Ceroid Lipofuscinoses. Semin Ophthalmol 2021; 36:582-595. [PMID: 34106804 DOI: 10.1080/08820538.2021.1936571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are a group of rare neurodegenerative storage disorders associated with devastating visual prognosis, with an incidence of 1/1,000,000 in the United States and comparatively higher incidence in European countries. The pathophysiological mechanisms causing NCLs occur due to enzymatic or transmembrane defects in various sub-cellular organelles including lysosomes, endoplasmic reticulum, and cytoplasmic vesicles. NCLs are categorized into different types depending upon the underlying cause i.e., soluble lysosomal enzyme deficiencies or non-enzymatic deficiencies (functions of identified proteins), which are sub-divided based on an axial classification system. In this review, we have evaluated the current evidence in the literature and reported the incidence rates, underlying mechanisms and currently available management protocols for these rare set of neuroophthalmological disorders. Additionally, we also highlighted the potential therapies under development that can expand the treatment of these rare disorders beyond symptomatic relief.
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Affiliation(s)
- Rohan Bir Singh
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.,Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
| | - Prakash Gupta
- Department of Internal Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Akash Kartik
- Department of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Naba Farooqui
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Sachi Singhal
- Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
| | - Sukhman Shergill
- Department of Anesthesiology, Yale-New Haven Hospital, New Haven, CT, USA
| | - Kanwar Partap Singh
- Department of Ophthalmology, Dayanand Medical College & Hospital, Ludhiana, India
| | - Aniruddha Agarwal
- Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
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11
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Bose S, He H, Stauber T. Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters. Front Cell Dev Biol 2021; 9:639231. [PMID: 33708769 PMCID: PMC7940362 DOI: 10.3389/fcell.2021.639231] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/03/2021] [Indexed: 12/15/2022] Open
Abstract
The regulation of luminal ion concentrations is critical for the function of, and transport between intracellular organelles. The importance of the acidic pH in the compartments of the endosomal-lysosomal pathway has been well-known for decades. Besides the V-ATPase, which pumps protons into their lumen, a variety of ion transporters and channels is involved in the regulation of the organelles' complex ion homeostasis. Amongst these are the intracellular members of the CLC family, ClC-3 through ClC-7. They localize to distinct but overlapping compartments of the endosomal-lysosomal pathway, partially with tissue-specific expression. Functioning as 2Cl−/H+ exchangers, they can support the vesicular acidification and accumulate luminal Cl−. Mutations in the encoding genes in patients and mouse models underlie severe phenotypes including kidney stones with CLCN5 and osteopetrosis or hypopigmentation with CLCN7. Dysfunction of those intracellular CLCs that are expressed in neurons lead to neuronal defects. Loss of endosomal ClC-3, which heteromerizes with ClC-4, results in neurodegeneration. Mutations in ClC-4 are associated with epileptic encephalopathy and intellectual disability. Mice lacking the late endosomal ClC-6 develop a lysosomal storage disease with reduced pain sensitivity. Human gene variants have been associated with epilepsy, and a gain-of-function mutation causes early-onset neurodegeneration. Dysfunction of the lysosomal ClC-7 leads to a lysosomal storage disease and neurodegeneration in mice and humans. Reduced luminal chloride, as well as altered calcium regulation, has been associated with lysosomal storage diseases in general. This review discusses the properties of endosomal and lysosomal Cl−/H+ exchange by CLCs and how various alterations of ion transport by CLCs impact organellar ion homeostasis and function in neurodegenerative disorders.
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Affiliation(s)
- Shroddha Bose
- Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Hailan He
- Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.,Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
| | - Tobias Stauber
- Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.,Department of Human Medicine and Institute for Molecular Medicine, MSH Medical School Hamburg, Hamburg, Germany
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Abstract
Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever.
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13
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Rosenberg JB, Chen A, Kaminsky SM, Crystal RG, Sondhi D. Advances in the Treatment of Neuronal Ceroid Lipofuscinosis. Expert Opin Orphan Drugs 2019; 7:473-500. [PMID: 33365208 PMCID: PMC7755158 DOI: 10.1080/21678707.2019.1684258] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/21/2019] [Indexed: 12/27/2022]
Abstract
Neuronal ceroid lipofuscinoses (NCL) represent a class of neurodegenerative disorders involving defective lysosomal processing enzymes or receptors, leading to lysosomal storage disorders, typically characterized by observation of cognitive and visual impairments, epileptic seizures, ataxia, and deterioration of motor skills. Recent success of a biologic (Brineura®) for the treatment of neurologic manifestations of the central nervous system (CNS) has led to renewed interest in therapeutics for NCL, with the goal of ablating or reversing the impact of these devastating disorders. Despite complex challenges associated with CNS therapy, many treatment modalities have been evaluated, including enzyme replacement therapy, gene therapy, stem cell therapy, and small molecule pharmacotherapy. Because the clinical endpoints for the evaluation of candidate therapies are complex and often reliant on subjective clinical scales, the development of quantitative biomarkers for NCLs has become an apparent necessity for the validation of potential treatments. We will discuss the latest findings in the search for relevant biomarkers for assessing disease progression. For this review, we will focus primarily on recent pre-clinical and clinical developments for treatments to halt or cure these NCL diseases. Continued development of current therapies and discovery of newer modalities will be essential for successful therapeutics for NCL. AREAS COVERED The reader will be introduced to the NCL subtypes, natural histories, experimental animal models, and biomarkers for NCL progression; challenges and different therapeutic approaches, and the latest pre-clinical and clinical research for therapeutic development for the various NCLs. This review corresponds to the literatures covering the years from 1968 to mid-2019, but primarily addresses pre-clinical and clinical developments for the treatment of NCL disease in the last decade and as a follow-up to our 2013 review of the same topic in this journal. EXPERT OPINION Much progress has been made in the treatment of neurologic diseases, such as the NCLs, including better animal models and improved therapeutics with better survival outcomes. Encouraging results are being reported at symposiums and in the literature, with multiple therapeutics reaching the clinical trial stage for the NCLs. The potential for a cure could be at hand after many years of trial and error in the preclinical studies. The clinical development of enzyme replacement therapy (Brineura® for CLN2), immunosuppression (CellCept® for CLN3), and gene therapy vectors (for CLN1, CLN2, CLN3, and CLN6) are providing encouragement to families that have a child afflicted with NCL. We believe that successful therapies in the future may involve the combination of two or more therapeutic modalities to provide therapeutic benefit especially as the patients grow older.
