Branched-Chain Keto Acid Dehydrogenase Kinase Deficiency

A number sign (#) is used with this entry because BCKDK deficiency is caused by homozygous mutation in the BCKDK (614901) gene on chromosome 16p11.

Clinical Features

Novarino et al. (2012) studied 3 consanguineous families with autism, epilepsy, intellectual disability, and reduced branched-chain amino acids (BCAAs). All patients were born at full term to unaffected parents. The first family (558), of Turkish origin, had 2 affected daughters. The first daughter developed normally until the age of 18 months, when she had her first seizure. She met criteria for autism by 15 years of age. At ages 20 and 21, electroencephalogram (EEG) detected extratemporal and generalized epileptiform abnormalities, and despite treatment with anticonvulsants, she had tonic-clonic seizures every 3 months lasting 3 to 4 minutes each. Her sister was similarly affected. The second family (18) was of Egyptian origin and consisted of an affected brother and sister. The girl had had a febrile seizure at 1 year of age and a generalized nonfebrile seizure at 8 years of age. EEG at age 8 showed frequent focal spike wave complexes over the left temporal region consistent with left temporal epileptogenic dysfunction. Her similarly affected brother had 4 febrile seizures at the age of 12 months; he was started on valproate and had a recurrence of febrile seizures every 4 to 5 months subsequently. At age 2 years 5 months he started on phenobarbital and had not had a seizure since. The family history was notable for a paternal uncle with schizophrenia, a second-degree cousin with intellectual disability, and a distant cousin also with schizophrenia. A third consanguineous family (1435) of Libyan origin consisted of 2 affected brothers. The first boy at 9 years of age was able to follow simple directions but did not speak. EEG was normal at age 11 years. He met criteria for autism on several scales. The similarly affected second brother had abnormal EEG at age 7, with right temporal slowing and rare surface negative frontal sharp waves.

Clinical Management

Novarino et al. (2012) reported that the children in the Turkish (558) and Egyptian (18) families were being treated with supplemental BCAAs. Transient superelevations of BCAAs occurred about 1 hour after ingestion. A trend toward normalization of BCAAs in the fasting state was observed. Urine organic acids showed no evidence of BCAA-related organic acids. Long-term effects were not known at that time; no adverse effects were reported.

Molecular Genetics

In 3 consanguineous families with autism, epilepsy, and intellectual disability, Novarino et al. (2012) detected homozygosity for mutation in the branched-chain keto acid dehydrogenase kinase (BCKDK) gene (614901.0001-614901.0003). Two families carried null mutations (nonsense and frameshift) and 1 family carried a missense mutation of a conserved amino acid. Induced pluripotent stem cells generated from fibroblasts of the healthy brother and the 2 sisters from family 558 all showed normal function and differentiation into neural stem cells. There was no notable difference in the morphology or proliferation of cells from wildtype and mutant genotypes. Cultured neurons also functioned normally, arguing against a major cell-autonomous role for BCKDK in the pathogenesis of disease.

Animal Model

Joshi et al. (2006) showed that Bckdk-null mice showed increased basal activity of the BCKDH complex as well as reduced BCAAs in various tissues. Bckdk-null mice were born at expected mendelian ratios and were healthy at birth but showed growth retardation that could be recovered by feeding a BCAA-rich diet. Adults developed neurologic abnormalities such as tremors, epileptic seizures, and hindlimb clasping phenotypes observed in some other mouse models of autism spectrum disorders. Brain histology was normal.

Novarino et al. (2012) quantified amino acid concentrations in brain homogenates from postnatal day 14 Bckdk wildtype and knockout mice. In addition to expected reduced brain BCAAs in Bckdk-null mice, there were also significantly increased levels of threonine, phenylalanine, tyrosine, histidine, and methionine. These large neutral amino acids are the same as those carried by the SLC7A5 (600182) and SLC3A2 (158070) transporters across the blood-brain barrier, which suggested imbalanced blood-brain barrier transport in these mice.

Novarino et al. (2012) studied the effects of 2 chow diets, one containing 2% BCAAs and the other an enriched diet containing 7% BCAAs, on the neurologic phenotypes of Bckdk-null mice. Mice raised on the BCAA-enriched diet were phenotypically normal. On the 2% BCAA diet, however, Bckdk-null mice had clear neurologic abnormalities not seen in wildtype mice, such as seizures and hindlimb clasping, that appeared within 4 days of instituting the 2% BCAA diet. These neurologic deficits were completely abolished within a week of the Bckdk-null mice starting a BCAA-enriched diet, suggesting that this is an inducible and reversible phenotype.