|
1
|
Maines E, Gugelmo G, Maiorana A, Martinelli D, Vitturi N, Lenzini L, Piccoli G, Soffiati M, Franceschi R. The role of the analysis of sialotransferrin isoforms in the management of hereditary fructose intolerance: a systematic review. J Diabetes Metab Disord 2025; 24:27. [PMID: 39735177 PMCID: PMC11680511 DOI: 10.1007/s40200-024-01527-y] [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] [Received: 09/06/2024] [Accepted: 10/19/2024] [Indexed: 12/31/2024]
Abstract
Background Untreated patients affected by hereditary fructose intolerance (HFI) present an abnormal transferrin (Tf) glycosylation pattern suggestive of N-hypoglycosylation. Analysis of defects in N-glycosylation is possible by analysis of serum sialotransferrin (sialoTf) pattern. The sialoTf profile is a valuable tool to facilitate the diagnosis of HFI. Its role in the monitoring of the diagnosed patients is less clear and debating. Objectives and methods We examined the literature for the role of profile of serum sialoTf isoforms in monitoring HFI patients aiming at (1) providing an up-to-date summary of the available evidences on the impact of sialoTf isoforms in the follow-up of HFI patients; 2) evaluating the multifactorial effect of genotype and age at diagnosis on sialoTf isoforms; 3) assessing the relation between sialoTf isoforms and long-term liver complications. We used the GRADE approach to rank the quality of evidence. Results Nine full papers were identified according to our search criteria. Elevated serum carbohydrate-deficient Tf (CDT) fraction, disialoTf and tetrasialoTf/disialoTf ratio, and the asialoTf, tetrasialoTf and pentasialoTf + hexasialoTf isoforms appeared as the most reliable indicators for a follow up. No clear statistical correlation links sialoTf isoforms and liver damage. Age at diagnosis, potentially related to fructose tolerance, does not overtly impact sialoTf isoforms. Strong genotype-phenotype correlation has not been found so far. Conclusions There is no consensus about which isoform of sialoTf is more valuable for monitoring HFI patients. No clear correlation links sialoTf isoforms and liver damage, fructose tolerance and genotype. More robust studies are needed to provide conclusive results.
Collapse
Affiliation(s)
- Evelina Maines
- Division of Pediatrics, Santa Chiara General Hospital, Azienda Provinciale per i Servizi Sanitari, Largo Medaglie d’oro, 9, 38122 Trento, Italy
| | - Giorgia Gugelmo
- Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, Via Nicolò Giustiniani 2, 35121 Padua, Italy
| | - Arianna Maiorana
- Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children’s Hospital, IRCCS, Piazza Di Sant’Onofrio 4, 00165 Rome, Italy
| | - Diego Martinelli
- Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children’s Hospital, IRCCS, Piazza Di Sant’Onofrio 4, 00165 Rome, Italy
| | - Nicola Vitturi
- Division of Metabolic Diseases, Department of Medicine, Padova University Hospital, Via Nicolò Giustiniani 2, 35121 Padua, Italy
| | - Livia Lenzini
- Department of Medicine, Padova University Hospital, Via Nicolò Giustiniani 2, 35121 Padua, Italy
| | - Giovanni Piccoli
- CIBIO - Department of Cellular, Computational and Integrative Biology, Università Degli Studi Di Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Massimo Soffiati
- Division of Pediatrics, Santa Chiara General Hospital, Azienda Provinciale per i Servizi Sanitari, Largo Medaglie d’oro, 9, 38122 Trento, Italy
| | - Roberto Franceschi
- Division of Pediatrics, Santa Chiara General Hospital, Azienda Provinciale per i Servizi Sanitari, Largo Medaglie d’oro, 9, 38122 Trento, Italy
| |
Collapse
|
|
2
|
Buziau AM, Lefeber DJ, Cassiman D, Rubio‐Gozalbo ME, Kwast H, Tolan DR, Schalkwijk CG, Brouwers MCGJ. Aldolase B Deficient Mice Are Characterized by Hepatic Nucleotide Sugar Abnormalities. J Inherit Metab Dis 2025; 48:e12836. [PMID: 39727106 PMCID: PMC11672228 DOI: 10.1002/jimd.12836] [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: 10/02/2024] [Revised: 11/20/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024]
Abstract
Hereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (Aldob-/-) were treated for four weeks with 5% mannose via the drinking water and compared to Aldob-/- mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated Aldob-/- mice when compared to water-treated wildtype mice (p = 0.002 and p = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-N-acetyl-beta-neuraminic acid, and CDP-ribitol (p = 0.002, p = 0.003, p = 0.002, p = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. Aldob-/- mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI. Trial Registration: PCT ID: PCTE0000340, this animal experiment is registered at (https://preclinicaltrials.eu/).
