A number sign (#) is used with this entry because branched-chain keto acid dehydrogenase kinase deficiency (BCKDKD) is caused by homozygous mutation in the BCKDK (614901) gene on chromosome 16p11.

Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) is a neurodevelopmental disorder characterized by autism, impaired intellectual development, and microcephaly (Tangeraas et al., 2023).

Novarino et al. (2012) studied 3 consanguineous families with autism, epilepsy, impaired intellectual development, 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.

Tangeraas et al. (2023) described 21 patients from 13 families with BCKDK deficiency and mutation in the BCKDK gene who were recruited from several countries. The average age at diagnosis was 5.8 years. Most patients were born at term and had normal head circumferences; however, 80% developed microcephaly. All of the patients had global developmental delay, all patients older than 2 years of age had a language impairment, and 19 patients had gross motor function impairment. Other neurologic features included epilepsy in 9 patients, movement disorders in 3, impaired intellectual development in 16, hyperreflexia in 3, and clumsiness in 12. Twelve patients had autism spectrum disorder. Other clinical features included dry skin in 2 patients and acrodermatitis enteropathica in 3. Brain MRIs were normal in 11 of 19 patients, and findings were nonspecific in the other 8, including agenesis of the corpus callosum in 2 patients and a thin corpus callosum in 2 patients.

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.

Tangeraas et al. (2023) reported that treatment with high protein diet and branch-chain amino acid supplementation in 19 patients resulted in improved plasma branched-chain amino acid levels and a trend towards improved CSF branched- chain amino acid levels. Outcomes included stabilization of head circumference in 11 patients, language improvement in 3 patients, and improvement or stabilization of motor function in 13 patients. None of the patients who were treated before 2 years of age developed autism spectrum disorder.

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.

Tangeraas et al. (2023) reported biallelic mutations in the BCKDK gene in 21 patients from 13 families with BCKDK deficiency recruited from several countries; 20 patients had homozygous mutations and 1 patient had compound heterozygous mutations. The mutations included 5 nonsense mutations (see, e.g., R156X, 614901.0001), 2 splicing mutations (see, e.g., c.264+1G-C, 614901.0004) 2 missense mutations, and 1 in-frame deletion.

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.