Clues and Challenges in the Ddiagnosis of Intermittent Maple Syrup Urine Disease

נעמי פודה-שקד ^2,3 Stanley H Korman ⁸ Ben Pode Shakked ^2,7 Yuval Landau ^2,5 Katya Kneller ^2,6 Smadar Abraham ¹¹ Avraham Shaag ⁹ Igor Ulanovsky ¹⁰ Suha Daas ¹⁰ Talya Saraf-Levy ¹⁰ Haike Reznik-Wolf ⁷ Elon Pras ^2,7 Shlomo Almashanu ¹⁰ Yair Anikster ^1,2,4

¹The Wohl Institute for Translational Medicine, Sheba Medical Center, ישראל
²Sackler Faculty of Medicine, Tel-Aviv University, ישראל
³Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, ישראל
⁴Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, ישראל
⁵Metabolic Disease Service, Day Care Department, Schneider Children's Medical Center of Israel, ישראל
⁷The Danek Gertner Institute of Human Genetics, Sheba Medical Center, ישראל
⁸Wilf Children’s Hospital, Shaare Zedek Medical Center, ישראל
⁹Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, ישראל
¹⁰National Newborn Screening Program, Ministry of Health, ישראל

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.