Clues and challenges in the diagnosis of intermittent maple syrup urine disease |
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| Affiliation: | 1. Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada;2. Division of Human Genetics, Cincinnati, Children''s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA;3. Department of Medical Genetics, University of Alberta, Stollery Children''s Hospital, Alberta Health Services, Edmonton, Alberta, Canada;4. Metabolic Genetics, Western University, Department of Pediatrics, Children''s Hospital-London Health Sciences Centre, London, Ontario, Canada;5. Hillman Center for Pediatric Transplantation, UPMC Children''s Hospital of Pittsburgh, Division of Pediatric Transplantation, Department of Surgery, Pittsburgh, PA, USA;6. Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, BC Children''s Hospital, BC Children''s Hospital Research Institute, Vancouver, Canada |
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| Abstract: | BackgroundMaple syrup urine disease is a rare autosomal-recessive aminoacidopathy, caused by deficient branched-chain 2-keto acid dehydrogenase (BCKD), with subsequent accumulation of branched-chain amino acids (BCAAs): leucine, isoleucine and valine. While most cases of MSUD are classic, some 20% of cases are non-classic variants, designated as intermediate- or intermittent-types. Patients with the latter form usually develop normally and are cognitively intact, with normal BCAA levels when asymptomatic. However, intercurrent febrile illness and catabolism may cause metabolic derailment with life-threatening neurological sequelae. Thus, early detection and dietary intervention are warranted in intermittent MSUD.Patients and methodsWe describe eight patients from four unrelated families, diagnosed with intermittent MSUD. Their presenting symptoms during metabolic crises varied from confusion and decreased consciousness, to ataxia, and acute psychosis. Molecular confirmation of MSUD was pursued via sequencing of the BCKDHA, BCKDHB and DBT genes.ResultsAll affected individuals were found to harbor bi-allelic pathogenic variants in either BCKDHB or DBT. Of the seven variants, four variants in BCKDHB (p.G101D, p. V103A, p. A221D, p. Y195C) and one variant in DBT (p.K427E) were not previously described.ConclusionsWhile newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis. |
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| Keywords: | Maple syrup urine disease (MSUD) Intermittent maple syrup urine disease |
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