ORPHA: 268145, 268162, 268173, 511;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q14.1 | Maple syrup urine disease, type Ib | 620698 | Autosomal recessive | 3 | BCKDHB | 248611 |
A number sign (#) is used with this entry because maple syrup urine disease type IB (MSUD1B) is caused by homozygous or compound heterozygous mutation in the BCKDHB gene (248611), which encodes a subunit of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), on chromosome 6q14.
The major clinical features of maple syrup urine disease (MSUD) are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids (BCAA) are present in the urine, resulting from a block in oxidative decarboxylation. There are 4 clinical subtypes of MSUD1B: the classic neonatal severe form, an intermediate form, an intermittent form, and a thiamine-responsive form (Chuang and Shih, 2001). The classic form is manifested within the first 2 weeks of life with poor feeding, lethargy, seizures, coma, and death if untreated. Intermediate MSUD is associated with elevated BCAAs and BCKA, with progressive mental retardation and developmental delay without a history of catastrophic illness. The diagnosis is usually delayed for many months. An intermittent form of MSUD may have normal levels of BCAAs, normal intelligence and development until a stress, e.g., infection, precipitates decompensation with ketoacidosis and neurologic symptoms, which are usually reversed with dietary treatment. Thiamine-responsive MSUD is similar to the intermediate phenotype but responds to pharmacologic doses of thiamine with normalization of BCAAs (Chuang et al., 1995).
For general phenotypic information and a discussion of genetic heterogeneity of MSUD, see MSUD1A (248600).
The transmission pattern of MSUD1B in the patient reported by Nobukuni et al. (1991) was consistent with autosomal recessive inheritance.
In a patient with classic maple syrup urine disease, Nobukuni et al. (1991) identified a homozygous 11-bp deletion in exon 1 of the E1-beta gene (248611.0001).
In 6 of 7 Ashkenazi Jewish patients with classic MSUD, Edelmann et al. (2001) identified homozygosity or compound heterozygosity for the same mutation in the BCKDHB gene (R183P; 248611.0002). The authors found that approximately 33% (10 of 34) of families with MSUD followed in their clinic in New York were of Ashkenazi Jewish descent. Large-scale population screening of Ashkenazi Jewish individuals for the R183P mutation revealed that the carrier frequency of the mutant allele was approximately 1 in 113 persons.
In 3 unrelated Israeli patients with classic MSUD, Chuang et al. (2004) identified homozygous or compound heterozygous mutations in the BCKDHB gene (248611.0003-248611.0006). Functional expression studies in E. coli showed that the different mutations had variable expression but no residual enzyme activity.
Nellis et al. (2003) evaluated and compared the clinical course of 11 unrelated patients with MSUD, including 3 with mutations in the E1-alpha gene, 5 with mutations in the E1-beta gene, and 3 with mutations in the E2 gene (2 were sibs). All had residual BCKD activity less than 3% of control values. All patients except 2, 1 with E1-alpha and 1 with an E1-beta mutations, had documented episodes of metabolic decompensation. IQ greater than 90 was observed in 70% of patients. Patients with mutations in the E1-alpha gene tended to have decreased IQs compared to other patients. In general, however, the results indicated no significant impact of 1 mutant locus to another in determining clinical outcome. The most important factor in determining outcome was early identification and institution of a protein-modified diet.
Among 15 patients with variant forms of MSUD, Flaschker et al. (2007) found that more severe phenotypes tended to be associated with mutations in the BCKDHA gene, whereas milder variants tended to be associated with mutations in the BCKDHB and DBT genes.
Chuang, D. T., Shih, V. E. Maple syrup urine disease (branched-chain ketoaciduria). In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 1971-2005.
Chuang, J. L., Davie, J. R., Chinsky, J. M., Wynn, R. M., Cox, R. P., Chuang, D. T. Molecular and biochemical basis of intermediate maple syrup urine disease: occurrence of homozygous G245R and F364C mutations at the E1-alpha locus of Hispanic-Mexican patients. J. Clin. Invest. 95: 954-963, 1995. [PubMed: 7883996] [Full Text: https://doi.org/10.1172/JCI117804]
Chuang, J. L., Wynn, R. M., Moss, C. C., Song, J., Li, J., Awad, N., Mandel, H., Chuang, D. T. Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients. J. Biol. Chem. 279: 17792-17800, 2004. [PubMed: 14742428] [Full Text: https://doi.org/10.1074/jbc.M313879200]
Edelmann, L., Wasserstein, M. P., Kornreich, R., Sansaricq, C., Snyderman, S. E., Diaz, G. A. Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. Am. J. Hum. Genet. 69: 863-868, 2001. [PubMed: 11509994] [Full Text: https://doi.org/10.1086/323677]
Flaschker, N., Feyen, O., Fend, S., Simon, E., Schadewaldt, P., Wendel, U. Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J. Inherit. Metab. Dis. 30: 903-909, 2007. [PubMed: 17922217] [Full Text: https://doi.org/10.1007/s10545-007-0579-x]
Nellis, M. M., Kasinski, A., Carlson, M., Allen, R., Schaefer, A. M., Schwartz, E. M., Danner, D. J. Relationship of causative genetic mutations in maple syrup urine disease with their clinical expression. Molec. Genet. Metab. 80: 189-195, 2003. [PubMed: 14567968] [Full Text: https://doi.org/10.1016/s1096-7192(03)00144-6]
Nobukuni, Y., Mitsubuchi, H., Akaboshi, I., Indo, Y., Endo, F., Yoshioka, A., Matsuda, I. Maple syrup urine disease: complete defect of the E1-beta subunit of the branched chain alpha-ketoacid dehydrogenase complex due to a deletion of an 11-bp repeat sequence which encodes a mitochondrial targeting leader peptide in a family with the disease. J. Clin. Invest. 87: 1862-1866, 1991. [PubMed: 2022752] [Full Text: https://doi.org/10.1172/JCI115209]