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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.
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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
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Hage G, Sacre Y, Haddad J, Hajj M, Sayegh LN, Fakhoury-Sayegh N. Food Hypersensitivity: Distinguishing Allergy from Intolerance, Main Characteristics, and Symptoms-A Narrative Review. Nutrients 2025; 17:1359. [PMID: 40284223 PMCID: PMC12029945 DOI: 10.3390/nu17081359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Food hypersensitivity remains an understudied and overlooked subject globally. It is characterized by adverse reactions to dietary substances, potentially triggered by various mechanisms. Food allergy, a subset of food hypersensitivity, denotes an immune response to food proteins categorized into immunoglobulin IgE-mediated or non-IgE-mediated reactions. Conversely, food intolerance, another facet of food hypersensitivity, refers to non-immunological reactions, in which the human body cannot properly digest certain foods or components, leading to gastrointestinal discomfort and other non-immune-related symptoms. The main objective of this study was to determine and differentiate the differences, characteristics, and types of food hypersensitivity. Methods: This study involved a comprehensive review of key research from 1990 onward, including review articles, prospective studies, nested case-control studies, and meta-analyses. Results: Recognizing these differences is essential for healthcare professionals to ensure accurate diagnosis, effective management, and improved patient outcomes, while also aiding dietitians in providing optimal nutritional and dietary guidance. Conclusions: there are big differences between the main characteristics, such as symptoms, complications, and treatments between allergies, and food intolerances. Commonly reported trigger foods include cow milk, gluten, eggs, nuts, and seafood.
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Affiliation(s)
- Gregory Hage
- Department of Nutrition and Food Science, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
- Hajj Medical Center-Medical & Dental Clinics, Green Zone A Building 71 Ground Floor, Naccache P.O. Box 1201, Lebanon
| | - Yonna Sacre
- Department of Nutrition and Food Science, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
| | - Joanne Haddad
- Hajj Medical Center-Medical & Dental Clinics, Green Zone A Building 71 Ground Floor, Naccache P.O. Box 1201, Lebanon
- Faculty of Dental Medicine, Saint Joseph University of Beirut, Medical Sciences Campus, Damascus Road, Riad Solh, Beirut P.O. Box 11-5076, Lebanon
| | - Marcel Hajj
- Hajj Medical Center-Medical & Dental Clinics, Green Zone A Building 71 Ground Floor, Naccache P.O. Box 1201, Lebanon
| | - Lea Nicole Sayegh
- Yale New Haven Hospital, P.O. Box 1880, 20 York Street, New Haven, CT 06510, USA
| | - Nicole Fakhoury-Sayegh
- Department of Nutrition and Food Science, Faculty of Arts and Sciences, Holy Spirit University of Kaslik, Jounieh P.O. Box 446, Lebanon
- Faculty of Pharmacy, Department of Nutrition, Saint Joseph University of Beirut, Medical Sciences Campus, Damascus Road, Riad Solh, Beirut P.O. Box 11-5076, Lebanon
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3
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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/).
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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
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Ng BG, Freeze HH, Himmelreich N, Blau N, Ferreira CR. Clinical and biochemical footprints of congenital disorders of glycosylation: Proposed nosology. Mol Genet Metab 2024; 142:108476. [PMID: 38653092 PMCID: PMC11251693 DOI: 10.1016/j.ymgme.2024.108476] [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: 01/30/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/25/2024]
Abstract
We have identified 200 congenital disorders of glycosylation (CDG) caused by 189 different gene defects and have proposed a classification system for CDG based on the mode of action. This classification includes 8 categories: 1. Disorders of monosaccharide synthesis and interconversion, 2. Disorders of nucleotide sugar synthesis and transport, 3. Disorders of N-linked protein glycosylation, 4. Disorders of O-linked protein glycosylation, 5. Disorders of lipid glycosylation, 6. Disorders of vesicular trafficking, 7. Disorders of multiple glycosylation pathways and 8. Disorders of glycoprotein/glycan degradation. Additionally, using information from IEMbase, we have described the clinical involvement of 19 organs and systems, as well as essential laboratory investigations for each type of CDG. Neurological, dysmorphic, skeletal, and ocular manifestations were the most prevalent, occurring in 81%, 56%, 53%, and 46% of CDG, respectively. This was followed by digestive, cardiovascular, dermatological, endocrine, and hematological symptoms (17-34%). Immunological, genitourinary, respiratory, psychiatric, and renal symptoms were less frequently reported (8-12%), with hair and dental abnormalities present in only 4-7% of CDG. The information provided in this study, including our proposed classification system for CDG, may be beneficial for healthcare providers caring for individuals with metabolic conditions associated with CDG.