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Affiliation(s)
- Jonathan B Rosenberg
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Alvin Chen
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Stephen M Kaminsky
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Ronald G Crystal
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Dolan Sondhi
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
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14
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Abstract
OBJECTIVE Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. METHODS We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. RESULTS Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection fibers were spared, but there was a profound loss of choline acetyltransferase within the caudate, putamen, and basal forebrain. This suggests a loss of choline acetyltransferase as opposed to a loss of the neurons. CONCLUSIONS This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain.
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15
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Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol 2019; 15:161-178. [PMID: 30783219 PMCID: PMC6681450 DOI: 10.1038/s41582-019-0138-8] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely overlapping symptoms and pathology. Phenotypically, patients with Batten disease have visual impairment and blindness, cognitive and motor decline, seizures and premature death. Pathologically, Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity and neuronal loss. Substantial progress has been made towards the development of effective therapies and treatments for the multiple forms of Batten disease. In 2017, cerliponase alfa (Brineura), a tripeptidyl peptidase enzyme replacement therapy, became the first globally approved treatment for CLN2 Batten disease. Here, we provide an overview of the promising therapeutic avenues for Batten disease, highlighting current FDA-approved clinical trials and prospective future treatments.
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Affiliation(s)
- Tyler B Johnson
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Jacob T Cain
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Katherine A White
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | | | - David A Pearce
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.
- Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA.
| | - Jill M Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.
- Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA.
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16
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Berkovic SF, Oliver KL, Canafoglia L, Krieger P, Damiano JA, Hildebrand MS, Morbin M, Vears DF, Sofia V, Giuliano L, Garavaglia B, Simonati A, Santorelli FM, Gambardella A, Labate A, Belcastro V, Castellotti B, Ozkara C, Zeman A, Rankin J, Mole SE, Aguglia U, Farrell M, Rajagopalan S, McDougall A, Brammah S, Andermann F, Andermann E, Dahl HHM, Franceschetti S, Carpenter S. Kufs disease due to mutation ofCLN6: clinical, pathological and molecular genetic features. Brain 2018; 142:59-69. [DOI: 10.1093/brain/awy297] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/02/2018] [Indexed: 01/22/2023] Open
Affiliation(s)
- Samuel F Berkovic
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Karen L Oliver
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Laura Canafoglia
- Department of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Penina Krieger
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - John A Damiano
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Michael S Hildebrand
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Michela Morbin
- Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Danya F Vears
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Vito Sofia
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Section of Neurosciences, University of Catania, Catania, Italy
| | - Loretta Giuliano
- Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, Section of Neurosciences, University of Catania, Catania, Italy
| | - Barbara Garavaglia
- Medical Genetics and Neurogenetics Unit, Bicocca Laboratories, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
| | - Alessandro Simonati
- Department of Neuroscience, Biomedicine, Movement-Neurology and Neuropathology, Policlinico GB Rossi, P.le LA Scuro, Verona, Italy
| | | | - Antonio Gambardella
- Institute of Neurology, University Magna Græcia Catanzaro, Italy; Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy
| | - Angelo Labate
- Institute of Neurology, University Magna Græcia Catanzaro, Italy; Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy
| | | | - Barbara Castellotti
- Unit Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy
| | - Cigdem Ozkara
- Istanbul University-Cerrahpaşa, Medical Faculty, Department of Neurology, Istanbul, Turkey
| | - Adam Zeman
- University of Exeter Medical School, St Luke’s Campus, Magdalen Road, Exeter EX1 2LU, UK
| | - Julia Rankin
- Clinical Genetics, Royal Devon and Exeter Hospital, Gladstone Road, Exeter, UK
| | - Sara E Mole
- MRC Laboratory for Molecular Cell Biology and UCL GOS Institute of Child Health, Department of Genetics, Evolution and Environment, University College London, London, UK
| | - Umberto Aguglia
- Department of Medical and Surgical Sciences, University Magna Græcia Catanzaro, Italy
- Institute of Molecular Bioimaging and Physiology of the National Research Council (IBFM-CNR) Germaneto, CZ, Italy
| | - Michael Farrell
- Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland
| | - Sulekha Rajagopalan
- Department of Clinical Genetics, Liverpool Hospital, Liverpool, New South Wales Australia
| | - Alan McDougall
- Department of Neurology, Liverpool Hospital, Liverpool, New South Wales Australia
| | - Susan Brammah
- Central Sydney Electron Microscope Unit, Concord Repatriation General Hospital, Concord, New South Wales, Australia
| | - Frederick Andermann
- Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada
- Departments of Neurology and Neurosurgery and Paediatrics, McGill University, Montreal, Quebec, Canada
| | - Eva Andermann
- Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada
- Departments of Neurology and Neurosurgery and Paediatrics, McGill University, Montreal, Quebec, Canada
| | - Hans-Henrik M Dahl
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
| | - Silvana Franceschetti
- Department of Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Stirling Carpenter
- Consultant in Neuropathology, Centro Hospitalar São João, Porto, Portugal
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Jentsch TJ, Pusch M. CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease. Physiol Rev 2018; 98:1493-1590. [DOI: 10.1152/physrev.00047.2017] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl−channels, whereas ClC-3 through ClC-7 are 2Cl−/H+-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl−channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.
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Affiliation(s)
- Thomas J. Jentsch
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy
| | - Michael Pusch
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy
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18
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Xiao F, Fan J, Tan J, Wang XF. Clinical Reasoning: Progressive cognitive decline, cerebellar ataxia, recurrent myoclonus, and epilepsy. Neurology 2018; 90:e1827-e1831. [PMID: 29760005 DOI: 10.1212/wnl.0000000000005528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Fei Xiao
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China
| | - Jingchuan Fan
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China
| | - Jiaze Tan
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China
| | - Xue-Feng Wang
- From the Department of Neurology (F.X., J.T., X.-f.W.), The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology; and Department of Medical Laboratory Technology (J.F.), Institute of Life Sciences of Chongqing Medical University, Chongqing, China.
