Retinitis pigmentosa (RP) encompasses inherited retinal dystrophies, appearing either as an isolated eye condition or as part of a broader systemic syndrome, known as syndromic RP. In these cases, RP includes systemic symptoms impacting other organs, complicating diagnosis and management. This review highlights key systemic syndromes linked with RP, such as Usher, Bardet-Biedl, and Alström syndromes, focusing on genetic mutations, inheritance, and clinical symptoms. These insights support clinicians in recognizing syndromic RP early. Ocular signs like nystagmus and congenital cataracts may indicate systemic disease, prompting genetic testing. Conversely, systemic symptoms may necessitate eye exams, even if vision symptoms are absent. Understanding the systemic aspects of these syndromes emphasizes the need for multidisciplinary collaboration among ophthalmologists, pediatricians, and other specialists to optimize patient care. The review also addresses emerging genetic therapies aimed at both visual and systemic symptoms, though more extensive studies are required to confirm their effectiveness. Overall, by detailing the genetic and clinical profiles of syndromic RP, this review seeks to aid healthcare professionals in diagnosing and managing these complex conditions more effectively, enhancing patient outcomes through timely, specialized intervention.

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.

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.

Neuronal ceroid lipofuscinosis (NCL) is a rare disease with onset typically during childhood; however, that developing during adulthood can lead to early-onset dementia. We report a 54-year-old man whose onset coincided with speech impairment, amnesia and dyscalculia. On brain MRI, marked diffuse leukoencephalopathy with periventricular predominance was observed. On a skin biopsy, characteristic fingerprint images were noted, and the patient was diagnosed with NCL. The differential diagnosis of cognitive impairment with leukoencephalopathy is wide ranging; however, when marked symmetrical periventricular-predominant leukoencephalopathy is prevalent and no peripheral neuropathy or gait disorders are evident, a diagnosis of NCL should be suspected and a skin biopsy should be performed.

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.

The neuronal ceroid lipofuscinoses are a group of dominant neurodegenerative, progressive, and fatal disorders characterized clinically by myoclonic epilepsy, in variable association with dementia, ataxia, and visual loss. Neuronal ceroid lipofuscinoses were classified into several phenotypes according to their age of onset: infantile, late infantile, juvenile, and adult. A specific phenotype was named "northern epilepsy," and its onset of signs occurs between ages 5-10 years. Deficiencies in the lysosomal activity of two specific enzymes were found in several types of neuronal ceroid lipofuscinosis: palmitoyl-protein thioesterase 1, encoded by the CLN1 gene, and tripeptidyl-peptidase 1, encoded by the CLN2 gene. Several mutations in CLN2 were described previously. We describe a novel mutation in two siblings of Israeli-Arab origin, with a clinical picture compatible with late infantile neuronal ceroid lipofuscinosis. Both siblings were found to be homozygous for a deletion of a C nucleotide at position 775 in exon 7 of the CLN2 gene. These findings have implications for the worldwide epidemiology of neuronal ceroid lipofuscinosis.

