BCKDK – Maple Syrup Urine Disease

BCKDK has been implicated in a mild form of maple syrup urine disease (MSUD) via a gain-of-function mechanism. In recent studies, a missense variant, c.486C>G (p.His162Gln), was identified in a neonate with biochemical abnormalities consistent with MSUD, with the same variant segregating in the affected father (PMID:35205278).

Genetic investigations across independent family studies have demonstrated an autosomal dominant inheritance pattern. Affected individuals across 2 families, with at least 3 additional affected relatives overall, exhibited similar biochemical phenotypes. These findings lend robust support to a strong gene-disease relationship (PMID:38736638).

The genetic evidence is primarily based on the detection of the reported missense variant in BCKDK and its segregation within families. The variant, c.486C>G (p.His162Gln), consistently appears in patients with a mild biochemical phenotype of MSUD, thereby underscoring its diagnostic relevance in neonatal screening and subsequent metabolic monitoring (PMID:35205278).

Functional and experimental studies have provided critical insight into the mechanism of pathogenicity. Molecular dynamics simulations revealed that the c.486C>G (p.His162Gln) change results in a conformational alteration of the protein that mitigates inhibitory binding, ultimately leading to increased kinase activity. This gain-of-function effect in BCKDK correlates with the impaired regulation of the branched-chain ketoacid dehydrogenase complex (PMID:38736638).

The combined genetic and functional evidence creates a coherent narrative linking the variant's molecular impact with the observed mild MSUD biochemical phenotype. Although traditional MSUD has been characterized by severe neonatal decompensation, the gain-of-function variants in BCKDK appear to confer a more benign clinical course, which is crucial for both diagnostic stratification and management.

In summary, the identification of the c.486C>G (p.His162Gln) variant in BCKDK provides an important molecular marker for a potentially asymptomatic form of MSUD, facilitating early diagnosis and targeted therapeutic decision-making. Awareness of this association is key to optimizing newborn screening interpretations and guiding clinical management in affected families.

References

• Genes • 2022 • A Gain-of-Function Mutation on BCKDK Gene and Its Possible Pathogenic Role in Branched-Chain Amino Acid Metabolism PMID:35205278
• JIMD reports • 2024 • Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype PMID:38736638

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