Collapse
Affiliation(s)
- Amée M. Buziau
- Department of Internal Medicine, Division of Endocrinology and Metabolic DiseaseMaastricht University Medical Center+MaastrichtThe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtThe Netherlands
- Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - Dirk J. Lefeber
- Translational Metabolic Laboratory, Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
- Department of Neurology, Donders Institute for Brain, Cognition and BehaviorRadboud University Medical CenterNijmegenThe Netherlands
| | - D. Cassiman
- Department of Gastroenterology‐Hepatology and Metabolic CenterUniversity Hospital LeuvenLeuvenBelgium
| | - M. Estela Rubio‐Gozalbo
- Department of Pediatrics and Clinical GeneticsMaastricht University Medical Center+MaastrichtThe Netherlands
| | - Hanneke Kwast
- Translational Metabolic Laboratory, Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
| | - Dean R. Tolan
- Department of BiologyBoston UniversityBostonMassachusettsUSA
| | - Casper G. Schalkwijk
- Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtThe Netherlands
- Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular MedicineMaastricht UniversityMaastrichtThe Netherlands
| | - Martijn C. G. J. Brouwers
- Department of Internal Medicine, Division of Endocrinology and Metabolic DiseaseMaastricht University Medical Center+MaastrichtThe Netherlands
- Cardiovascular Research Institute Maastricht (CARIM)Maastricht UniversityMaastrichtThe Netherlands
- Department of Internal MedicineMaastricht University Medical Center+MaastrichtThe Netherlands
- United for Metabolic DiseasesThe Netherlands
| |
Collapse
|
|
3
|
Garbowski L, Walasek M, Firszt R, Chilińska-Kopko E, Błażejewska-Gała P, Popielnicki D, Dzięcioł-Anikiej Z. A Case Study of a Rare Disease (Fructosemia) Diagnosed in a Patient with Abdominal Pain. J Clin Med 2024; 13:3394. [PMID: 38929922 PMCID: PMC11204229 DOI: 10.3390/jcm13123394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/22/2024] [Accepted: 05/29/2024] [Indexed: 06/28/2024] Open
Abstract
Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously. Consuming fructose triggers biochemical abnormalities, disrupting liver processes like glycogenolysis and gluconeogenesis. Recent studies have revealed elevated intrahepatic fat levels in affected individuals. Symptoms include aversion to fructose-containing foods, hypoglycemia, liver and kidney dysfunction, and growth delays, with severe cases leading to liver enlargement, fatty liver disease, kidney failure, and life-threatening hypoglycemia. In this case study, we present a 20-month-old child with symptoms including difficulty passing stool, abdominal rigidity, abdominal pain with bloating and hypoglycemia. Initial clinical findings revealed elevated liver enzymes, a mildly enlarged hyperechoic liver, hypercholesterolemia, and borderline alpha-fetoprotein values. Diagnostic assessments identified hereditary fructose intolerance (HFI) with pathogenic variants in the ALDOB gene, along with a diagnosis of celiac disease. Genetic testing of the parents revealed carrier status for pathological aldolase B genes. This case underscores the importance of comprehensive clinical evaluation and genetic testing in pediatric patients with complex metabolic presentations.
Collapse
Affiliation(s)
- Leszek Garbowski
- Public Independent Healthcare Services of the Ministry of Internal Affairs and Administration in Białystok, 15-471 Białystok, Poland
- Department of Human Anatomy, Medical University of Białystok, 15-089 Białystok, Poland (P.B.-G.); (D.P.)
| | - Marzena Walasek
- Public Independent Healthcare Services of the Ministry of Internal Affairs and Administration in Białystok, 15-471 Białystok, Poland
| | - Rafał Firszt
- Department of Ornamental Plants and Garden Art, Faculty of Biotechnology and Horticulture, University of Agriculture in Krakow, 31-425 Kraków, Poland;
| | - Ewelina Chilińska-Kopko
- Department of Human Anatomy, Medical University of Białystok, 15-089 Białystok, Poland (P.B.-G.); (D.P.)
| | - Paulina Błażejewska-Gała
- Department of Human Anatomy, Medical University of Białystok, 15-089 Białystok, Poland (P.B.-G.); (D.P.)
- Department of Neonatology and Newborn Intensive Care, University Clinical Hospital in Białystok, 15-276 Białystok, Poland
| | - Daniel Popielnicki
- Department of Human Anatomy, Medical University of Białystok, 15-089 Białystok, Poland (P.B.-G.); (D.P.)