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Affiliation(s)
- Bobby G Ng
- Human Genetics Program, Sanford Children's Health Research Center, La Jolla, CA, USA
| | - Hudson H Freeze
- Human Genetics Program, Sanford Children's Health Research Center, La Jolla, CA, USA.
| | - Nastassja Himmelreich
- Dietmar-Hopp Metabolic Center and Centre for Pediatrics and Adolescent Medicine, University Children's Hospital, Heidelberg, Germany; Center for Human Genetics Tübingen, Tübingen, Germany
| | - Nenad Blau
- Divisions of Metabolism, University Children's Hospital, Zürich, Switzerland.
| | - Carlos R Ferreira
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
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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.
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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;
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6
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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.
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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
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7
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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.
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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
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8
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Pinheiro FC, Sperb-Ludwig F, Schwartz IVD. Epidemiological aspects of hereditary fructose intolerance: A database study. Hum Mutat 2021; 42:1548-1566. [PMID: 34524712 DOI: 10.1002/humu.24282] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 09/05/2021] [Accepted: 09/11/2021] [Indexed: 12/11/2022]
Abstract
Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism of autosomal recessive inheritance caused by pathogenic variants in the ALDOB gene that lead to aldolase B deficiency in the liver, kidneys, and intestine. Patients manifest symptoms, such as ketotic hypoglycemia, vomiting, nausea, in addition to hepatomegaly and other liver and kidney dysfunctions. The treatment consists of a fructose-restricted diet, which results in a good prognosis. To analyze the distribution of ALDOB variants described in patients and to estimate the prevalence of HFI based on carrier frequency in the gnomAD database, a systematic review was conducted to assess ALDOB gene variants among patients with HFI. The prevalence of HFI was estimated from the carrier frequency of variants described in patients, as well as rare variants predicted as pathogenic by in silico tools. The p.(Ala150Pro) and p.(Ala175Asp) variants are the most frequent and are distributed worldwide. However, these variants have particular distribution patterns in Europe. The analysis of the prevalence of HFI showed that the inclusion of rare alleles predicted as pathogenic is a more informative approach for populations with few patients. The data show that HFI has a wide distribution and an estimated prevalence of ~1:10,000.
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Affiliation(s)
- Franciele C Pinheiro
- Post-Graduate Program in Genetics and Molecular Biology, Federal University of do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.,BRAIN Laboratory, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.,Federal University of Pampa, Itaqui, Rio Grande do Sul, Brazil
| | - Fernanda Sperb-Ludwig
- Post-Graduate Program in Genetics and Molecular Biology, Federal University of do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.,BRAIN Laboratory, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Ida V D Schwartz
- Post-Graduate Program in Genetics and Molecular Biology, Federal University of do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.,BRAIN Laboratory, Center of Experimental Research, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.,Department of Genetics, Bioscience Institute, Federal University of do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.,Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
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9
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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.
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10
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Lee J, Arenth J, Kasi N. Neonatal Hereditary Fructose Intolerance: Diagnostic Misconceptions and the Role of Genomic Sequencing. JPGN REPORTS 2021; 2:e076. [PMID: 37207065 PMCID: PMC10191584 DOI: 10.1097/pg9.0000000000000076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 02/24/2021] [Indexed: 05/21/2023]
Abstract
Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism due to deficiency of the enzyme aldolase B, preventing metabolism of fructose. Patients remain asymptomatic until exposed to fructose, sucrose, or sorbitol. HFI presenting as acute liver failure in the neonatal period is rare due to lack of exposure as breast milk and infant formulas are considered to be fructose free. Diagnosis can be delayed due to vague symptoms and lack of specific biomarkers. Recent advances in genetic testing have led to rapid diagnosis and favorable outcomes. We present the case of a formula-fed neonate who presented with acute liver failure where definitive diagnosis of HFI was made using expedited whole exome sequencing. Through this communication, we aim to bring attention to neonatal presentations of HFI from exposure to fructose in infant formulas and also highlight advances in rapid turnaround genomic testing in diagnosis.
