BCKDHA – Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder resulting from deficient activity of the branched-chain α-ketoacid dehydrogenase complex. The E1α subunit, encoded by BCKDHA, is essential for decarboxylation of branched-chain keto acids. Biallelic loss-of-function or deleterious missense variants in BCKDHA cause classic MSUD, characterized by ketoacidosis, irritability, lethargy, and coma due to toxic accumulation of leucine, isoleucine and valine ([PMID:8037208]).

Inheritance is autosomal recessive with confirmed segregation in consanguineous families and prenatal testing in an affected pedigree, underscoring a complete penetrance in homozygotes. Carrier screening in high-risk populations, such as Mennonites and Portuguese Gypsies, has revealed founder effects for recurrent alleles, facilitating targeted molecular diagnosis.

Case reports have identified numerous pathogenic variants. A novel nonsense change c.529C>T (p.Gln177Ter) was found homozygous in a late-diagnosed patient from a consanguineous family; prenatal testing accurately identified heterozygous status in the fetus ([PMID:19240989]). Other reported variants include frameshift deletions and missense substitutions across the catalytic domain.

In a founder study of Portuguese Gypsies, the c.117delC (p.Arg40GlyfsTer23) deletion was detected in all patients, indicating a mutational hotspot and enabling community-specific carrier screening ([PMID:19456321]). Multi-ethnic cohorts have expanded the variant spectrum to include intronic splicing, gross deletions, and hypomorphic alleles associated with intermediate or variant MSUD phenotypes.

Functional assays corroborate pathogenicity: the p.Tyr368Cys substitution disrupts E1α–E1β assembly and accelerates subunit degradation in transfected cells, while the intronic c.288+9C>T change activates a cryptic splice site causing aberrant transcripts subject to nonsense-mediated decay ([PMID:20431954]). These data support haploinsufficiency and loss of enzymatic activity as the disease mechanism.

Integration of genetic and experimental evidence confirms a definitive gene–disease relationship. Molecular diagnosis of BCKDHA variants guides early therapeutic intervention, dietary management, and reproductive counseling. Key Take-home: Comprehensive BCKDHA testing is clinically actionable for diagnosis, carrier screening, prenatal testing, and management of MSUD.

References

• American journal of human genetics • 1994 • Molecular basis of maple syrup urine disease: novel mutations at the E1 alpha locus that impair E1(alpha 2 beta 2) assembly or decrease steady-state E1 alpha mRNA levels of branched-chain alpha-keto acid dehydrogenase complex. PMID:8037208
• Journal of inherited metabolic disease • 2009 • Prenatal diagnosis of a novel mutation, c.529C>T (p.Q177X), in the BCKDHA gene in a family with maple syrup urine disease. PMID:19240989
• Journal of inherited metabolic disease • 2010 • Functional characterization of the novel intronic nucleotide change c.288+9C>T within the BCKDHA gene: understanding a variant presentation of maple syrup urine disease. PMID:20431954
• Annals of human genetics • 2009 • Revisiting MSUD in Portuguese Gypsies: evidence for a founder mutation and for a mutational hotspot within the BCKDHA gene. PMID:19456321

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