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19
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Wang C, Xu H, Yuan Y, Lian Y, Xie N, Ming L. Novel compound heterozygous mutations causing Kufs disease type B. Int J Neurosci 2017; 128:573-576. [PMID: 29120254 DOI: 10.1080/00207454.2017.1403439] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND Kufs disease type B (also termed CLN13), an adult-onset form of neuronal ceroid lipofuscinosis (NCL), is genetically heterogeneous and challenging to diagnose. Recently, mutations in cathepsin-F have been identified as the causative gene for autosomal recessive Kufs disease type B. RESULTS Here, we report a sporadic case of Kufs disease type B with novel compound heterozygous mutations, a novel missense mutation c.977G>T (p.C326F) and a novel nonsense mutation c.416C>A (p.S139X), in the cathepsin-F gene. The magnetic resonance imaging findings were consistent with those demonstrated in adult neuronal ceroid lipofuscinosis: diffuse cortical atrophy, mild hyperintensity and reduction of the deep white matter on T2-weighted images. A skin biopsy was negative for abnormalities. CONCLUSIONS Altogether, our findings broaden the mutation database in relation to the neuronal ceroid lipofuscinosis, and the clinical diagnosis of Kufs disease type B was confirmed.
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Affiliation(s)
- Cui Wang
- a Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China.,b Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Hongliang Xu
- c Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Yun Yuan
- d Department of Neurology , Peking University First Hospital , Beijing , China
| | - Yajun Lian
- c Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Nanchang Xie
- c Department of Neurology , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Liang Ming
- a Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China.,b Key Clinical Laboratory of Henan Province, Department of Clinical Laboratory , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
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20
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Magrinelli F, Pezzini F, Moro F, Santorelli FM, Simonati A. Diagnostic methods and emerging treatments for adult neuronal ceroid lipofuscinoses (Kufs disease). Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1325359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Francesca Magrinelli
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Francesco Pezzini
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Francesca Moro
- Molecular Medicine and Neurogenetics Unit, IRCCS Stella Maris, Pisa, Italy
| | | | - Alessandro Simonati
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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21
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Berkovic SF, Staropoli JF, Carpenter S, Oliver KL, Kmoch S, Anderson GW, Damiano JA, Hildebrand MS, Sims KB, Cotman SL, Bahlo M, Smith KR, Cadieux-Dion M, Cossette P, Jedličková I, Přistoupilová A, Mole SE. Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease). Neurology 2016; 87:579-84. [PMID: 27412140 DOI: 10.1212/wnl.0000000000002943] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 04/29/2016] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes.
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Affiliation(s)
- Samuel F Berkovic
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK.
| | - John F Staropoli
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Stirling Carpenter
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Karen L Oliver
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Stanislav Kmoch
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Glenn W Anderson
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - John A Damiano
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Michael S Hildebrand
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Katherine B Sims
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Susan L Cotman
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Melanie Bahlo
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Katherine R Smith
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Maxime Cadieux-Dion
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Patrick Cossette
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Ivana Jedličková
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
| | - Anna Přistoupilová
- From the Epilepsy Research Centre, Department of Medicine (S.F.B., K.L.O., J.A.D., M.S.H.), University of Melbourne, Austin Health, Heidelberg, Australia; Biogen, Inc. (J.F.S.), Cambridge, MA; Department of Pathology (S.C.), Centro Hospitalar São João, Porto, Portugal; Institute of Inherited Metabolic Disorders (S.K., I.J., A.P.), First Faculty of Medicine, Charles University in Prague; General University Hospital in Prague (S.K.), Czech Republic; Great Ormond Street Hospital for Children NHS Foundation Trust (G.W.A.), London, UK; Center for Human Genetic Research and Department of Neurology (K.B.S., S.L.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Population Health and Immunity Division (M.B., K.R.S.), The Walter and Eliza Hall Institute of Medical Research; Departments of Mathematics and Statistics and Medical Biology (M.B.), University of Melbourne, Australia; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.C.-D., P.C.), University of Montreal, Canada; and MRC Laboratory for Cell Biology (S.E.M.), Department of Genetics, Evolution & Environment and UCL Institute of Child Health, University College London, UK
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22
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Bras J, Djaldetti R, Alves AM, Mead S, Darwent L, Lleo A, Molinuevo JL, Blesa R, Singleton A, Hardy J, Clarimon J, Guerreiro R. Exome sequencing in a consanguineous family clinically diagnosed with early-onset Alzheimer's disease identifies a homozygous CTSF mutation. Neurobiol Aging 2016; 46:236.e1-6. [PMID: 27524508 DOI: 10.1016/j.neurobiolaging.2016.06.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 06/23/2016] [Accepted: 06/26/2016] [Indexed: 12/16/2022]
Abstract
We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD.
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Affiliation(s)
- Jose Bras
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal
| | - Ruth Djaldetti
- Department of Neurology, Rabin Medical Center, Beilinson Campus, and Felsenstein Research Center, Petah Tiqva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ana Margarida Alves
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
| | - Simon Mead
- MRC Prion Unit, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK
| | - Lee Darwent
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
| | - Alberto Lleo
- Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; CIBERNED, Center for Networked Biomedical Research into Neurodegenerative Diseases, Madrid, Spain
| | - Jose Luis Molinuevo
- Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Institute of Neurosciences, Hospital Clínic i Universitari de Barcelona, IDIBAPS, Barcelona, Spain
| | - Rafael Blesa
- Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Andrew Singleton
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
| | - John Hardy
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
| | - Jordi Clarimon
- Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rita Guerreiro
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK; Department of Medical Sciences and Institute of Biomedicine - iBiMED, University of Aveiro, Aveiro, Portugal.
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23
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Canafoglia L, Gilioli I, Invernizzi F, Sofia V, Fugnanesi V, Morbin M, Chiapparini L, Granata T, Binelli S, Scaioli V, Garavaglia B, Nardocci N, Berkovic SF, Franceschetti S. Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. Neurology 2015; 85:316-24. [PMID: 26115733 DOI: 10.1212/wnl.0000000000001784] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 03/31/2015] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVES To describe the clinical and neurophysiologic patterns of patients with neuronal ceroid lipofuscinoses associated with CLN6 mutations. METHODS We reviewed the features of 11 patients with different ages at onset. RESULTS Clinical disease onset occurred within the first decade of life in 8 patients and in the second and third decades in 3. All children presented with progressive cognitive regression associated with ataxia and pyramidal and extrapyramidal signs. Recurrent seizures, visual loss, and myoclonus were mostly reported after a delay from onset; 7 children were chairbound and had severe dementia less than 4 years from onset. One child, with onset at 8 years, had a milder course. Three patients with a teenage/adult onset presented with a classic progressive myoclonic epilepsy phenotype that was preceded by learning disability in one. The EEG background was slow close to disease onset in 7 children, and later showed severe attenuation; a photoparoxysmal response (PPR) was present in all. The 3 teenage/adult patients had normal EEG background and an intense PPR. Early attenuation of the electroretinogram was seen only in children with onset younger than 5.5 years. Somatosensory evoked potentials were extremely enlarged in all patients. CONCLUSIONS In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature.