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Affiliation(s)
- Jeffrey Lee
- From the Division of Pediatric Gastroenterology and Hepatology, Medical University of South Carolina, Shawn Jenkins Children’s Hospital, Charleston, SC
| | - Joshua Arenth
- Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Shawn Jenkins Children’s Hospital, Charleston, SC
| | - Nagraj Kasi
- From the Division of Pediatric Gastroenterology and Hepatology, Medical University of South Carolina, Shawn Jenkins Children’s Hospital, Charleston, SC
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11
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Bogdańska A, Lipiński P, Szymańska-Rożek P, Jezela-Stanek A, Rokicki D, Socha P, Tylki-Szymańska A. Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up. Orphanet J Rare Dis 2021; 16:17. [PMID: 33407696 PMCID: PMC7789416 DOI: 10.1186/s13023-020-01657-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Background Congenital disorders of glycosylation (CDG) result from defects in the synthesis of glycans and the attachment of glycans to proteins and lipids. Our study aimed to describe the clinical, biochemical, and molecular findings of CDG patients, and to present the long-term follow-up. Material and methods A single-center study (1995–2019 years) of patients with congenital disorders of N-glycosylation and combined N- and O-hypoglycosylation was performed. Results Among 32 patients included into the study, there were 12 PMM2-CDG, 3 ALG13-CDG, 3 ALG1-CDG, 1 ALG3-CDG, 3 MPI-CDG, 1 PGM1-CDG, 4 SRD5A3-CDG, 1 DPAGT1-CDG, 3 ATP6AP1-CDG, 1 ATP6V0A2-CDG. The phenotypic and genotypic spectrum during long-term (in some cases over 20 years) observation was characterised and several measurements of serum Tf isoforms taken. Statistical analysis revealed strong negative correlation between asialo-Tf and tetrasialo-Tf, as well as between disialo-Tf and tetrasialo-Tf. Within CDG type I, no difference in % Tf isoforms was revealed between PMM2-CDG and non-PMM2-CDG patients. However, these two groups differed significantly in such diagnostic features as: cerebellar ataxia, failure to thrive, hypothyroidism, pericardial effusion, cardiomyopathy, inverted nipples, prolonged INR. The effect of treatment with mannose in 2 patients with MPI-CDG was assessed and we found that % of asialo-Tf, monosialo-Tf, and disialo-Tf was significantly lowered, whereas tetrasialo-Tf and pentasialo-Tf rose, coming closer or falling into the reference range. Conclusions The novel finding was an abnormal Tf IEF pattern in two ALG13-CDG patients and normal in one ALG1-CDG patient. Clinical manifestation of presented CDG patients was similar to that reported in the literature. Mannose supplementation in MPI-CDG patients, as well as galactose supplementation in PGM1-CDG patient, improved patients’ clinical picture and Tf isoform profiles.
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Affiliation(s)
- Anna Bogdańska
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
| | - Patryk Lipiński
- Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland
| | | | - Aleksandra Jezela-Stanek
- Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland
| | - Dariusz Rokicki
- Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Feeding Difficulties and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Anna Tylki-Szymańska
- Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
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12
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Altassan R, Radenkovic S, Edmondson AC, Barone R, Brasil S, Cechova A, Coman D, Donoghue S, Falkenstein K, Ferreira V, Ferreira C, Fiumara A, Francisco R, Freeze H, Grunewald S, Honzik T, Jaeken J, Krasnewich D, Lam C, Lee J, Lefeber D, Marques-da-Silva D, Pascoal C, Quelhas D, Raymond KM, Rymen D, Seroczynska M, Serrano M, Sykut-Cegielska J, Thiel C, Tort F, Vals MA, Videira P, Voermans N, Witters P, Morava E. International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management. J Inherit Metab Dis 2021; 44:148-163. [PMID: 32681750 PMCID: PMC7855268 DOI: 10.1002/jimd.12286] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/07/2020] [Accepted: 07/14/2020] [Indexed: 12/13/2022]
Abstract
Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.