| | - Zofia Dzięcioł-Anikiej
- Department of Rehabilitation, University Clinical Hospital in Białystok, 15-276 Białystok, Poland
| |
Collapse
|
|
4
|
Zuriaga E, Santander S, Lomba L, Izquierdo-García E, Luesma MJ. Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy. Healthcare (Basel) 2024; 12:573. [PMID: 38470684 PMCID: PMC10930640 DOI: 10.3390/healthcare12050573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/21/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet. Limited information exists on the relationship between pregnancy outcomes and HFI. This study aims to analyze pregnancy-related factors in a cohort of thirty Spanish women, with twenty-three being carriers and seven being HFI-affected (45 pregnancies). (2) Methods: A descriptive, cross-sectional and retrospective study utilized an anonymous questionnaire. (3) Results: Findings encompassed physical and emotional states, nutritional habits, pathology development and baby information. Notable results include improved physical and emotional states compared to the general population, with conventional analyses mostly within normal ranges. Persistent issues after pregnancy included hepatic steatosis, liver adenomas and hemangiomas. Carrier mothers' babies exhibited higher weight than those of patient mothers, while the weights of carrier children born with HFI were similar to disease-affected children. (4) Conclusions: Pregnant women with HFI did not significantly differ in physical and emotional states, except for nausea, vomiting, and cravings. Post-pregnancy, HFI patients and carriers exhibited persistent hepatic issues. Significantly, babies born to HFI-affected mothers had lower weights. This study sheds light on pregnancy outcomes in HFI, emphasizing potential complications and the need for ongoing monitoring and care.
Collapse
Affiliation(s)
- Estefanía Zuriaga
- Facultad de Ciencias de la Salud, Universidad San Jorge, Campus Universitario, Autov A23 km 299, 50830 Villanueva de Gállego Zaragoza, Spain; (E.Z.); (L.L.)
| | - Sonia Santander
- Faculty of Health and Sports Sciences, University of Zaragoza, 22002 Huesca, Spain
| | - Laura Lomba
- Facultad de Ciencias de la Salud, Universidad San Jorge, Campus Universitario, Autov A23 km 299, 50830 Villanueva de Gállego Zaragoza, Spain; (E.Z.); (L.L.)
| | | | - María José Luesma
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain;
| |
Collapse
|
|
5
|
Vakili O, Mafi A, Pourfarzam M. Liver Disorders Caused by Inborn Errors of Metabolism. Endocr Metab Immune Disord Drug Targets 2024; 24:194-207. [PMID: 37357514 DOI: 10.2174/1871530323666230623120935] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 06/27/2023]
Abstract
Inborn errors of metabolism (IEMs) are a vast array of inherited/congenital disorders, affecting a wide variety of metabolic pathways and/or biochemical processes inside the cells. Although IEMs are usually rare, they can be represented as serious health problems. During the neonatal period, these inherited defects can give rise to almost all key signs of liver malfunction, including jaundice, coagulopathy, hepato- and splenomegaly, ascites, etc. Since the liver is a vital organ with multiple synthetic, metabolic, and excretory functions, IEM-related hepatic dysfunction could seriously be considered life-threatening. In this context, the identification of those hepatic manifestations and their associated characteristics may promote the differential diagnosis of IEMs immediately after birth, making therapeutic strategies more successful in preventing the occurrence of subsequent events. Among all possible liver defects caused by IEMs, cholestatic jaundice, hepatosplenomegaly, and liver failure have been shown to be manifested more frequently. Therefore, the current study aims to review substantial IEMs that mostly result in the aforementioned hepatic disorders, relying on clinical principles, especially through the first years of life. In this article, a group of uncommon hepatic manifestations linked to IEMs is also discussed in brief.
Collapse
Affiliation(s)
- Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morteza Pourfarzam
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
- Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
6
|
Zingone F, Bertin L, Maniero D, Palo M, Lorenzon G, Barberio B, Ciacci C, Savarino EV. Myths and Facts about Food Intolerance: A Narrative Review. Nutrients 2023; 15:4969. [PMID: 38068827 PMCID: PMC10708184 DOI: 10.3390/nu15234969] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Most adverse reactions to food are patient self-reported and not based on validated tests but nevertheless lead to dietary restrictions, with patients believing that these restrictions will improve their symptoms and quality of life. We aimed to clarify the myths and reality of common food intolerances, giving clinicians a guide on diagnosing and treating these cases. We performed a narrative review of the latest evidence on the widespread food intolerances reported by our patients, giving indications on the clinical presentations, possible tests, and dietary suggestions, and underlining the myths and reality. While lactose intolerance and hereditary fructose intolerance are based on well-defined mechanisms and have validated diagnostic tests, non-coeliac gluten sensitivity and fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP) intolerance are mainly based on patients' reports. Others, like non-hereditary fructose, sorbitol, and histamine intolerance, still need more evidence and often cause unnecessary dietary restrictions. Finally, the main outcome of the present review is that the medical community should work to reduce the spread of unvalidated tests, the leading cause of the problematic management of our patients.
