Naomi Pode-Shakked1, Stanley H Korman2, Ben Pode-Shakked3, Yuval Landau4, Katya Kneller5, Smadar Abraham6, Avraham Shaag7, Igor Ulanovsky8, Suha Daas8, Talya Saraf-Levy8, Haike Reznik-Wolf9, Asaf Vivante10, Elon Pras11, Shlomo Almashanu8, Yair Anikster12. 1. Department of Pediatrics A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 2. Wilf Children's Hospital, Shaare Zedek Medical Center, Jerusalem, Israel. 3. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel; Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 4. Metabolic Disease Service, Day Care Department, Schneider Children's Medical Center of Israel, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 5. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 6. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. 7. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 8. National Newborn Screening Program, Ministry of Health, Tel-HaShomer, Israel. 9. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel. 10. Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel; Department of Pediatrics B, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 11. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 12. Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: Yair.Anikster@sheba.health.gov.il.
Abstract
BACKGROUND: Maple 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 METHODS: We 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. RESULTS: All 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. CONCLUSIONS: While 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.
BACKGROUND: Maple 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 METHODS: We 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. RESULTS: All 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. CONCLUSIONS: While 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.
Authors: Diana Ruffato Resende Campanholi; Ana Vitoria Barban Margutti; Wilson A Silva; Daniel F Garcia; Greice A Molfetta; Adriana A Marques; Ida Vanessa Döederlein Schwartz; V Cornejo; Valerie Hamilton; Gabriela Castro; Fernanda Sperb-Ludwig; Ester S Borges; José S Camelo Journal: Mol Genet Genomic Med Date: 2021-05-06 Impact factor: 2.183