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Affiliation(s)
- Ruqaiah Altassan
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Silvia Radenkovic
- Metabolomics Expertise Center, Center for Cancer Biology, VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory of Hepatology, Department CHROMETA, KU Leuven, Leuven, Belgium
- Department of Clinical Genomics and Laboratory of Medical Pathology, Mayo Clinic, Rochester, Minnesota
| | - Andrew C. Edmondson
- Department of Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Rita Barone
- Child Neurology and Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Sandra Brasil
- Portuguese Association for Congenital Disorders of Glycosylation (CDG), Lisbon, Portugal
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Lisbon, Portugal
- Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Lisbon, Portugal
| | - Anna Cechova
- Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - David Coman
- Metabolic Medicine, Queensland Children’s Hospital, Brisbane, Australia
| | - Sarah Donoghue
- Department of Metabolic Medicine, The Royal Children’s Hospital, Melbourne, Victoria, Australia
| | - Kristina Falkenstein
- Center for Child and Adolescent Medicine, Department, University of Heidelberg, Heidelberg, Germany
| | - Vanessa Ferreira
- Portuguese Association for Congenital Disorders of Glycosylation (CDG), Lisbon, Portugal
| | - Carlos Ferreira
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Agata Fiumara
- Child Neurology and Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Rita Francisco
- Portuguese Association for Congenital Disorders of Glycosylation (CDG), Lisbon, Portugal
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Lisbon, Portugal
- Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Lisbon, Portugal
| | - Hudson Freeze
- Sanford Children’s Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California
| | - Stephanie Grunewald
- Metabolic Department, Great Ormond Street Hospital NHS Foundation Trust and Institute for Child Health, NIHR Biomedical Research Center (BRC), University College London, London, UK
| | - Tomas Honzik
- Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Jaak Jaeken
- Center for Metabolic Diseases, KU Leuven, Leuven, Belgium
| | - Donna Krasnewich
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Christina Lam
- Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington
- Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington
| | - Joy Lee
- Department of Metabolic Medicine, The Royal Children’s Hospital, Melbourne, Victoria, Australia
| | - Dirk Lefeber
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Dorinda Marques-da-Silva
- Portuguese Association for Congenital Disorders of Glycosylation (CDG), Lisbon, Portugal
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Lisbon, Portugal
- Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Lisbon, Portugal
| | - Carlota Pascoal
- Portuguese Association for Congenital Disorders of Glycosylation (CDG), Lisbon, Portugal
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Lisbon, Portugal
- Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Lisbon, Portugal
| | - Dulce Quelhas
- Centro de Genética Médica Doutor Jacinto Magalhães, Unidade de Bioquímica Genética, Porto, Portugal
| | - Kimiyo M. Raymond
- Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Daisy Rymen
- Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium
| | - Malgorzata Seroczynska
- Department of Inborn Errors of Metabolism and Paediatrics, the Institute of Mother and Child, Warsaw, Poland
| | - Mercedes Serrano
- Neurology Department, Hospital Sant Joan de Déu, U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Barcelona, Spain
| | - Jolanta Sykut-Cegielska
- Department of Inborn Errors of Metabolism and Paediatrics, the Institute of Mother and Child, Warsaw, Poland
| | - Christian Thiel
- Center for Child and Adolescent Medicine, Department, University of Heidelberg, Heidelberg, Germany
| | - Frederic Tort
- Section of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, CIBERER, Barcelona, Spain
| | - Mari-Anne Vals
- Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Paula Videira
- UCIBIO, Departamento Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Lisbon, Portugal
- Professionals and Patient Associations International Network (CDG & Allies-PPAIN), Lisbon, Portugal
| | - Nicol Voermans
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Peter Witters
- Department of Paediatrics and Metabolic Center, University Hospitals Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Eva Morava
- Department of Clinical Genomics and Laboratory of Medical Pathology, Mayo Clinic, Rochester, Minnesota
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Magalhães APPSD, Burin MG, Souza CFMD, de Bitencourt FH, Sebastião FM, Silva TO, Vairo FPE, Schwartz IVD. Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten-year experience in a Brazilian center. J Pediatr (Rio J) 2020; 96:710-716. [PMID: 31677975 PMCID: PMC9432258 DOI: 10.1016/j.jped.2019.05.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 05/14/2019] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVES To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. METHOD Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age=36 months, 25-75 IQR=10-108; males=810) submitted to the TfIEF test during the period were reviewed. RESULTS Fifty-one individuals (3%) had an altered TfIEF pattern (5±2.8 cases/year; median age=24 months, 25-75 IQR=11-57 months; males=27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia=4; hereditary fructose intolerance=4; peroxisomal diseases=2; PMM2-CDG=2; MPDU1-CDG=1; SLC35A2-CDG=1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. CONCLUSIONS The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.
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Affiliation(s)
- Ana Paula Pereira Scholz de Magalhães
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós Graduação em Ciências Médicas, Porto Alegre, RS, Brazil; Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Porto Alegre, RS, Brazil
| | - Maira Graeff Burin
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Porto Alegre, RS, Brazil
| | | | | | - Fernanda Medeiros Sebastião
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós Graduação em Ciências Médicas, Porto Alegre, RS, Brazil; Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Porto Alegre, RS, Brazil
| | - Thiago Oliveira Silva
- Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Porto Alegre, RS, Brazil
| | - Filippo Pinto E Vairo
- Mayo Clinic, Departament of Clinical Genomics, Rochester, United States; Mayo Clinic, Center for Individualized Medicine, Rochester, United States
| | - Ida Vanessa Doederlein Schwartz
- Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós Graduação em Ciências Médicas, Porto Alegre, RS, Brazil; Hospital de Clínicas de Porto Alegre (HCPA), Serviço de Genética Médica, Porto Alegre, RS, Brazil; Universidade Federal do Rio Grande do Sul (UFRGS), Departamento de Genética, Porto Alegre, RS, Brazil.