Collapse
Affiliation(s)
- Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (L.B.); (D.M.); (M.P.); (G.L.); (E.V.S.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Luisa Bertin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (L.B.); (D.M.); (M.P.); (G.L.); (E.V.S.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Daria Maniero
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (L.B.); (D.M.); (M.P.); (G.L.); (E.V.S.)
| | - Michela Palo
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (L.B.); (D.M.); (M.P.); (G.L.); (E.V.S.)
| | - Greta Lorenzon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (L.B.); (D.M.); (M.P.); (G.L.); (E.V.S.)
| | - Brigida Barberio
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| | - Carolina Ciacci
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Salerno, Italy;
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy; (L.B.); (D.M.); (M.P.); (G.L.); (E.V.S.)
- Gastroenterology Unit, Azienda Ospedale—Università Padova, 35128 Padua, Italy;
| |
Collapse
|
|
7
|
Andres-Hernando A, Orlicky DJ, Kuwabara M, Cicerchi C, Pedler M, Petrash MJ, Johnson RJ, Tolan DR, Lanaspa MA. Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance. Nutrients 2023; 15:4376. [PMID: 37892451 PMCID: PMC10609559 DOI: 10.3390/nu15204376] [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: 09/01/2023] [Revised: 10/06/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Collapse
Affiliation(s)
- Ana Andres-Hernando
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, CO 80045, USA;
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, USA;
| | - Masanari Kuwabara
- Department of Cardiology, Toranomon Hospital, Tokyo 105-8470, Japan;
- Division of Public Health, Center for Community Medicine, Jichi Medical University, Tochigi 329-0431, Japan
| | - Christina Cicerchi
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA; (C.C.); (R.J.J.)
| | - Michelle Pedler
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045, USA; (M.P.); (M.J.P.)
| | - Mark J. Petrash
- Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO 80045, USA; (M.P.); (M.J.P.)
| | - Richard J. Johnson
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO 80045, USA; (C.C.); (R.J.J.)
| | - Dean R. Tolan
- Department of Biology, Boston University, Boston, MA 02215, USA;
| | - Miguel A. Lanaspa
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, CO 80045, USA;
| |
Collapse
|
|
8
|
Panis B, Janssen LEF, Lefeber DJ, Simons N, Rubio‐Gozalbo ME, Brouwers MCGJ. Development of tools to facilitate the diagnosis of hereditary fructose intolerance. JIMD Rep 2023; 64:353-359. [PMID: 37701328 PMCID: PMC10494505 DOI: 10.1002/jmd2.12379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 09/14/2023] Open
Abstract
Although hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism that classically presents at infancy, the diagnosis is often missed or delayed. In this study, we aimed to develop tools to facilitate the diagnosis of HFI. The intake of fructose-containing food products, that is, fruit, fruit juice and sugar-sweetened beverages, was assessed by a 3-day food diary in adult HFI patients (n = 15) and age, sex, and BMI-matched controls (n = 15). Furthermore, glycosylation of transferrin was examined using high-resolution mass spectrometry and abnormally glycosylated transferrin was expressed as ratio of normal glycosylated transferrin. We found that the sensitivity and specificity of the 3-day food diary for the intake of at least one fructose-containing food product were both 100%. Both mono-glyco:diglyco transferrin and a-glyco+mono-glyco:di-glyco transferrin were greater in HFI patients and had a high-discriminatory power (area under the receiver operating characteristic curve: 0.97 and 0.94, respectively). In this well-characterized cohort of adult HFI patients, the 3-day food questionnaire and the glycosylation pattern of transferrin are valuable tools to facilitate the recognition and diagnosis of HFI in adult patients.
