BCKDK gene mutations as a rare condition responsible for comorbid neurodevelopmental delay, autism, and epilepsy: a case series of four patients.

Introduction: Mutations in the branched-chain keto-acid dehydrogenase kinase gene (BCKDK), leading to low plasma branched-chain amino acids (BCAAs) levels, have been reported as a contributor to comorbid intellectual disability, autism, epilepsy, and neurodevelopmental delay (NDD). Due to the rarity of knowledge about these mutations, the current case series aims to introduce four confirmed cases. Methods: This case series study analyzed children from a neurometabolic clinic. Social and adaptive functions were assessed using the vineland social maturity scale (VSMS). Whole exome sequencing (WES) identified genetic variants filtered using population databases. Candidate variants were confirmed through Sanger sequencing and interpreted based on ACMG guidelines. Results: Four children of unrelated consanguineous families suffering from global NDD and autism were referred to our center. Neuroimaging assessments revealed negligible findings; thus, metabolic tests were sent, in which BCAAs were lower than normal limits. Therefore, genetic testing was done, and genetic variants compatible with BCKDK deficiency were detected. By initiating a BCAAs-rich regimen, the patients had significant improvements in psychomotor and speech development. Conclusion: The diagnosis of BCKDK deficiency should be suspected in patients with NDD and autism, and BCAA supplementation should be initiated as soon as diagnosis confirmation to prevent irreversible brain damage. The results emphasize that early diagnosis and dietary intervention by regulating plasma BCAA levels lead to the prevention of irreversible neurodevelopmental implications.