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14
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Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten‐year experience in a Brazilian center. JORNAL DE PEDIATRIA (VERSÃO EM PORTUGUÊS) 2020. [DOI: 10.1016/j.jpedp.2019.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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15
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Casetta B, Malvagia S, Funghini S, Martinelli D, Dionisi-Vici C, Barone R, Fiumara A, Donati MA, Guerrini R, la Marca G. A new strategy implementing mass spectrometry in the diagnosis of congenital disorders of N-glycosylation (CDG). Clin Chem Lab Med 2020; 59:165-171. [PMID: 32776892 DOI: 10.1515/cclm-2020-0650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/24/2020] [Indexed: 12/14/2022]
Abstract
Objectives Congenital disorders of N-glycosylation (CDG) are a large group of rare metabolic disorders caused by defects in the most common post-translational modification of proteins. CDGs are often difficult to diagnose as they are manifested with non-specific symptoms and signs. Analysis of serum transferrin (TRF) isoforms, as the classical procedure used to identify a CDG patient, enables to predict pathological steps in the N-linked glycosylation process. Methods We devised a new strategy based on liquid chromatography-mass spectrometry (LC-MS) for the analysis of TRF isoforms by combining a simple and fast sample preparation with a specific chromatographic cleanup/separation step followed by mass-spectrometric measurement. Single TRF isoform masses were obtained through reconstruction of multiply charged electrospray data collected by quadrupole-MS technology. Hereby, we report the first analyzed serum samples obtained from 20 CDG patients and 100 controls. Results The ratio of desialylated isoforms to total TRF was calculated for patients and controls. CDG-Type I patients showed higher amounts of bi-sialo isoform (range: 6.7-29.6%) compared to controls (<5.5%, mean percentage 3.9%). CDG-Type II pattern showed an increased peak of tri-sialo isoforms. The mean percentage of tri-sialo-TRF was 9.3% (range: 2.9-12.9%) in controls, which was lower than that obtained from two patients with COG5-CDG and MAN1B1-CDG (18.5 and 24.5%). Intraday and between-day imprecisions were less than 9 and 16%, respectively, for bi-sialo- and less than 3 and 6% for tri-sialo-TRF. Conclusions This LC-MS-based approach provides a simple, sensitive and fast analytical tool for characterizing CDG disorders in a routine clinical biochemistry while improving diagnostic accuracy and speeding clinical decision-making.
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Affiliation(s)
- Bruno Casetta
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy
| | - Sabrina Malvagia
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy
| | - Silvia Funghini
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy
| | - Diego Martinelli
- Division of Metabolism, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Carlo Dionisi-Vici
- Division of Metabolism, Department of Pediatric Specialties, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Rita Barone
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Agata Fiumara
- Department of Pediatrics, Regional Referral Center for Inherited Metabolic Disease, University of Catania, Catania, Italy
| | - Maria Alice Donati
- Metabolic and Neuromuscular Unit, Meyer Children's University Hospital, Florence, Italy
| | - Renzo Guerrini
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy.,Neuroscience Department, Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Giancarlo la Marca
- Newborn Screening, Biochemistry and Pharmacology Laboratory, Pediatric Neurology Unit and Laboratories, Meyer Children's University Hospital, Florence, Italy.,Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
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16
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Buziau AM, Schalkwijk CG, Stehouwer CDA, Tolan DR, Brouwers MCGJ. Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease. Cell Mol Life Sci 2020; 77:1709-1719. [PMID: 31713637 PMCID: PMC11105038 DOI: 10.1007/s00018-019-03348-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 10/02/2019] [Accepted: 10/16/2019] [Indexed: 12/31/2022]
Abstract
Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.
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Affiliation(s)
- Amée M Buziau
- 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
- Cardiovascular Research Institute Maastricht (CARIM), 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
- Cardiovascular Research Institute Maastricht (CARIM), 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
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands
- Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Dean R Tolan
- Department of Biology, Boston University, Boston, MA, USA.
| | - 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.