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Affiliation(s)
- Laura Canafoglia
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia.
| | - Isabella Gilioli
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Federica Invernizzi
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Vito Sofia
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Valeria Fugnanesi
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Michela Morbin
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Luisa Chiapparini
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Tiziana Granata
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Simona Binelli
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Vidmer Scaioli
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Barbara Garavaglia
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Nardo Nardocci
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Samuel F Berkovic
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
| | - Silvana Franceschetti
- From the Neurophysiopathology and Epilepsy Centre (L. Canafoglia, I.G., S.B., V. Scaioli, S.F.), Neuropathology-Neurology 5 (V.F., M.M.), Neuroradiology (L. Chiapparini), and Child Neurology and Psychiatry (T.G., N.N.), IRCCS Foundation C. Besta Neurological Institute, Milan; Molecular Neurogenetics (F.I., B.G.), IRCCS Foundation C. Besta Neurological Institute-Bicocca, Milan; G.F. Ingrassia Department (V. Sofia), University of Catania, Italy; and Epilepsy Research Center (S.F.B.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
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Gilliam D, Kolicheski A, Johnson GS, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, Katz ML. Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. Mol Genet Metab 2015; 115:101-9. [PMID: 25934231 DOI: 10.1016/j.ymgme.2015.04.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/14/2015] [Accepted: 04/14/2015] [Indexed: 11/20/2022]
Abstract
We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.
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Affiliation(s)
- D Gilliam
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - A Kolicheski
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - G S Johnson
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - T Mhlanga-Mutangadura
- Department of Veterinary Pathobiology, University of Missouri-Columbia, Columbia, MO, USA.
| | - J F Taylor
- Division of Animal Science, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO, USA.
| | - R D Schnabel
- Division of Animal Science, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, MO, USA.
| | - M L Katz
- Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO, USA.
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Cell biology of the NCL proteins: What they do and don't do. Biochim Biophys Acta Mol Basis Dis 2015; 1852:2242-55. [PMID: 25962910 DOI: 10.1016/j.bbadis.2015.04.027] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 04/23/2015] [Accepted: 04/24/2015] [Indexed: 02/06/2023]
Abstract
The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12 and CLN13) but also in the Endoplasmic Reticulum (CLN6 and CLN8), or in the cytosol associated to vesicular membranes (CLN4 and CLN14). Some of them such as CLN1 (palmitoyl protein thioesterase 1), CLN2 (tripeptidyl-peptidase 1), CLN5, CLN10 (cathepsin D), and CLN13 (cathepsin F), are lysosomal soluble proteins; others like CLN3, CLN7, and CLN12, have been proposed to be lysosomal transmembrane proteins. In this review, we give our views and attempt to summarize the proposed and confirmed functions of each NCL protein and describe and discuss research results published since the last review on NCL proteins. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)".
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Peters J, Rittger A, Weisner R, Knabbe J, Zunke F, Rothaug M, Damme M, Berkovic SF, Blanz J, Saftig P, Schwake M. Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease. Biochem Biophys Res Commun 2015; 457:334-40. [PMID: 25576872 DOI: 10.1016/j.bbrc.2014.12.111] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 12/26/2014] [Indexed: 01/06/2023]
Abstract
The lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) has been identified as a receptor for enterovirus 71 uptake and mannose-6-phosphate-independent lysosomal trafficking of the acid hydrolase β-glucocerebrosidase. Here we show that LIMP-2 undergoes proteolytic cleavage mediated by lysosomal cysteine proteases. Heterologous expression and in vitro studies suggest that cathepsin-F is mainly responsible for the lysosomal processing of wild-type LIMP-2. Furthermore, examination of purified lysosomes revealed that LIMP-2 undergoes proteolysis in vivo. Mutations in the gene encoding cathepsin-F (CTSF) have recently been associated with type-B-Kufs-disease, an adult form of neuronal ceroid-lipofuscinosis. In this study we show that disease-causing cathepsin-F mutants fail to cleave LIMP-2. Our findings provide evidence that LIMP-2 represents an in vivo substrate of cathepsin-F with relevance for understanding the pathophysiology of type-B-Kufs-disease.
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Affiliation(s)
- Judith Peters
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Andrea Rittger
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Rebecca Weisner
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Johannes Knabbe
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Friederike Zunke
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Michelle Rothaug
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Markus Damme
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Samuel F Berkovic
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Australia
| | - Judith Blanz
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Paul Saftig
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
| | - Michael Schwake
- Biochemie III, Fakultät für Chemie, Universität Bielefeld, Universitätsstr. 25, D-33615, Germany.
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Mancini C, Nassani S, Guo Y, Chen Y, Giorgio E, Brussino A, Di Gregorio E, Cavalieri S, Lo Buono N, Funaro A, Pizio NR, Nmezi B, Kyttala A, Santorelli FM, Padiath QS, Hakonarson H, Zhang H, Brusco A. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. J Neurol 2015; 262:173-8. [PMID: 25359263 DOI: 10.1007/s00415-014-7553-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 10/17/2014] [Accepted: 10/18/2014] [Indexed: 12/01/2022]
Abstract
Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.
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Affiliation(s)
- Cecilia Mancini
- Department of Medical Sciences, University of Torino, Via Santena 19, 10126, Turin, Italy
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Craiu D, Dragostin O, Dica A, Hoffman-Zacharska D, Gos M, Bastian AE, Gherghiceanu M, Rolfs A, Nahavandi N, Craiu M, Iliescu C. Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs. Eur J Paediatr Neurol 2015; 19:78-86. [PMID: 25439737 DOI: 10.1016/j.ejpn.2014.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 07/16/2014] [Accepted: 07/27/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.