Collapse
Affiliation(s)
- Bianca Panis
- Division of Genetic Metabolic Diseases, Department of PediatricsMaastricht University Medical CenterMaastrichtThe Netherlands
- Member of European Reference Network for Hereditary Metabolic Diseases (MetabERN)
- Member of United for Metabolic Diseases (UMD)
| | - Lise E. F. Janssen
- Division of Endocrinology and Metabolic Diseases, Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
| | - Dirk J. Lefeber
- Translational Metabolic Laboratory, Department of Laboratory MedicineRadboud University Medical CenterNijmegenThe Netherlands
- Department of NeurologyRadboud University Medical CenterNijmegenThe Netherlands
| | - Nynke Simons
- Division of Endocrinology and Metabolic Diseases, Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
- CARIM, School for Cardiovascular DiseasesMaastrichtThe Netherlands
| | - M. Estela Rubio‐Gozalbo
- Division of Genetic Metabolic Diseases, Department of PediatricsMaastricht University Medical CenterMaastrichtThe Netherlands
- Member of European Reference Network for Hereditary Metabolic Diseases (MetabERN)
- Member of United for Metabolic Diseases (UMD)
- Department of Clinical GeneticsMaastricht University Medical Center, Maastricht UniversityMaastrichtThe Netherlands
- GROW‐School for Oncology and Developmental Biology, Faculty of Health, Medicine and Life SciencesMaastricht UniversityMaastrichtThe Netherlands
| | - Martijn C. G. J. Brouwers
- Member of European Reference Network for Hereditary Metabolic Diseases (MetabERN)
- Member of United for Metabolic Diseases (UMD)
- Division of Endocrinology and Metabolic Diseases, Department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, department of Internal MedicineMaastricht University Medical CenterMaastrichtThe Netherlands
- CARIM, School for Cardiovascular DiseasesMaastrichtThe Netherlands
| |
Collapse
|
|
9
|
Gu L, Zhu Y, Watari K, Lee M, Liu J, Perez S, Thai M, Mayfield JE, Zhang B, Cunha E Rocha K, Li F, Kim LC, Jones AC, Wierzbicki IH, Liu X, Newton AC, Kisseleva T, Lee JH, Ying W, Gonzalez DJ, Saltiel AR, Simon MC, Karin M. Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness. Cell Metab 2023; 35:1009-1021.e9. [PMID: 37084733 PMCID: PMC10430883 DOI: 10.1016/j.cmet.2023.03.021] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/16/2023] [Accepted: 03/30/2023] [Indexed: 04/23/2023]
Abstract
Insulin inhibits gluconeogenesis and stimulates glucose conversion to glycogen and lipids. How these activities are coordinated to prevent hypoglycemia and hepatosteatosis is unclear. Fructose-1,6-bisphosphatase (FBP1) is rate controlling for gluconeogenesis. However, inborn human FBP1 deficiency does not cause hypoglycemia unless accompanied by fasting or starvation, which also trigger paradoxical hepatomegaly, hepatosteatosis, and hyperlipidemia. Hepatocyte FBP1-ablated mice exhibit identical fasting-conditional pathologies along with AKT hyperactivation, whose inhibition reversed hepatomegaly, hepatosteatosis, and hyperlipidemia but not hypoglycemia. Surprisingly, fasting-mediated AKT hyperactivation is insulin dependent. Independently of its catalytic activity, FBP1 prevents insulin hyperresponsiveness by forming a stable complex with AKT, PP2A-C, and aldolase B (ALDOB), which specifically accelerates AKT dephosphorylation. Enhanced by fasting and weakened by elevated insulin, FBP1:PP2A-C:ALDOB:AKT complex formation, which is disrupted by human FBP1 deficiency mutations or a C-terminal FBP1 truncation, prevents insulin-triggered liver pathologies and maintains lipid and glucose homeostasis. Conversely, an FBP1-derived complex disrupting peptide reverses diet-induced insulin resistance.
Collapse
Affiliation(s)
- Li Gu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Yahui Zhu
- School of Medicine, Chongqing University, Chongqing 400030, China
| | - Kosuke Watari
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Maiya Lee
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Junlai Liu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Sofia Perez
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Melinda Thai
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Joshua E Mayfield
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Bichen Zhang
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Karina Cunha E Rocha
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Fuming Li
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
| | - Laura C Kim
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alexander C Jones
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Igor H Wierzbicki
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Xiao Liu
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Alexandra C Newton
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA
| | - Jun Hee Lee
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Wei Ying
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - David J Gonzalez
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Alan R Saltiel
- Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
| |
Collapse
|
|
10
|
Barretta F, Uomo F, Fecarotta S, Albano L, Crisci D, Verde A, Fisco MG, Gallo G, Dottore Stagna D, Pricolo MR, Alagia M, Terrone G, Rossi A, Parenti G, Ruoppolo M, Mazzaccara C, Frisso G. Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy. Genes (Basel) 2023; 14:genes14050980. [PMID: 37239340 DOI: 10.3390/genes14050980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.
Collapse
Affiliation(s)
- Ferdinando Barretta
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| | - Fabiana Uomo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Simona Fecarotta
- Metabolic Diseases Unit, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy
| | - Lucia Albano
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| | - Daniela Crisci
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| | - Alessandra Verde
- Metabolic Diseases Unit, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy
| | | | - Giovanna Gallo
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| | - Daniela Dottore Stagna
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | | | - Marianna Alagia
- Metabolic Diseases Unit, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy
| | - Gaetano Terrone
- Metabolic Diseases Unit, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy
| | - Alessandro Rossi
- Metabolic Diseases Unit, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy
| | - Giancarlo Parenti
- Metabolic Diseases Unit, Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, 80131 Naples, Italy
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| | - Cristina Mazzaccara
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| | - Giulia Frisso
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
- CEINGE Advanced Biotechnologies Franco Salvatore, 80131 Naples, Italy
| |
Collapse
|
|
11
|
Carnovale V, Scialò F, Gelzo M, Iacotucci P, Amato F, Zarrilli F, Celardo A, Castaldo G, Corso G. Cystic Fibrosis Patients with F508del/Minimal Function Genotype: Laboratory and Nutritional Evaluations after One Year of Elexacaftor/Tezacaftor/Ivacaftor Treatment. J Clin Med 2022; 11:6900. [PMID: 36498475 PMCID: PMC9735556 DOI: 10.3390/jcm11236900] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/03/2022] [Accepted: 11/21/2022] [Indexed: 11/24/2022] Open
Abstract
The last ten years have been characterized by an enormous step forward in the therapy and management of patients with Cystic Fibrosis (CF), thanks to the development and combination of Cystic Fibrosis Transmembrane Receptor (CFTR) correctors and potentiators. Specifically, the last approved triple combination elexacaftor/tezacaftor/ivacaftor has been demonstrated to improve lung function in CF patients with both homozygous Phe508del and Phe508del/minimal function genotypes. Here we have assessed the effect of elexacaftor/tezacaftor/ivacaftor in patients carrying the Phe508del/minimal function genotype (n = 20) after one year of treatments on liver function and nutrient absorption with a focus on lipid metabolism. We show that weight, BMI, and albumin significantly increase, suggesting a positive impact of the treatment on nutrient absorption. Furthermore, cholesterol levels as a biomarker of lipid metabolism increased significantly after one year of treatment. Most importantly, we suggest that these results were not dependent on the diet composition, possibly indicating that the drug improves the hepatic synthesis and secretion of proteins and cholesterol.