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
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17
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Simons N, Debray FG, Schaper NC, Kooi ME, Feskens EJM, Hollak CEM, Lindeboom L, Koek GH, Bons JAP, Lefeber DJ, Hodson L, Schalkwijk CG, Stehouwer CDA, Cassiman D, Brouwers MCGJ. Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content. J Clin Endocrinol Metab 2019; 104:5056-5064. [PMID: 30901028 DOI: 10.1210/jc.2018-02795] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 03/18/2019] [Indexed: 02/09/2023]
Abstract
CONTEXT There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates. OBJECTIVE To translate these experimental findings to the human situation. DESIGN Case-control study. SETTING Outpatient clinic for inborn errors of metabolism. PATIENTS OR OTHER PARTICIPANTS Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). MAIN OUTCOME MEASURE IHTG content, assessed by proton magnetic resonance spectroscopy. RESULTS IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009). CONCLUSIONS This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.
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Affiliation(s)
- Nynke Simons
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
| | | | - Nicolaas C Schaper
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
- School for Public Health and Primary Care (CAPHRI), Maastricht, Netherlands
| | - M Eline Kooi
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Edith J M Feskens
- Division of Human Nutrition, Wageningen University, Wageningen, Netherlands
| | - Carla E M Hollak
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands
| | - Lucas Lindeboom
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
- Department of Nutrition and Movement Sciences, Maastricht University Medical Center, Maastricht, Netherlands
| | - Ger H Koek
- School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Maastricht University Medical Center, Maastricht, Netherlands
- Department of Surgery, Klinikum, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Judith A P Bons
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands
| | - Dirk J Lefeber
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Neurology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Casper G Schalkwijk
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, 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, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
- Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, 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, Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
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Li H, Byers HM, Diaz-Kuan A, Vos MB, Hall PL, Tortorelli S, Singh R, Wallenstein MB, Allain M, Dimmock DP, Farrell RM, McCandless S, Gambello MJ. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab 2018; 123:428-432. [PMID: 29510902 DOI: 10.1016/j.ymgme.2018.02.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 02/23/2018] [Accepted: 02/23/2018] [Indexed: 12/22/2022]
Abstract
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.
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Affiliation(s)
- Hong Li
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, United States; Department of Pediatrics, School of Medicine, Emory University, Children's Healthcare of Atlanta, Atlanta, GA, United States.
| | - Heather M Byers
- Division of Medical Genetics, Department of Pediatrics, School of Medicine, Stanford University, Palo Alto, CA, United States
| | - Alicia Diaz-Kuan
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, United States
| | - Miriam B Vos
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, United States
| | | | - Silvia Tortorelli
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Rani Singh
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, United States; Department of Pediatrics, School of Medicine, Emory University, Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Matthew B Wallenstein
- Division of Neonatal and Developmental Medicine, Department of Pediatrics, School of Medicine, Stanford University, Palo Alto, CA, United States
| | - Meredith Allain
- Division of Medical Genetics, Department of Pediatrics, School of Medicine, Stanford University, Palo Alto, CA, United States
| | - David P Dimmock
- Rady Children's Institute for Genomic Medicine, San Diego, CA, United States
| | - Ryan M Farrell
- Department of Pediatrics, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Shawn McCandless
- Department of Pediatrics, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, United States; Department of Genetics and Genome Sciences, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
| | - Michael J Gambello
- Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, United States; Department of Pediatrics, School of Medicine, Emory University, Children's Healthcare of Atlanta, Atlanta, GA, United States
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19
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Reid ES, Papandreou A, Drury S, Boustred C, Yue WW, Wedatilake Y, Beesley C, Jacques TS, Anderson G, Abulhoul L, Broomfield A, Cleary M, Grunewald S, Varadkar SM, Lench N, Rahman S, Gissen P, Clayton PT, Mills PB. Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes. Brain 2017; 139:2844-2854. [PMID: 27604308 PMCID: PMC5091046 DOI: 10.1093/brain/aww221] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/14/2016] [Indexed: 12/15/2022] Open
Abstract
Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts.
