A Classic Case of Maple Syrup Urine Disease and a Novel Mutation in the BCKDHA Gene


1 Shiraz University of Medical Sciences, Shiraz, Iran

2 Neonatology Research Center, Department of Pediatrics, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

3 Department of Pediatric Endocrinology, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

4 Center for Human Genetics, Freiburg, Germany

5 Hematology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


Background: Maple syrup urine disease (MSUD) is an inherited branched-chain amino acid metabolic disorder caused by the deficiency in the branched-chain alpha-keto acid dehydrogenase (BCKD) complex. In MSUD, elevation of the branched-chain amino acids, such as alpha-keto acid and alpha-hydroxy acid, occurs due to the BCKDC gene deficiency, appearing in the blood, urine, and cerebrospinal fluid, which leads to neurological damage and mental retardation. MSUD phenotypically penetrates due to the mutations in the coding genes of four subunits of the BCKD complex, including the BCKDHA, BCKDHB, DBT, and DLD genes.
Case report: We aimed to report the cases of three families whose children were affected by MSUD and presented with symptomatic features during the first week of birth, which were identified by mass spectrometry. DNA study was performed as a diagnosis panel containing four encoded BCKDC subunit genes.
Conclusion: In the current study, DNA analysis and phenotypic manifestations indicated a novel mutation of c.143delT, p.L48Rfs*15 in the BCKDHA gene in a homozygous state, which is a causative mutation for the classic MSUD phenotype. Early diagnosis and neonatal screening are recommended for the accurate and effective treatment of this disease


1. Harris RA, Zhang B, Goodwin GW, Kuntz MJ, Shimomura Y, Rougraff P, et al. Regulation of the branched-chain alpha-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease. Adv Enzyme Regul. 1990; 30:245-63.
2. Strauss KA, Puffenberger EG, Morton DH. Maple Syrup urine disease. Washington: GeneReviews; 2013.
 3. Nellis MM, Kasinski A, Carlson M, Allen R, Schaefer AM, Schwartz EM, et al. Relationship of causative genetic mutations in maple syrup urine disease with their clinical expression. Mol Genet Metab. 2003; 80(1-2):189-95.
 4. Howell RR; Advisory Committee on Heri Disorders and Genetic Diseases in Newborns and Children. Advisory committee on heri disorders and genetic diseases in newborns and children. Ment Retard Dev Disabil Res Rev. 2006; 12(4):313-5.
5. Imtiaz F, Al-Mostafa A, Allam R, Ramzan K, AlTassan N, Tahir AI, et al. Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease. Mol Genet Metab Rep. 2017; 11:17-23.
 6. Ellaway CJ, Wilcken B, Christodoulou J. Clinical approach to inborn errors of metabolism presenting in the newborn period. J Paediatr Child Health. 2002; 38(5):511-7.
7. Miryounesi M, Ghafouri-Fard S, Goodarzi H, Fardaei M. A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD). J Pediatr Endocrinol Metab. 2015; 28(5- 6):673-5.
 8. Menkes JH, Hurst PL, Craig JM. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics. 1954; 14(5):462-7.
 9. Chuang DT. Maple syrup urine disease (branchedchain ketoaciduria). In: Scriver CR, editor. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. P. 1971-2005.
 10. Gupta D, Bijarnia-Mahay S, Saxena R, Kohli S, DuaPuri R, Verma J, et al. Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients. Eur J Med Genet. 2015; 58(9):471-8.
11. Morton DH, Strauss KA, Robinson DL, Puffenberger EG, Kelley RI. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics. 2002; 109(6):999-1008.
12. Rodriguez-Pombo P, Navarrete R, Merinero B, Gomez-Puertas P, Ugarte M. Mutational spectrum of maple syrup urine disease in Spain. Hum Mutat. 2006; 27(7):715.