Collapse
Affiliation(s)
- Vincenzo Carnovale
- Department of Translational Medical Science, University of Naples Federico II, 80131 Naples, Italy
| | - Filippo Scialò
- Department of Translational and Medical Science, University of Campania “L. Vanvitelli”, 80131 Naples, Italy
- CEINGE—Biotecnologie Avanzate, 80131 Naples, Italy
| | - Monica Gelzo
- CEINGE—Biotecnologie Avanzate, 80131 Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Paola Iacotucci
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
| | - Felice Amato
- CEINGE—Biotecnologie Avanzate, 80131 Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Federica Zarrilli
- CEINGE—Biotecnologie Avanzate, 80131 Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Assunta Celardo
- Department of Translational Medical Science, University of Naples Federico II, 80131 Naples, Italy
| | - Giuseppe Castaldo
- CEINGE—Biotecnologie Avanzate, 80131 Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Gaetano Corso
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| |
Collapse
|
|
12
|
Yu J, Xie J, Xie H, Hu Q, Wu Z, Cai X, Guo Z, Lin J, Han L, Zhang D. Strategies for Taste Masking of Orodispersible Dosage Forms: Time, Concentration, and Perception. Mol Pharm 2022; 19:3007-3025. [PMID: 35848076 DOI: 10.1021/acs.molpharmaceut.2c00199] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Orodispersible dosage forms, characterized as quick dissolving and swallowing without water, have recently gained great attention from the pharmaceutical industry, as these forms can satisfy the needs of children, the elderly, and patients suffering from mental illnesses. However, poor taste by thorough exposure of the drugs' dissolution in the oral cavity hinders the effectiveness of the orodispersible dosage forms. To bridge this gap, we put forward three taste-masking strategies with respect to the intensity of time, concentration, and perception. We further investigated the raw material processing, the composition of auxiliary material, formulation techniques, and process control in each strategy and drew conclusions about their effects on taste masking.
Collapse
Affiliation(s)
- Ji Yu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Jin Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Huijuan Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Qi Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Zhenfeng Wu
- Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, PR China
| | - Xinfu Cai
- Sichuan Guangda Pharmaceutical Co., Ltd., Pengzhou 611930, PR China
| | - Zhiping Guo
- Sichuan Houde Pharmaceutical Technology Co., Ltd., Chengdu 610041, PR China
| | - Junzhi Lin
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China
| | - Li Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Dingkun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| |
Collapse
|
|
13
|
Singh SK, Sarma MS. Hereditary fructose intolerance: A comprehensive review. World J Clin Pediatr 2022; 11:321-329. [PMID: 36052111 PMCID: PMC9331401 DOI: 10.5409/wjcp.v11.i4.321] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 05/08/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Hereditary fructose intolerance (HFI) is a rare autosomal recessive inherited disorder that occurs due to the mutation of enzyme aldolase B located on chromosome 9q22.3. A fructose load leads to the rapid accumulation of fructose 1-phosphate and manifests with its downstream effects. Most commonly children are affected with gastrointestinal symptoms, feeding issues, aversion to sweets and hypoglycemia. Liver manifestations include an asymptomatic increase of transaminases, steatohepatitis and rarely liver failure. Renal involvement usually occurs in the form of proximal renal tubular acidosis and may lead to chronic renal insufficiency. For confirmation, a genetic test is favored over the measurement of aldolase B activity in the liver biopsy specimen. The crux of HFI management lies in the absolute avoidance of foods containing fructose, sucrose, and sorbitol (FSS). There are many dilemmas regarding tolerance, dietary restriction and occurrence of steatohepatitis. Patients with HFI who adhere strictly to FSS free diet have an excellent prognosis with a normal lifespan. This review attempts to increase awareness and provide a comprehensive review of this rare but treatable disorder.