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Affiliation(s)
- Emma S Reid
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK
| | - Apostolos Papandreou
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.,Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Suzanne Drury
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Christopher Boustred
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Wyatt W Yue
- Structural Genomics Consortium, University of Oxford, Oxford, UK
| | - Yehani Wedatilake
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK
| | - Clare Beesley
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Thomas S Jacques
- Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.,Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, UK
| | - Glenn Anderson
- Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Lara Abulhoul
- Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Alex Broomfield
- Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Maureen Cleary
- Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Stephanie Grunewald
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.,Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Sophia M Varadkar
- Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Nick Lench
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Shamima Rahman
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.,Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Paul Gissen
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.,Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Peter T Clayton
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK
| | - Philippa B Mills
- Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK
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20
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Bortolotti F, Sorio D, Bertaso A, Tagliaro F. Analytical and diagnostic aspects of carbohydrate deficient transferrin (CDT): A critical review over years 2007-2017. J Pharm Biomed Anal 2017; 147:2-12. [PMID: 28912047 DOI: 10.1016/j.jpba.2017.09.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Revised: 08/30/2017] [Accepted: 09/01/2017] [Indexed: 02/07/2023]
Abstract
The need for investigating alcohol abuse by means of objective tools is worldwide accepted. Among the currently available biomarkers of chronic alcohol abuse, carbohydrate-deficient transferrin (CDT) is one of the most used indicator, mainly because of its high specificity. However, some CDT analytical and interpretation aspects are still under discussion, as witnessed by numerous research papers and reviews. The present article presents a critical review of the literature on CDT appeared in the period from 2007 to 2017 (included). The article is organized in the following sections: (1) introduction, (2) pre-analytical aspects (3) analytical aspects (4) diagnostic aspects (5) concluding remarks. As many as 139 papers appeared in the international literature and retrieved by the search engines PubMed, Web of Science and Scopus are quoted.
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Affiliation(s)
- F Bortolotti
- Dept of Diagnostics and Public Health, Unit of Forensic Medicine, University of Verona, Italy.
| | - D Sorio
- Dept of Diagnostics and Public Health, Unit of Forensic Medicine, University of Verona, Italy
| | - A Bertaso
- Dept of Diagnostics and Public Health, Unit of Forensic Medicine, University of Verona, Italy
| | - F Tagliaro
- Dept of Diagnostics and Public Health, Unit of Forensic Medicine, University of Verona, Italy; Institute of Pharmacy and Translational Medicine, Sechenov First Medical University, Moskow, Russia
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21
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Maitre A, Maw A, Ramaswami U, Morley SL. Relapsing Acute Axonal Neuropathy in Hereditary Fructose Intolerance. Pediatr Neurol 2016; 64:92-93. [PMID: 27720712 DOI: 10.1016/j.pediatrneurol.2016.06.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 06/26/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND A severe neurological abnormality has not been previously described in individuals with hereditary fructose intolerance, which typically presents early in childhood with severe metabolic acidosis and hypoglycemia. PATIENT DESCRIPTION We describe a boy who by age five years had required multiple admissions to the pediatric intensive care unit for an aggressive and atypical, relapsing and remitting neuropathy with features of acute motor axonal neuropathy (AMAN). It was later discovered that he also had undiagnosed hereditary fructose intolerance, and the severity and frequency of his neurological episodes diminished following an exclusion diet. His asymptomatic younger brother was diagnosed with hereditary fructose intolerance on screening. He is on a fructose-free diet and has not developed neurological symptoms. CONCLUSIONS Ongoing low-level exposure to fructose prior to diagnosis may have contributed to our patient's neurological dysfunction. Early diagnosis and treatment may prevent neurological complications of hereditary fructose intolerance.
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Affiliation(s)
- Anna Maitre
- Paediatric Intensive Care, Department of Paediatrics, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Anna Maw
- Paediatric Intensive Care, Department of Paediatrics, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Uma Ramaswami
- Paediatric Intensive Care, Department of Paediatrics, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Sarah L Morley
- Paediatric Intensive Care, Department of Paediatrics, Addenbrooke's Hospital, Cambridge, United Kingdom.
