BCKDHB – Maple Syrup Urine Disease

Autosomal recessive biallelic variants in BCKDHB underlie maple syrup urine disease, a branched-chain amino acid oxidation defect. A classic neonatal form presents with feeding difficulties, poor tone, encephalopathy and characteristic leucine-derived ketoacid elevation, whereas intermittent and intermediate forms manifest later with episodic ataxia and encephalopathy.

Genetic evidence is definitive: over 200 unrelated probands from >100 families have been reported with missense, nonsense, frameshift, splice and large-deletion alleles in BCKDHB. Key variants include c.1037A>G (p.Gln346Arg) affecting E1β subunit assembly (PMID:22326532), and founder alleles such as p.Arg183Pro in Ashkenazi Jewish individuals (carrier frequency ~1/113) (PMID:11509994). Segregation studies demonstrate co-segregation in multiple sibships with compound heterozygosity and homozygosity consistent with recessive inheritance.

The variant spectrum spans at least 250 distinct alleles: missense (~60%), predicted loss-of-function (nonsense, frameshift, splice; ~30%), and structural deletions (~10%). Recurrent and population-specific variants have been documented in Ashkenazi Jewish, Portuguese Gypsy and Thai cohorts. The prevalence of biallelic BCKDHB variants in screened populations supports a global incidence of ~1:200,000 newborns.

Functional assays and in silico modeling support a loss-of-function mechanism. Structural modeling of novel missense variants reveals disruption of β–β and α–β subunit contacts, leading to enzyme instability. Eukaryotic expression of p.Ala137Val in vitro shows abolished dehydrogenase activity, confirming pathogenicity (PMID:26830710).

No convincing contrary evidence has been reported; variant carriers are asymptomatic heterozygotes, and genotype–phenotype correlations generally align with residual enzyme activity. Expanded newborn screening improves detection of variant forms but occasional intermittent presentations escape early diagnosis.

In summary, BCKDHB-related MSUD is a clinically actionable autosomal recessive disorder. Molecular diagnosis of BCKDHB variants informs prognosis, guides dietary management and enables carrier and prenatal testing. Key take-home: Genetic testing for BCKDHB variants is essential for diagnosis of classical and non-classical MSUD and supports early intervention to reduce morbidity.

References

• Gene • 2012 • Two novel mutations in the BCKDHB gene (R170H, Q346R) cause the classic form of maple syrup urine disease (MSUD). PMID:22326532
• American Journal of Human Genetics • 2001 • Maple syrup urine disease: identification and carrier-frequency determination of a novel founder mutation in the Ashkenazi Jewish population. PMID:11509994
• Clinical Genetics • 2016 • Molecular and phenotypic characteristics of seven novel mutations causing branched-chain organic acidurias. PMID:26830710

Evidence Based Scoring (AI generated)