Progressive myoclonic epilepsy (PME) is a syndrome complex encompassing different diagnostic entities and often cause problems in diagnosis. We describe the clinical, electrophysiological and pathological features of 97 patients with the diagnosis of PME evaluated over 25 years. Case records of confirmed patients of Neuronal ceroid lipofuscinosis (NCL = 40), Lafora body disease (LBD = 38), Myoclonic epilepsy with ragged red fibers (MERRF = 10), and probable Unverricht-Lundberg disease (ULD = 9) were reviewed. The mean age at onset in patients with NCL (n = 40) was 5.9+/-9.1 years (M:F:: 28:12). Subtypes of NCL were: late infantile (n = 19), infantile (n = 8), juvenile (n = 11) and adult (n = 2) NCL. EEG (n = 37) showed varying degree of diffuse slowing of background activity in 94.6% and epileptiform discharges in 81.1% of patients. Slow frequency photic stimulation evoked photo-convulsive response in 5 patients only. Giant SSEP was demonstrated in 7 and VEP study revealed a prolonged P100 (2) and absent waveform (7). Electrophysiological features of neuropathy were present in 3 patients. Presence of PAS and Luxol Fast Blue (LFB) positive, auto fluorescent (AF) ceroid material in brain tissue (n = 12) and electron microscopy of brain (n = 5), skin (n = 28) and muscle (n = 1) samples showing curvilinear and lamellar bodies established the diagnosis. Patients of LBD (mean age of onset at 14.4+/-3.9 years, M:F:: 24:14) with triad of PME symptoms were evaluated. EEG (n = 37) showed variable slowing of background activity in 94.6% and epileptiform discharges in 97.4%. Photosensitivity with fast frequency was observed only in 5 patients. CT (n = 32) and MRI (n = 4) revealed diffuse cortical atrophy. Giant SSEP was demonstrated in 24 patients of LBD while VEP study revealed a prolonged P100 (4) and absent waveform (8). Electrophysiological features of neuropathy were present in one patient. Diagnosis was established by the presence of PAS positive diastase resistant, Lugol's Iodine labeled inclusions in sweat glands of axillary skin (n = 35), brain (n = 2) and liver (n = 1). Ten patients with MERRF (mean age at onset: 14.6+/-5.8 years; M: F:: 3:2) had triad of PME symptoms. Muscle biopsy revealed oxidative reaction product and classical ragged red fibers. In nine patients of PME without cognitive decline, probable diagnosis of ULD (mean age at onset: 13.8+/-9.5 years) was considered after biopsy of skin and/or muscle excluded other forms of PMEs. Neuronal ceroid lipofuscinosis and Lafora body diseases were the common causes of PME in the series from south India. This is one of the largest series from the Indian subcontinent to the best of our knowledge. Photosensitivity is notably less common in LBD/NCL in this series distinctly different from those reported in the literature. Further exploration is required to determine whether different genotype is responsible. Morphological changes were helpful in diagnosis and could be confirmed by biopsy of peripheral tissues like skin and muscle in majority (60%). Electron microscopy was helpful in the diagnosis NCL and MERRF.

The neuronal ceroid lipofuscinoses (NCLs) are a group of severe neurodegenerative diseases with onset usually in childhood and characterised by the intracellular accumulation of autofluorescent storage material. Within the last decade, mutations that cause NCL have been found in six human genes (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8). Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice. Approximately 160 NCL disease-causing mutations have now been described (listed and fully cited in the NCL Mutation Database, http://www.ucl.ac.uk/ncl/ ). Most mutations result in a classic morphology and disease phenotype, but some mutations are associated with disease that is of later onset, less severe or protracted in its course, or with atypical morphology. Seven common mutations exist, some having a worldwide distribution and others associated with families originating from specific geographical regions. This review attempts to correlate the gene, disease-causing mutation, morphology and clinical phenotype for each type of NCL.

Progressive myoclonic epilepsies (PMEs) are a group of rare disorders characterized by the occurrence of seizures, myoclonus, and progressive neurological dysfunction. This article discusses epidemiology, genetics, pathology, clinical manifestations, EEG characteristics, methods of diagnosis and treatment of the most common causes of PME, including Unverricht-Lundborg Disease (Baltic Myoclonus), MERRF, neuronal ceroid lipofuscinosis, dentatorubropallidoluysan atrophy, Gaucher disease, Lafora disease, and sialidosis. The aim of this paper is to provide clinicians with useful clinical information in order to facilitate the diagnosis and treatment of these rare diseases.