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Affiliation(s)
- Dana Craiu
- "Carol Davila" University of Medicine Bucharest, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Discipline Pediatric Neurology, Romania; Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
| | - Octavia Dragostin
- Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
| | - Alice Dica
- Pediatric Neurology Clinic, Research Department, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
| | - Dorota Hoffman-Zacharska
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland.
| | - Monika Gos
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland.
| | - Alexandra Eugenia Bastian
- "Carol Davila" University of Medicine Bucharest, Department II, Dental Medicine, Pathology Discpline, Romania; Pathology Lab., Colentina University Hospital, Sos Stefan cel Mare 19-21, Sector 2, 020125 Bucharest, Romania.
| | - Mihaela Gherghiceanu
- Ultrastructural Pathology Lab., 'Victor Babes' National Institute of Pathology, 99-101 Spl. Independentei, 050096 Bucharest 5, Romania.
| | - Arndt Rolfs
- Albrecht-Kossel-Institute for Neurogenetics, Medical Faculty, University of Rostock, Gehlsheimerstrasse 20, 18157 Rostock, Germany; Centogene AG, Schillingallee 69, 18057 Rostock, Germany.
| | | | - Mihai Craiu
- "Carol Davila" University of Medicine Bucharest, Department of Pediatrics and Medical Genetics, Discipline Pediatrics, Romania; Pediatric II Clinic, "Alfred Rusescu" Clinical Pediatric Hospital, Institute of Mother and Child Health, B-dul Lacul Tei No. 120, Sector 2, Bucharest, Romania.
| | - Catrinel Iliescu
- "Carol Davila" University of Medicine Bucharest, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Discipline Pediatric Neurology, Romania; Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
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Yang X, Xu Y. Mutations in the ATP13A2 gene and Parkinsonism: a preliminary review. BIOMED RESEARCH INTERNATIONAL 2014; 2014:371256. [PMID: 25197640 PMCID: PMC4147200 DOI: 10.1155/2014/371256] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/14/2014] [Accepted: 07/28/2014] [Indexed: 02/05/2023]
Abstract
Parkinson's disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.
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Affiliation(s)
- Xinglong Yang
- Department of Neurology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan 610041, China
| | - Yanming Xu
- Department of Neurology, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu, Sichuan 610041, China
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Franceschetti S, Michelucci R, Canafoglia L, Striano P, Gambardella A, Magaudda A, Tinuper P, La Neve A, Ferlazzo E, Gobbi G, Giallonardo AT, Capovilla G, Visani E, Panzica F, Avanzini G, Tassinari CA, Bianchi A, Zara F. Progressive myoclonic epilepsies: definitive and still undetermined causes. Neurology 2014; 82:405-11. [PMID: 24384641 DOI: 10.1212/wnl.0000000000000077] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. METHODS We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. RESULTS We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. CONCLUSIONS Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.
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Affiliation(s)
- Silvana Franceschetti
- From the Department of Neurophysiopathology and Epilepsy Centre (S.F., L.C., E.V., F.P., G.A.), IRCCS Foundation C. Besta Neurological Institute, Milan; Unit of Neurology (R.M.), IRCCS Institute of Neurological Sciences, Bellaria Hospital, Bologna; Pediatric Neurology and Muscular Diseases Unit (P.S.), DINOGMI-Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, G. Gaslini Institute; Department of Medical and Surgical Sciences (A.G., E.F.), Magna Graecia University, Catanzaro; Institute of Neurological Sciences (A.G.), National Research Council, Mangone, Cosenza; Epilepsy Centre (A.M.), Department of Neuroscience, University of Messina; IRCCS Institute of Neurological Sciences and Department of Biomedical and Neuromotor Sciences (P.T.), University of Bologna; Epilepsy Centre (A.L.N.), Azienda Ospedaliero Universitaria Consorziale, Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso, Policlinico, Bari; Child Neurology Unit (G.G.), IRCCS delle Scienze Neurologiche, Bologna; Department of Neurology and Psychiatry (A.T.G.), Neurology Unit, La Sapienza University, Rome; Epilepsy Center (G.C.), Department of Child Neuropsychiatry, C. Poma Hospital, Mantua; University of Bologna (C.A.T.); Department of Neurology and Epilepsy Centre (A.B.), San Donato Hospital, Arezzo; and Istituto Gaslini (F.Z.), Laboratory of Neurogenetics, Genoa, Italy. Coinvestigators are listed on the Neurology® Web site at www.neurology.org
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Clinical, ultrastructural, and molecular studies in a patient with Kufs disease. Neurol Sci 2013; 35:605-7. [DOI: 10.1007/s10072-013-1587-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Accepted: 11/14/2013] [Indexed: 01/23/2023]
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Mink JW, Augustine EF, Adams HR, Marshall FJ, Kwon JM. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol 2013; 28:1101-5. [PMID: 23838030 PMCID: PMC3979348 DOI: 10.1177/0883073813494268] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The neuronal ceroid lipofuscinoses represent a group of disorders characterized by neurodegeneration and intracellular accumulation of an auto-fluorescent lipopigment (ceroid lipofuscin). Together, they represent the most prevalent class of childhood neurodegenerative disease. The neuronal ceroid lipofuscinoses encompass several distinct biological entities that vary in age of onset, specific neurologic phenotype, and rate of progression. In this review, we describe 9 major forms and present a classification scheme. Understanding the age of onset, clinical features, and natural history can inform rational diagnostics. Better knowledge of the natural histories of these disorders is necessary to shed light on the underlying pathobiology and to develop new therapeutics.
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Affiliation(s)
- Jonathan W. Mink
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Erika F. Augustine
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Heather R. Adams
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Frederick J. Marshall
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Jennifer M. Kwon
- Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
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Masellis M, Sherborn K, Neto P, Sadovnick DA, Hsiung GYR, Black SE, Prasad S, Williams M, Gauthier S. Early-onset dementias: diagnostic and etiological considerations. ALZHEIMERS RESEARCH & THERAPY 2013; 5:S7. [PMID: 24565469 PMCID: PMC3936399 DOI: 10.1186/alzrt197] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect.
