ORPHA: 268145, 268162, 268173, 511;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p21.2 | Maple syrup urine disease, type II | 620699 | Autosomal recessive | 3 | DBT | 248610 |
A number sign (#) is used with this entry because maple syrup urine disease type II (MSUD2) is caused by homozygous or compound heterozygous mutation in the DBT gene (248610), which encodes a subunit of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), on chromosome 1p21.
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 MSUD2: 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 MSUD2 in the patients reported by Tsuruta et al. (1998) was consistent with autosomal recessive inheritance.
In a case of classic MSUD, Herring et al. (1991) identified a 124-bp deletion in the DBT gene encoding the E2 component of the BCKDH complex (248610.0001).
In a cell line from a patient with thiamine-responsive MSUD, Fisher et al. (1991) identified compound heterozygosity for mutations in the DBT gene (248610.0002 and 248610.0003).
In several Japanese patients with the intermediate form of MSUD, Tsuruta et al. (1998) identified homozygosity or compound heterozygosity for mutations in the DBT gene (248610.0005-248610.0008).
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]
Fisher, C. W., Lau, K. S., Fisher, C. R., Wynn, R. M., Cox, R. P., Chuang, D. T. A 17-bp insertion and a phe215-to-cys missense mutation in the dihydrolipoyl transacylase (E2) mRNA from a thiamine-responsive maple syrup urine disease patient WG-34. Biochem. Biophys. Res. Commun. 174: 804-809, 1991. [PubMed: 1847055] [Full Text: https://doi.org/10.1016/0006-291x(91)91489-y]
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]
Herring, W. J., Litwer, S., Weber, J. L., Danner, D. J. Molecular genetic basis of maple syrup urine disease in a family with two defective alleles for branched chain acyltransferase and localization of the gene to human chromosome 1. Am. J. Hum. Genet. 48: 342-350, 1991. [PubMed: 1990841]
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]
Tsuruta, M., Mitsubuchi, H., Mardy, S., Miura, Y., Hayashida, Y., Kinugasa, A., Ishitsu, T., Matsuda, I., Indo, Y. Molecular basis of intermittent maple syrup urine disease: novel mutations in the E2 gene of the branched-chain alpha-keto acid dehydrogenase complex. J. Hum. Genet. 43: 91-100, 1998. [PubMed: 9621512] [Full Text: https://doi.org/10.1007/s100380050047]