We report the clinical, electrophysiological, radiological and morphological features in a series of 12 patients of histopathologically confirmed cases (infantile, juvenile and adult onset) of neuronal ceroid lipofuscinosis (NCL) observed from 1979 to 1998 at National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore (South India). The commonest type of NCL was juvenile (n = 8, 67%) while infantile and adult forms were two each (n = 2, 16.8%). The age at presentation ranged from 2 to 45 years (mean--12.6, 14.3 years; median--7 years; M:F ratio of 2:1). Four patients (33%) had positive family history and five patients had history of consanguineous parentage (41.6%). The commonest presenting symptoms were regression of milestones (83.3%) and/or seizures, myoclonus (83.8%) followed by involuntary choreiform movements (50%), visual loss (41.6%), ataxia (33.3%) and abnormal behaviour (16.6%). Neuro-ophthalmological abnormalities like optic atrophy (50%), macular degeneration (33.3%) and retinitis pigmentosa (8.3%) were seen in two thirds. Nerve conduction studies (n = 4) revealed abnormalities in two, suggestive of sensorimotor neuropathy. Scalp EEG (n = 9) showed slowing of background activity (BGA) of varying degrees with paroxysmal bursts of seizure discharges in majority. Cranial CT scan (n = 4) revealed varying degrees of diffuse atrophy. Diagnostic brain biopsy was carried out in 11 and brain was examined at autopsy in 1 case. Histological examination revealed characteristic PAS and Luxol Fast Blue (LFB) positive, autofluorescent (AF) intracellular ceroid material, both in neurons and astrocytes in the grey matter. Electron microscopy (n = 5) revealed curvilinear (n = 4), lamellar (n = 2) and electron dense (n = 2) inclusions in neurons, astrocytes and vascular endothelial cells. To conclude, this neurodegenerative disease had varied but characteristic clinical presentations and required histopathological confirmation of diagnosis.

Pigmentary type of orthochromatic leukodystrophy (POLD) is an adult-onset leukodystrophy, characterized pathologically by the presence of glial and microglial cytoplasmic pigment inclusions. The complete phenotype, genotype and pathogenetic mechanisms in POLD have not been elucidated. We followed for 18 years a woman with autopsy-proven POLD, who presented with 'frontal' dementia and spasticity. Her further course was marked by progressive mutism, apraxia and seizures. Her sister had died of the same disease after a much more rapidly progressing course. These sisters had primary infertility with pathologic evidence of streak ovaries. Diagnosis was confirmed in both cases by post-mortem examination. POLD is a rare cause of adult-onset leukodystrophy presenting with dementia. Ovarian dysgenesis is extremely rare in the absence of demonstrable chromosomal abnormalities and extends the clinical spectrum of POLD.

We describe a family with adult neuronal ceroid lipofuscinosis, with apparent autosomal dominant inheritance, observed in six affected individuals in three generations. Disease onset was usually in the fifth decade, but was earlier in the youngest generation. Early symptoms consisted of myoclonus in face and arms, epilepsy, auditory symptoms, cognitive decline, or depression. Parkinsonism occurred a few years after disease onset, with stooped posture, shuffling gait, bradykinesia, and mask face. Four subjects deteriorated to a state of severe handicap, with severe dementia, contractures, dysphagia, and dysarthria. Leg weakness evolved to flaccid paraparesis in two patients. Diagnosis was confirmed by brain biopsy in one patient and full autopsy in two patients. Abundant intraneuronal storage of autofluorescent material was found throughout the brain. Electron microscopy showed granular osmiophilic deposits and scarce fingerprint profiles. Striking loss of neurons in the substantia nigra pars compacta and reticulata was found. (123)I-IBZM Single photon emission computed tomography in two patients showed loss of postsynaptic D2 receptor binding in the striatum. We conclude that parkinsonism in ANCL is likely to be caused by both presynaptic nigral cell loss and postsynaptic striatal degeneration.

The neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders characterized by accumulation of ceroid lipopigment in lysosomes in various tissues and organs. The childhood forms of the NCLs represent the most common neurogenetic disorders of childhood and are inherited in an autosomal-recessive mode. The adult form of NCL is rare and shows either an autosomal-recessive or autosomal dominant mode of inheritance. Currently, five genes associated with various childhood forms of NCLs, designated CLN1, CLN2, CLN3, CLN5, and CLN8, have been isolated and characterized. Two of these genes, CLN1 and CLN2, encode lysosomal enzymes: palmitoyl protein thioesterase 1 (PPT1) and tripetidyl peptidase 1 (TPP1), respectively. CLN3, CLN5, and CLN8 encode proteins of predicted transmembrane topology, whose function has not been characterized yet. Two other genes, CLN6 and CLN7, have been assigned recently to small chromosomal regions. Gene(s) associated with the adult form of NCLs (CLN4) are at present unknown. This study summarizes the current classification and new diagnostic criteria of NCLs based on clinicopathological, biochemical, and molecular genetic data. Material includes 159 probands with NCL (37 CLNI, 72 classical CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR) as well as a comprehensive review of the literature. The results of our study indicate that although only biochemical and molecular genetic studies allow for definitive diagnosis, ultrastructural studies of the biopsy material are still very useful. Thus, although treatments for NCLs are not available at present, the diagnosis has become better defined.

The neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative disorders of childhood. The CLN1, CLN2 and CLN3 genes are associated to the infantile, late infantile and juvenile forms of NCL, respectively. We have subcloned the cDNAs encoding CLN1, CLN2 and BTN1, the yeast homologue of human CLN3, into plasmid vectors to evaluate whether these proteins interact with other proteins co-expressed from either a cDNA library derived from human cerebellum or from yeast, respectively, using the two-hybrid system. We concluded that CLN1 most likely does not interact with any other proteins in vivo. Furthermore, it is unlikely that CLN2 interacts with other proteins in vivo, although this study utilized a cDNA encoding the CLN2 precursor and it is possible that interacting partners may be excluded by the nature of this protein structure. Finally, we conclude that proteins that interact with Btn1p and therefore CLN3 cannot be identified using the whole proteins in a two-hybrid system, due to the hydrophobic nature of this protein. By understanding the topology of CLN3, specific regions of CLN3 need to be tested by two-hybrid to identify any interacting partners.

The neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative disorders of childhood. We have examined mRNA levels of the CLN1, CLN2, and CLN3 genes, which are associated with the infantile, late infantile, and juvenile forms of NCL in 64 different human tissues, and have grouped the results into gastrointestinal tract, central nervous system, glandular/secretory, muscle, and carcinoma tissue types. mRNA levels for CLN3 are highest in gastrointestinal tissue and are also high in glandular/secretory tissue, whereas mRNA levels for CLN1 and CLN2 do not appear to be preferentially elevated in any tissue type. The significance of extraneural expression of CLN3 is reviewed in the context of the function of the protein.

The CLN3 gene, which encodes the protein whose absence is responsible for Batten disease, the most common inherited neurovisceral storage disease of childhood, was identified in 1995. The function of the protein, Cln3p, still remains elusive. We previously cloned the Saccharomyces cerevisiae homolog to the human CLN3 gene, designated BTN1, whose product is 39% identical and 59% similar to Cln3p. We report that yeast strains lacking Btn1p, btn1-Delta deletion yeast strains, are more resistant to d-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP), in a pH-dependent manner. This phenotype is complemented in yeast by the human CLN3 gene. In addition, point mutations characterized in CLN3 from individuals with less severe forms of Batten disease, when introduced into BTN1, altered the degree of ANP resistance. Severity of Batten disease due to mutations in CLN3 and the degree of ANP resistance in yeast are related when the equivalent amino acid replacements in Cln3p and Btn1p are compared. These results indicate that yeast can be used as a model for the study of Batten disease.

Although the CLN3 gene for Batten disease, the most common inherited neurovisceral storage disease of childhood, was identified in 1995, the function of the corresponding protein still remains elusive. We previously cloned the Saccharomyces cerevisiae homologue to the human CLN3 gene, designated BTN1, which is not essential and whose product is 39% identical and 59% similar to Cln3p. We report that btn1-Delta deletion yeast strains are more resistant to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (denoted ANP), a phenotype that is complemented in yeast by the human CLN3 gene. Furthermore, the severity of Batten disease in humans and the degree of ANP resistance in yeast are related when the equivalent amino acid replacements in Cln3p and Btn1p are compared. These results indicate that yeast can be used as a model for the study of Batten disease.

The authors report a case of neuronal ceroid lipofuscinosis (Kufs' disease) confirmed by stereotactically obtained brain biopsy findings and initially diagnosed as a butterfly glioma. The presenting symptoms in the 64-year-old patient were mental alterations with progressive dementia, followed by muscular atrophy and myoclonia with distal preponderance. The mild initial disturbances of coordination increased, and the patient developed a markedly ataxic gait. Computerized tomography (CT) scanning and magnetic resonance imaging revealed generalized cerebral atrophy and a bifrontal space-occupying lesion involving the callosum. The original "clearcut" diagnosis of glioblastoma multiforme, based on CT scans, was unexpectedly disproved by examination of stereotactically obtained brain biopsy specimens, which revealed a neuronal ceroid lipofuscinosis (Kufs' disease). To the authors' knowledge, this is the first report of a case presenting with both diffuse brain atrophy and localized accumulation of neuronal lipofuscin, mimicking a mass lesion on radiological studies.