Collapse
Affiliation(s)
- Sumit Kumar Singh
- Department of Pediatrics, Sri Aurobindo Medical College and PGI, Indore 453555, Madhya Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| |
Collapse
|
|
14
|
Fructose and Mannose in Inborn Errors of Metabolism and Cancer. Metabolites 2021; 11:metabo11080479. [PMID: 34436420 PMCID: PMC8397987 DOI: 10.3390/metabo11080479] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/21/2021] [Accepted: 07/21/2021] [Indexed: 12/19/2022] Open
Abstract
History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto kitchen tables, is sucrose, which is made up of glucose and fructose dimers. While sugar is commonly associated with flavor, there is a myriad of biochemical properties that explain how sugars as biological molecules function in physiological contexts. Substantial research and reviews have been done on the role of glucose in disease. This review aims to describe the role of its isomers, fructose and mannose, in the context of inborn errors of metabolism and other metabolic diseases, such as cancer. While structurally similar, fructose and mannose give rise to very differing biochemical properties and understanding these differences will guide the development of more effective therapies for metabolic disease. We will discuss pathophysiology linked to perturbations in fructose and mannose metabolism, diagnostic tools, and treatment options of the diseases.
Collapse
|
|
15
|
Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance. J Clin Med 2021; 10:jcm10132932. [PMID: 34208868 PMCID: PMC8267838 DOI: 10.3390/jcm10132932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/17/2021] [Accepted: 06/28/2021] [Indexed: 12/11/2022] Open
Abstract
Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = -0.386, p = 0.024) and FSS (R = -0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.
Collapse
|
|
16
|
Saborido-Fiaño R, Martinón-Torres N, Crujeiras-Martinez V, Couce ML, Leis R. Letter to the editor concerning the article 'Safety of vaccines administration in hereditary fructose intolerance'. Hum Vaccin Immunother 2021; 17:2593-2594. [PMID: 33653220 DOI: 10.1080/21645515.2021.1891816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The most important approach for the management of hereditary fructose intolerance is a strict avoidance of fructose, sucrose and sorbitol from the diet and medications. A safe threshold of 2.4 mg/kg/dose was recently established by the Instituto Superiore di Sanità of Italy for both oral and parenteral routes, thus shouldering a safe administration of a majority of vaccines in these patients. This would not include, Rotarix® pre-established oral suspension and Rotateq® vaccines, which are indeed contraindicated. Moreover, Rotarix® white powder and solvent for oral suspension would only be safely administered at a weight above 9.3 kg.Overall, these recommendations to avoid rotavirus vaccination are difficult to implement because these vaccines are given during exclusive breastfeeding, prior to fructose-containing food introduction.
Collapse
Affiliation(s)
- Rebeca Saborido-Fiaño
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Paediatrics, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Nazareth Martinón-Torres
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Paediatrics, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Vanesa Crujeiras-Martinez
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Paediatrics, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Maria Luz Couce
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Paediatrics, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Rosaura Leis
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Paediatrics, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| |
Collapse
|
|
17
|
Casertano A, Rossi A, Fecarotta S, Rosanio FM, Moracas C, Di Candia F, Parenti G, Franzese A, Mozzillo E. An Overview of Hypoglycemia in Children Including a Comprehensive Practical Diagnostic Flowchart for Clinical Use. Front Endocrinol (Lausanne) 2021; 12:684011. [PMID: 34408725 PMCID: PMC8366517 DOI: 10.3389/fendo.2021.684011] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/31/2021] [Indexed: 02/04/2023] Open
Abstract
Hypoglycemia is the result of defects/impairment in glucose homeostasis. The main etiological causes are metabolic and/or endocrine and/or other congenital disorders. Despite hypoglycemia is one of the most common emergencies in neonatal age and childhood, no consensus on the definition and diagnostic work-up exists yet. Aims of this review are to present the current age-related definitions of hypoglycemia in neonatal-pediatric age, to offer a concise and practical overview of its main causes and management and to discuss the current diagnostic-therapeutic approaches. Since a systematic and prompt approach to diagnosis and therapy is essential to prevent hypoglycemic brain injury and long-term neurological complications in children, a comprehensive diagnostic flowchart is also proposed.
