Branched-Chain Ketoacid Dehydrogenase Kinase Deficiency via the BCKDK Gene

Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) is a neurodevelopmental disorder characterized by intellectual disability and epileptic activity. Patients present with psychomotor delay within the first two years of life, most often noticed as delayed milestones such as walking and talking (Novarino et al. 2012; García-Cazorla et al. 2014). Microcephaly, without any abnormalities detected by MRI, is common in BCKDKD. Patients may experience febrile or afebrile seizures, but even in absence of seizures epileptic activity is detected via EEG. BCKDKD patients have moderate to severe intellectual disability and have noticeable language and social deficits resembling autism spectrum disorders. Reduced plasma levels of branched-chain amino acids (BCAAs) have been seen in all reported BCKDKD patients.

BCKDKD is inherited in an autosomal recessive manner and is caused by variants in the BCKDK gene. Missense, nonsense, splice site, and frameshift variants in BCKDK have been reported (Novarino et al. 2012; García-Cazorla et al. 2014).

BCKDK encodes the kinase BDK. Branched-chain amino acids (BCAAs) are required for a variety of biological processes. BCAAs are broken down by the BCKDH complex. BCKDH activity is regulated by the kinase BDK. When BCKDH is phosphorylated by BDK it is inactive and cannot break down BCAAs. When BCKDK is mutated BDK function is lost and BCKDH remains unphosphorylated and completely active (Harris et al. 2005). High BCKDH activity leads to reduced serum levels of BCAAs. Imbalance of these amino acids is believed to underlie the neurological phenotypes associated with BCKDKD. BDK knockout mice show reduced levels of BCAAs in the blood, brain, heart, muscle, and kidney. In addition, BDK-/- mice show impaired growth, have an abnormal gait, and are prone to seizures (Joshi et al. 2006). There is evidence in mice and humans that supplementation with diets high in BCAAs can help treat some of the symptoms of BCKDKD (Joshi et al. 2006; Novarino et al. 2012; García-Cazorla et al. 2014).

The frequency of BCKDK mutations in BCKDKD or epilepsy cases is currently unknown, but all reported BCKDK mutations would be detected via this sequencing method (Novarino et al. 2012; García-Cazorla et al. 2014).

This test provides full coverage of all coding exons of the BCKDK gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.