BCKDK – branched-chain ketoacid dehydrogenase kinase deficiency

Branched-chain ketoacid dehydrogenase kinase deficiency is an autosomal recessive metabolic disorder caused by biallelic loss-of-function variants in the BCKDK gene, leading to depletion of branched-chain amino acids (BCAAs) and a treatable neurodevelopmental phenotype ([PMID:36729635]).

Genetic analysis in 21 patients from 13 unrelated families confirmed autosomal recessive inheritance, with a spectrum of inactivating and missense variants identified in BCKDK ([PMID:36729635]). All patients exhibited global neurodevelopmental delay; 18/21 had gross motor impairment (five with GMF level III or worse), 16/16 had intellectual disability, 17/17 had language impairment, 12/17 met criteria for autism spectrum disorder, 9/21 had seizures, 3/21 had sensorineural hearing loss, 4/20 had feeding difficulties, and 17/20 developed microcephaly during follow-up ([PMID:36729635]). Movement disorders including hyperkinetic movements (1), truncal ataxia (1), and dystonia (2) were observed in three patients ([PMID:36729635]).

Newborn screening using dried blood spot amino acid profiling revealed significantly lower BCAA levels compared to controls, enabling early diagnosis ([PMID:36729635]). Therapeutic intervention with a high-protein diet (≥2 g/kg/day) and BCAA supplementation (100–250 mg/kg/day) led to significant increases in plasma BCAA (p < 0.001) and stabilization or improvement of motor function in 13/13 and head circumference in 11/15 treated patients, respectively ([PMID:36729635]). Notably, none of the three patients treated before two years of age developed autism, and the earliest treated patient (8 months) demonstrated normal development at three years ([PMID:36729635]).

Functional studies of two homozygous variants, c.520C>G (p.Arg174Gly) and c.1166T>C (p.Leu389Pro), demonstrated a splicing defect and complete loss of kinase activity, respectively. Patient-derived fibroblasts showed undetectable or barely detectable BCKDK protein and its phosphorylated substrate, resulting in increased BCKD complex activity and rapid BCAA catabolism. Dietary intervention in one patient normalized plasma BCAA and improved growth and neurobehavioral outcomes ([PMID:24449431]).

The combined genetic, clinical, and experimental evidence supports a loss-of-function mechanism and establishes a definitive association between BCKDK and branched-chain ketoacid dehydrogenase kinase deficiency. This treatable disorder warrants inclusion in newborn screening panels to enable early dietary intervention and prevent irreversible neurodevelopmental decline.

References

• Brain • 2023 • BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening. PMID:36729635
• Human mutation • 2014 • Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients. PMID:24449431

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