Collapse
Affiliation(s)
- Alberto Casertano
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Alessandro Rossi
- Department of Translational Medical Science, Section of Pediatrics, Metabolic Diseases Unit, Federico II University of Naples, Naples, Italy
- Section of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
| | - Simona Fecarotta
- Department of Translational Medical Science, Section of Pediatrics, Metabolic Diseases Unit, Federico II University of Naples, Naples, Italy
- *Correspondence: Enza Mozzillo, ; Simona Fecarotta, ;
| | - Francesco Maria Rosanio
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Cristina Moracas
- Department of Translational Medical Science, Section of Pediatrics, Federico II University of Naples, Naples, Italy
| | - Francesca Di Candia
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Giancarlo Parenti
- Department of Translational Medical Science, Section of Pediatrics, Metabolic Diseases Unit, Federico II University of Naples, Naples, Italy
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Adriana Franzese
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Enza Mozzillo
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
- *Correspondence: Enza Mozzillo, ; Simona Fecarotta, ;
| |
Collapse
|
|
18
|
Pinheiro FC, Sperb-Ludwig F, Schwartz IVD. KHK inhibition for the treatment of hereditary fructose intolerance and nonalcoholic fatty liver disease: a double-edged sword. Cell Mol Life Sci 2020; 77:3465-3466. [PMID: 32591859 PMCID: PMC11104886 DOI: 10.1007/s00018-020-03575-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 06/08/2020] [Accepted: 06/15/2020] [Indexed: 12/24/2022]
Affiliation(s)
- Franciele Cabral Pinheiro
- Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul RS, Brazil.
- BRAIN Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
- Federal University of Pampa (Unipampa), Itaqui, RS, Brazil.
- Medical Genetic Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 350, Porto Alegre, RS, 90035-903, Brazil.
| | - Fernanda Sperb-Ludwig
- Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul RS, Brazil
- BRAIN Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
| | - Ida Vanessa Doederlein Schwartz
- Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul RS, Brazil
- BRAIN Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil
- Genetics Department, Biosciences Institute, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Medical Genetics Department, HCPA, Porto Alegre, RS, Brazil
| |
Collapse
|
|
19
|
Simons N, Debray FG, Schaper NC, Feskens EJ, Hollak CE, Bons JA, Bierau J, Houben AJ, Schalkwijk CG, Stehouwer CD, Cassiman D, Brouwers MC. Kidney and vascular function in adult patients with hereditary fructose intolerance. Mol Genet Metab Rep 2020; 23:100600. [PMID: 32426234 PMCID: PMC7225396 DOI: 10.1016/j.ymgmr.2020.100600] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 04/30/2020] [Indexed: 01/10/2023] Open
Abstract
Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.
Collapse
Key Words
- 95% confidence interval, (95% CI)
- Blood
- CKD-EPI equation based on creatinine and cystatin c combined, (eGFRcr-cys)
- CKD-EPI equation based on cystatin c, (eGFRcys)
- CKD-EPI equation based on serum creatinine, (eGFRcr)
- Case-control study
- Fanconi syndrome
- Hereditary fructose intolerance
- Kidney
- Vessels
- alanine, (Ala)
- aldolase B, (ALDOB)
- arginine, (Arg)
- asparagine, (Asn)
- carotid-femoral pulse wave velocity, (cf-PWV)
- chronic kidney disease epidemiology collaboration, (CKD-EPI)
- citrulline, (Cit)
- cysteine, (Cys)
- difference, (Δ)
- estimated glomerular filtration rate, (eGFR)
- glucokinase regulatory protein, (GKRP)
- glutamic acid, (Glu)
- glutamine, (Gln)
- glycine, (Gly)
- hereditary fructose intolerance, (HFI)
- histidine, (His)
- intrahepatic triglyceride, (IHTG)
- isoleucine, (Ile)
- laser doppler flowmetry, (LDF)
- leucine, (Leu)
- lysine, (Lys)
- methionine, (Met)
- ornithine, (Orn)
- perfusion units, (PU)
- phenylalanine, (Phe)
- proline, (Pro)
- ratio of tubular maximum reabsorption of phosphate to GFR, (TmP/GFR)
- reactive hyperemia index, (RHI)
- reactive hyperemia peripheral arterial tonometry, (RH-PAT)
- serine, (Ser)
- soluble E-selectin, (sE-selectin)
- statistical package of social sciences, (SPSS)
- taurine, (Tau)
- threonine, (Thr)
- tryptophan, (Try)
- tubular reabsorption of phosphate, (TRP)
- tyrosine, (Tyr)
- valine, (Val)
- von willebrand factor, (vWF)
Collapse
Affiliation(s)
- Nynke Simons
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
| | | | - Nicolaas C. Schaper
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
- CAPHRI School for Public Health and Primary Care, Maastricht, The Netherlands
| | - Edith J.M. Feskens
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - Carla E.M. Hollak
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Judith A.P. Bons
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jörgen Bierau
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Alfons J.H.M. Houben
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
- Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Casper G. Schalkwijk
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
| | - Coen D.A. Stehouwer
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
- Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - David Cassiman
- Department of Gastroenterology-Hepatology and Metabolic Center, University Hospital Leuven, Leuven, Belgium
| | - Martijn C.G.J. Brouwers
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands
- Corresponding author at: Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
| |
Collapse
|