Abstract
Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999_1001delCAC; p.Thr334del) of BCKDK. Plasma and cerebrospinal fluid concentrations of BCAA were markedly reduced. Hyperactivity of BCKDH and over-consumption of BCAA were demonstrated by functional tests in cells transfected with the mutant BCKDK. Treatment with pharmacological doses of BCAA allowed the restoring of BCAA concentrations and greatly improved seizure control. Behavioral and developmental skills of the patients improved to a lesser extent. Importantly, a retrospective review of the newborn screening results allowed the identification of a strong decrease in BCAA concentrations on dried blood spots, suggesting that BCKDK is a new treatable metabolic disorder probably amenable to newborn screening programs.
Highlights
This study reports on three patients from an inbred family with branched-chain α-ketoacid dehydrogenase kinase (BCKDK) deficiency
We showed that the mutated BCKDK protein was unable to phosphorylate the E1α-subunit of Branched-chain ketoacid dehydrogenase (BCKDH) complex, leading to an increased consummation of Branched-chain amino acids (BCAA) in the culture media
BCKDK deficiency is a dietary-treatable disorder of BCAA mitochondrial metabolism [11]
Summary
In humans, branched-chain amino acid (BCAA; leucine, isoleucine and valine) homeostasis is essentially under the control of the mitochondrial branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which catalyzes the oxidative decarboxylation of branched short-chain α-ketoacids [1]. Beside their role of substrate for protein synthesis, BCAA are involved in multiple metabolic pathways and play essential functions in growth and development [2,3,4]. Besides classical MSUD, deficiencies in BCAT2 [6], PPM1K [7] and BCKDK [8] genes have recently been identified as disruptors of BCAA homeostasis. We describe the experiments we carried out to confirm the pathogenicity of this new variant and present the clinical follow-up of affected patients under treatment
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