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Walterfang M, Bonnot O, Mocellin R, Velakoulis D. The neuropsychiatry of inborn errors of metabolism. J Inherit Metab Dis 2013; 36:687-702. [PMID: 23700255 DOI: 10.1007/s10545-013-9618-y] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/29/2013] [Accepted: 04/30/2013] [Indexed: 12/15/2022]
Abstract
A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood as a phenocopy of a major psychiatric syndrome such as psychosis, depression, anxiety or mania. An understanding and awareness of secondary syndromes in metabolic disorders is of great importance as it can lead to the early diagnosis of such disorders. Many of these metabolic disorders are progressive and may have illness-modifying treatments available. Earlier diagnosis may prevent or delay damage to the central nervous system and allow for the institution of appropriate treatment and family and genetic counselling. Metabolic disorders appear to result in neuropsychiatric illness either through disruption of late neurodevelopmental processes (metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, Niemann-Pick type C, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis, and alpha mannosidosis) or via chronic or acute disruption of excitatory/inhibitory or monoaminergic neurotransmitter systems (acute intermittent porphyria, maple syrup urine disease, urea cycle disorders, phenylketonuria and disorders of homocysteine metabolism). In this manuscript we review the evidence for neuropsychiatric illness in major metabolic disorders and discuss the possible models for how these disorders result in psychiatric symptoms. Treatment considerations are discussed, including treatment resistance, the increased propensity for side-effects and the possibility of some treatments worsening the underlying disorder.
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Affiliation(s)
- Mark Walterfang
- Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Parkville, Australia.
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Clinical utility of vagus nerve stimulation for progressive myoclonic epilepsy. Seizure 2012; 21:810-2. [DOI: 10.1016/j.seizure.2012.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 08/23/2012] [Accepted: 08/27/2012] [Indexed: 11/20/2022] Open
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Michelucci R, Pasini E, Riguzzi P, Volpi L, Dazzo E, Nobile C. Genetics of epilepsy and relevance to current practice. Curr Neurol Neurosci Rep 2012; 12:445-55. [PMID: 22618127 DOI: 10.1007/s11910-012-0281-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Genetic factors are likely to play a major role in many epileptic conditions, spanning from classical idiopathic (genetic) generalized epilepsies to epileptic encephalopathies and focal epilepsies. In this review we describe the genetic advances in progressive myoclonus epilepsies, which are strictly monogenic disorders, genetic generalized epilepsies, mostly exhibiting complex genetic inheritance, and SCN1A-related phenotypes, namely genetic generalized epilepsy with febrile seizure plus and Dravet syndrome. Particular attention is devoted to a form of familial focal epilepsies, autosomal-dominant lateral temporal epilepsy, which is a model of non-ion genetic epilepsies. This condition is associated with mutations of the LGI1 gene, whose protein is secreted from the neurons and exerts its action on a number of targets, influencing cortical development and neuronal maturation.
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Affiliation(s)
- Roberto Michelucci
- Unit of Neurology, IRCCS Institute of Neurological Sciences, Bellaria Hospital, Via Altura 3, 40139, Bologna, Italy.
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Gourfinkel-An I, Baulac S, Brice A, Leguern E, Baulac M. Genetics of inherited human epilepsies. DIALOGUES IN CLINICAL NEUROSCIENCE 2012. [PMID: 22034131 PMCID: PMC3181638 DOI: 10.31887/dcns.2001.3.1/igourfinkelan] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly spectacular with respect to idiopathic epilepsies, with the discovery that mutations in ion channel subunits are implicated. However, important advances have also been made in many inherited symptomatic epilepsies, for which direct molecular diagnosis is now possible, simplifying previously complex investigations, it is expected that identification of the genes implicated in familial forms of epilepsies will lead to a better understanding of the underlying pathophysiological mechanisms of these disorders and to the development of experimental models and new therapeutic strategies, in this article, we review the clinical and genetic data concerning most of the inherited human epilepsies.
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Affiliation(s)
- I Gourfinkel-An
- Unité d'Epileptologie, Hôpital Pitié-Salpêtrière, Paris, France; Service d'Electrophysiologie, Hôpital Pitié-Salpêtrière, Paris, France
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Ferlazzo E, Gasparini S, Pasquinelli G, Labate A, Gambardella A, Sofia V, Cianci V, Branca D, Quattrone A, Aguglia U. Usefulness of rectal biopsy for the diagnosis of Kufs disease: a controlled study and review of the literature. Eur J Neurol 2012; 19:1331-6. [PMID: 22568672 DOI: 10.1111/j.1468-1331.2012.03748.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 03/30/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND PURPOSE Rectal biopsy is usually performed for in vivo diagnosis of Kufs disease (KD). We evaluated the usefulness of rectal biopsy in the diagnosis of such condition by comparing ultrastructural data of patients with suspicion of KD with those of control subjects. Furthermore, we reviewed literature data concerning the value of such a diagnostic procedure in the diagnosis of KD. METHODS Sixty-five subjects were enrolled and underwent rectal biopsy. Of these, 13 had a clinical picture in keeping with KD, whereas 52, affected by Irritable Bowel Syndrome, constituted the control group. RESULTS Ultrastructural analysis evidenced fingerprint (FP) inclusions in 12 subjects, 4/13 with suspicion of KD and 8/52 controls. In patients, FPs were mainly located in vascular smooth muscle cells (VSMC) while in controls they were mostly found in pericytes and VSMC. No FPs were found in one patient with genetically confirmed KD. In literature, we identified 14 KD patients who underwent rectal biopsy. In most reports, ultrastructural features were not systematically analyzed or described. CONCLUSIONS Fingerprints are the most common ultrastructural finding in rectal biopsy in patients with suspicion of KD. However, their presence in pericytes and VSMC is not specific for KD because they may be found in controls subjects. Our literature review revealed that data on the value of rectal biopsy in the diagnosis of KD are scarce. In light of these findings, the relevance of rectal biopsy in such condition should be re-evaluated.
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Affiliation(s)
- E Ferlazzo
- Institute of Neurology, Magna Graecia University, Catanzaro, Italy
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Abstract
Early-onset dementia, presenting before age 65 years, is increasingly recognized. It is often difficult to diagnose, since non-Alzheimer's etiologies and unusual dementias are common. These conditions are more commonly genetic, and important potentially inherited causes of early-onset dementia include early-onset Alzheimer's disease, frontotemporal dementia, Kufs' disease, and Niemann-Pick disease type C. For each of these diseases, this review provides information on common clinical presentations, etiology, pathophysiology, and current and experimental treatments. A discussion of the diagnosis and workup for early-onset dementia is included with an emphasis on conditions that may have other involved family members.