The neuronal ceroid lipofuscinoses (NCL) are a relatively frequent group of progressive neurodegenerative disorders in children with similar, but not identical, clinical and morphological features, entailing different clinical groups, some of which have been found to represent different genetic entities, ie, infantile (INCL) or CLN1, late-infantile (LINCL) or CLN2, juvenile (JNCL) or CLN3, and a Finnish variant of LINCL or CLN5. Within the clinical pentad are included seizures, motor disturbances, visual impairment, dementia, and familial occurrence in an autosomal-recessive fashion. The ultrastructure of accruing lipopigments is diagnostically required to recognize an individual patient's NCL by showing granular lipopigments in INCL, curvilinear profiles (with or without fingerprint profiles) in LINCL and fingerprint profiles (with or without curvilinear profiles) in JNCL. Identification of genes for INCL and JNCL, together with electron microscopy in LINCL, allows safe prenatal diagnosis which is still impossible by biochemical techniques, unlike other lysosomal disorders. However, both cause and pathogenesis of the individual forms of NCL are still unknown, and therapy is gravely insufficient.

The neuronal ceroid-lipofuscinoses (NCL) are a group of different genetic diseases. The major types of NCL are expressed by six forms which represent different clinicopathologic and genetic forms. These are CLN-1, Infantile; CLN-2, Late Infantile; CLN-3, Juvenile; CLN-4, Adult-Recessive; CLN-5, Adult-Dominant; and CLN-6, Early Juvenile. The distinction between CLN-4 and CLN-5 is still disputatious. CLN-6 has been called CLN-5. A seventh classification of NCL represents from 12 to 20% of those afflicted. This group consists of an extensive array of atypical types of ceroid-lipofuscin accumulation in the secondary lysosomes of neurons and cells of other tissues (e.g., skin, conjunctiva, and lymphocytes) or by presumed clinical and genetic relationships. The authors have identified 15 atypical subtypes of NCL. These as a group are here described as a seventh form. Further biochemical, molecular, and genetic studies will identify more precisely the phenotypic and genotypic expression of these "minor" forms of NCL.

The molecular defects underlying neuronal ceroid-lipofuscinoses (NCL) are still unknown. However, more data exist on the composition of the hydrophobic storage material characteristic of NCL. Accumulation of subunit c of the mitochondrial ATP synthase has been shown in most forms of human NCL with the exception of the infantile NCL (INCL) for which we have recently demonstrated storage of sphingolipid activator proteins (SAP). In the present study we raised an antiserum against storage cytosomes purified from INCL brain. Using the anti-INCL antiserum and monospecific SAP antisera, we studied storage material isolated from the brains of patients affected with NCL by Western analysis, and found a 12-kDa protein showing a SAP-like immunoreactivity not only in INCL, but also in all the childhood forms of NCL. Furthermore, using the anti-sap-D antiserum for immunohistochemistry, we observed strong immunoreactivity of the storage cytosomes in all major forms of NCL, and also in tissues of non-neuroectodermal origin. From these data we conclude that the presence of SAP within the storage bodies is a phenomenon common to all major forms of human NCL.

The mouse mutant Motor neuron degeneration (Mnd) displays an adult-onset progressive degeneration of upper and lower motor neurons, with mild symptoms recognizable at 6 months, leading to spastic paralysis and premature death at 10-12 months on the C57B1/6 background. Despite this late onset, abnormally-accumulating autofluorescent material can be seen in both the spinal cord and other regions as early as the first month. This pigmented material is present in both increasing numbers of cells, and in increasing amounts within individual cells, as the animals age. Motor neurons then go on to degenerate, while most other cell types stabilize. The level of pathological involvement, well before the onset of clear clinical symptoms, suggests that the full degenerative process is an extremely gradual and protracted one with some selectivity for motor neurons.