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22
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Moraitou M, Dimitriou E, Mavridou I, Michelakakis H, Georgouli H, Ploski R, Pollak A. Transferrin isoelectric focusing and plasma lysosomal enzyme activities in the diagnosis and follow‐up of hereditary fructose intolerance. Clin Chim Acta 2012; 413:1714-5. [DOI: 10.1016/j.cca.2012.06.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Revised: 06/01/2012] [Accepted: 06/02/2012] [Indexed: 11/16/2022]
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23
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Novel techniques and newer markers for the evaluation of “proximal tubular dysfunction”. Int Urol Nephrol 2011; 43:1107-15. [DOI: 10.1007/s11255-011-9914-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2010] [Accepted: 02/07/2011] [Indexed: 10/18/2022]
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24
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Quintana E, Sturiale L, Montero R, Andrade F, Fernandez C, Couce ML, Barone R, Aldamiz-Echevarria L, Ribes A, Artuch R, Briones P. Secondary disorders of glycosylation in inborn errors of fructose metabolism. J Inherit Metab Dis 2009; 32 Suppl 1:S273-8. [PMID: 19768653 DOI: 10.1007/s10545-009-1219-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2009] [Revised: 07/20/2009] [Accepted: 07/23/2009] [Indexed: 02/02/2023]
Abstract
Adamowicz and colleagues raised the alert in 2007 about patients with atypical hereditary fructose intolerance (HFI) primarily misdiagnosed as CDG Ix. We describe a girl with neonatal hypertonia, facial trismus, absent swallowing and coughing reflexes, gastro-oesophageal reflux and sporadically elevated Krebs cycle metabolites and lactate. At 14 months microcephaly and hepatomegaly were noted, with hypertransaminasaemia but normal blood coagulation, glucose, phosphate, and absent urinary reducing substances. Neurological impairment persisted. Because of hepatic and neurological abnormalities with developmental delay, Tf IEF was performed and showed a severe type 1 pattern, resulting in a wrong diagnosis of CDG. Subsequently, an aversion to fruits suggested HFI, confirmed by the finding of ALDOB mutations (p.A150P/p.N335K). The girl improved with fructose-free diet, but liver cirrhosis led to hepatic transplantation. She is now 7 years old with good evolution; facial trismus and hypertonia reversed, but microcephaly persists. Transferrin MALDI-TOF MS characterization revealed underoccupation of glycosylation sites and glycan abnormalities, which reversed with dietary treatment. High maternal fructose concentrations might have caused neonatal abnormalities. Although in our patient's mother there is no fructose accumulation at present, it is possible that increased ingestion of fruits and vegetables during pregnancy, together with her heterozygosity, caused an accumulation of fructose that finally affected the fetus. We also describe slightly abnormal transferrin isoelectric focusing and MALDI-TOF MS patterns of intact transferrin and N-glycans in a fructose-1,6-bisphosphatase (FBP1)-deficient patient. While HFI is a well-known cause of secondary CDG, we found no reports of abnormal transferrin isoelectric focusing patterns in FBP1 deficiency and we introduce this condition as a possible secondary cause for altered transferrin isoelectric focusing.
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Affiliation(s)
- E Quintana
- Institut de Bioquímica Clínica, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Edificio Helios III, c/ Mejia Lequerica s/n, 08028, Barcelona, Spain
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25
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Michelakakis H, Moraitou M, Mavridou I, Dimitriou E. Plasma lysosomal enzyme activities in congenital disorders of glycosylation, galactosemia and fructosemia. Clin Chim Acta 2009; 401:81-3. [DOI: 10.1016/j.cca.2008.11.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Revised: 11/14/2008] [Accepted: 11/14/2008] [Indexed: 10/21/2022]
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26
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Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta Mol Basis Dis 2009; 1792:827-34. [PMID: 19272306 DOI: 10.1016/j.bbadis.2009.01.003] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 01/08/2009] [Accepted: 01/09/2009] [Indexed: 02/05/2023]
Abstract
Congenital disorders of glycosylation are a clinically and genetically heterogeneous group of disorders resulting from abnormal glycosylation of various glycoconjugates. The first description of congenital disorders of glycosylation was published in the early 80s and once screening tests for glycosylation disorders (CDGs) became readily available, CDG-Ia became the most frequently diagnosed CDG subtype. CDG-Ia is pan-ethnic and the spectrum of the clinical manifestations is still evolving: it spans from severe hydrops fetalis and fetal loss to a (nearly) normal phenotype. However, the most common presentation in infancy is of a multisystem disorder with central nervous system involvement.
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Affiliation(s)
- Stephanie Grünewald
- Metabolic Medicine Unit, Great Ormond Street Hospital for Children NHS Trust with the UCL Institute of Child Health, London WC1N 3JH, UK.
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27
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Sturiale L, Barone R, Palmigiano A, Ndosimao CN, Briones P, Adamowicz M, Jaeken J, Garozzo D. Multiplexed glycoproteomic analysis of glycosylation disorders by sequential yolk immunoglobulins immunoseparation and MALDI-TOF MS. Proteomics 2008; 8:3822-32. [DOI: 10.1002/pmic.200700496] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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28
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Guery M, Douillard C, Marcelli-Tourvieille S, Dobbelaere D, Wemeau J, Vantyghem M. Doctor, my son is so tired… about a case of hereditary fructose intolerance. ANNALES D'ENDOCRINOLOGIE 2007; 68:456-9. [DOI: 10.1016/j.ando.2007.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2007] [Accepted: 09/17/2007] [Indexed: 10/22/2022]
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