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Affiliation(s)
- Brian S. Rogers
- Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Carol F. Lippa
- Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, USA
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Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro RJ. Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum Mol Genet 2012; 21:2646-50. [PMID: 22388936 PMCID: PMC3363329 DOI: 10.1093/hmg/dds089] [Citation(s) in RCA: 192] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor–Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease.
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Affiliation(s)
- Jose Bras
- Department of Molecular Neuroscience, Institute of Neurology, UCL, London, UK
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Rubboli G, Franceschetti S, Berkovic SF, Canafoglia L, Gambardella A, Dibbens LM, Riguzzi P, Campieri C, Magaudda A, Tassinari CA, Michelucci R. Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations. Epilepsia 2011; 52:2356-63. [PMID: 22050460 DOI: 10.1111/j.1528-1167.2011.03307.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Mutations of the SCARB2 gene cause action myoclonus renal failure syndrome (AMRF), a rare condition that combines progressive myoclonus epilepsy (PME) with severe renal dysfunction. We describe the clinical and neurophysiologic features of PME associated with SCARB2 mutations without renal impairment. METHODS Clinical and neurophysiologic investigations, including wakefulness and sleep electroencephalography (EEG), polygraphic recording (with jerk-locked back-averaging and analysis of the EEG-EMG (electromyography) relationship by coherence spectra and phase calculation), multimodal evoked potentials, and electromyography were performed on five Italian patients with SCARB2 mutations. KEY FINDINGS The main clinical features were adolescent-young adulthood onset, progressive action myoclonus, ataxia, absence of cognitive deterioration and, in most cases, epilepsy. The severity of the epilepsy could vary from uncontrolled seizures and status epilepticus in patients with adolescent onset to absent or rare seizures in patients with adult onset. Relevant neurophysiologic findings were a pronounced photosensitivity and massive action myoclonus associated with rhythmic myoclonic jerks at a frequency of 12-20 Hz, clinically resembling a postural tremor. The cortical origin of rhythmic myoclonus was demonstrated mainly by coherence and phase analysis of EEG-EMG signals indicating a significant EEG-EMG coupling and a direct corticospinal transfer. SIGNIFICANCE Our patients with SCARB2 mutations showed the clinical and neurophysiologic phenotype of PME, in which epilepsy could be extremely severe, extending the spectrum reported in the typical AMRF syndrome. Patients with PME of unknown origin of adolescent or young adult onset, with these neurophysiologic features, should be tested for SCARB2 mutations, even in the absence of renal impairment.
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Affiliation(s)
- Guido Rubboli
- Neurology Unit, IRCCS Institute of Neurological Sciences, Bologna, Italy.
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Benitez BA, Alvarado D, Cai Y, Mayo K, Chakraverty S, Norton J, Morris JC, Sands MS, Goate A, Cruchaga C. Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal ceroid-lipofuscinosis. PLoS One 2011; 6:e26741. [PMID: 22073189 PMCID: PMC3208569 DOI: 10.1371/journal.pone.0026741] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 10/02/2011] [Indexed: 02/06/2023] Open
Abstract
We performed whole-exome sequencing in two autopsy-confirmed cases and an elderly unaffected control from a multigenerational family with autosomal dominant neuronal ceroid lipofuscinosis (ANCL). A novel single-nucleotide variation (c.344T>G) in the DNAJC5 gene was identified. Mutational screening in an independent family with autosomal dominant ANCL found an in-frame single codon deletion (c.346_348 delCTC) resulting in a deletion of p.Leu116del. These variants fulfill all genetic criteria for disease-causing mutations: they are found in unrelated families with the same disease, exhibit complete segregation between the mutation and the disease, and are absent in healthy controls. In addition, the associated amino acid substitutions are located in evolutionarily highly conserved residues and are predicted to functionally affect the encoded protein (CSPα). The mutations are located in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of CSPα. We performed a comprehensive in silico analysis of the functional and structural impact of both mutations on CSPα. We found that these mutations dramatically decrease the affinity of CSPα for the membrane. We did not identify any significant effect on palmitoylation status of CSPα. However, a reduction of CSPα membrane affinity may change its palmitoylation and affect proper intracellular sorting. We confirm that CSPα has a strong intrinsic aggregation propensity; however, it is not modified by the mutations. A complementary disease-network analysis suggests a potential interaction with other NCLs genes/pathways. This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs and constitutes a great advance toward the development of new molecular diagnostic tests and may lead to the development of potential therapies.
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Affiliation(s)
- Bruno A. Benitez
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
| | - David Alvarado
- Department of Pediatrics, Washington University, St. Louis, Missouri, United States of America
| | - Yefei Cai
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
| | - Kevin Mayo
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
| | - Sumitra Chakraverty
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
| | - Joanne Norton
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
| | - John C. Morris
- Department of Neurology, Washington University, St. Louis, Missouri, United States of America
| | - Mark S. Sands
- Department of Pediatrics, Washington University, St. Louis, Missouri, United States of America
- Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, Missouri, United States of America
| | - Alison Goate
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
- Department of Neurology, Washington University, St. Louis, Missouri, United States of America
- Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, Missouri, United States of America
- Department of Genetics, Washington University, St. Louis, Missouri, United States of America
| | - Carlos Cruchaga
- Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America
- Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University, St. Louis, Missouri, United States of America
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Arsov T, Smith K, Damiano J, Franceschetti S, Canafoglia L, Bromhead C, Andermann E, Vears D, Cossette P, Rajagopalan S, McDougall A, Sofia V, Farrell M, Aguglia U, Zini A, Meletti S, Morbin M, Mullen S, Andermann F, Mole S, Bahlo M, Berkovic S. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. Am J Hum Genet 2011; 88:566-73. [PMID: 21549341 DOI: 10.1016/j.ajhg.2011.04.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Revised: 04/07/2011] [Accepted: 04/08/2011] [Indexed: 10/18/2022] Open
Abstract
The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.
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Farias FHG, Zeng R, Johnson GS, Wininger FA, Taylor JF, Schnabel RD, McKay SD, Sanders DN, Lohi H, Seppälä EH, Wade CM, Lindblad-Toh K, O'Brien DP, Katz ML. A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers. Neurobiol Dis 2011; 42:468-74. [PMID: 21362476 DOI: 10.1016/j.nbd.2011.02.009] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 02/05/2011] [Accepted: 02/22/2011] [Indexed: 11/24/2022] Open
Abstract
A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations; however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.
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Affiliation(s)
- Fabiana H G Farias
- Department of Veterinary Pathobiology, University of Missouri, Columbia, USA
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Bisceglia M, Carosi I, D'Errico M, Di Giorgio G, Castagnoli A, Pasquinelli G. Lipofuscin-like granules of the juxtaglomerular apparatus of the kidney. The diagnostic significance of a quasi-normal subcellular structure incidentally encountered in the course of routine ultrastructural evaluation of renal biopsies. Pathol Res Pract 2011; 207:79-85. [PMID: 21159450 DOI: 10.1016/j.prp.2010.11.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 11/04/2010] [Indexed: 01/10/2023]
Abstract
Lipofuscin-like granules, first described by Biava and West in 1965, are a subcellular, quasi-physiologic finding mainly seen in the smooth muscle cells of renal arterioles, but also in juxtaglomerular cells and the lacis cells of human kidneys. They increase in number in subjects affected by arterial hypertension and diabetes. They do not correlate with a specific primary renal disease. Lipofuscin-like granules are not related to renin granules. The world literature on this subject is almost non-existent, and the awareness of this finding or its clinical significance among either pathologists or nephrologists is very poor. We incidentally observed these lipofuscin-like granules in 8 cases during the routine electron microscope examination of 440 renal biopsies, and report herein on their ultrastructural features. Six of these 8 patients were affected by arterial hypertension, one of whom was also concomitantly affected by diabetes mellitus. These lipofuscin-like granules appear as dense bodies with a lipid component, a coarsely granular matrix, and a crystalloid component which may appear in a band or dot pattern, according to the plane of sectioning. The pathologist has to be aware of these lipofuscin-like granules in order not to confuse them with the semicircularly organized (fingerprint) linear immune deposits associated with some specific glomerulopathies.
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Affiliation(s)
- Michele Bisceglia
- Unit of Anatomic Pathology, IRCCS Casa Sollievo della Sofferenza Hospital, 71403 San Giovanni Rotondo (FG), Italy.
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Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC-6 or ClC-7/Ostm1. J Neuropathol Exp Neurol 2010; 69:1228-46. [PMID: 21107136 DOI: 10.1097/nen.0b013e3181ffe742] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The proteins ClC-6 and ClC-7 are expressed in the endosomal-lysosomal system. Because Clcn6-deficient mice display some features of neuronal ceroid lipofuscinosis (NCL), CLCN6 may be a candidate gene for novel forms of NCL. Using landmarks of disease progression from NCL mouse models as a guide, we examined neuropathologic alterations in the central nervous system of Clcn6(-/-), Clcn7(-/-), andgl mice. gl mice bear a mutation in Ostm1, the β-subunit critical for Clcn7 function. Severely affected Clcn7(-/-) and gl mice have remarkably similar neuropathologic phenotypes, with pronounced reactive changes and neuron loss in the thalamocortical system, similar to findings in early-onset forms of NCL. In contrast, Clcn6(-/-) mice display slowly progressive, milder neuropathologic features with very little thalamic involvement or microglial activation. These findings detail for the first time the markedly different neuropathologic consequences of mutations in these two CLC genes. Clcn7(-/-) and gl mice bear a close resemblance to the progressive neuropathologic phenotypes of early onset forms of NCL, whereas the distinct phenotype of Clcn6-deficient mice suggests that this gene could be a candidate for a later-onset form of mild neurologic dysfunction with some NCL-like features.
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Berkovic SF, Cochius J, Andermann E, Andermann F. Progressive myoclonus epilepsies: clinical and genetic aspects. Epilepsia 2010; 34 Suppl 3:S19-30. [PMID: 8500430 DOI: 10.1111/j.1528-1167.1993.tb06256.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The progressive myoclonus epilepsies (PMEs) are a group of rare genetic disorders previously shrouded in nosological confusion. Recent advances have clarified the features of these disorders and provided a rational approach to diagnosis. The major causes of PME are now known to be Unverricht-Lundborg disease, myoclonus epilepsy ragged-red fiber (MERRF) syndrome, Lafora disease, neuronal ceroid lipofuscinoses, and sialidoses. Over the past 3 years, a series of molecular genetic findings have further refined the understanding of the PMEs. The specific mutation responsible for many cases of MERRF has been identified, and the genes for Unverricht-Lundborg disease and for juvenile neuronal ceroid lipofuscinosis have been linked to chromosomes 21 and 16, respectively. Although the PMEs are among the rarest of the inherited epilepsies, because of molecular genetic discoveries they may soon be the best understood at the neurobiologic level.
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Affiliation(s)
- S F Berkovic
- Department of Neurology, Austin Hospital, Melbourne, Australia
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A canine Arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A 2010; 107:14775-80. [PMID: 20679209 DOI: 10.1073/pnas.0914206107] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) represent the most common group of inherited progressive encephalopathies in children. They are characterized by progressive loss of vision, mental and motor deterioration, epileptic seizures, and premature death. Rare adult forms of NCL with late onset are known as Kufs' disease. Loci underlying these adult forms remain unknown due to the small number of patients and genetic heterogeneity. Here we confirm that a late-onset form of NCL recessively segregates in US and French pedigrees of American Staffordshire Terrier (AST) dogs. Through combined association, linkage, and haplotype analyses, we mapped the disease locus to a single region of canine chromosome 9. We eventually identified a worldwide breed-specific variant in exon 2 of the Arylsulfatase G (ARSG) gene, which causes a p.R99H substitution in the vicinity of the catalytic domain of the enzyme. In transfected cells or leukocytes from affected dogs, the missense change leads to a 75% decrease in sulfatase activity, providing a functional confirmation that the variant might be the NCL-causing mutation. Our results uncover a protein involved in neuronal homeostasis, identify a family of candidate genes to be screened in patients with Kufs' disease, and suggest that a deficiency in sulfatase is part of the NCL pathogenesis.
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