Amino acid or protein metabolism disease with epilepsy
-Rare neurologic disease
Disorder of branched-chain amino acid metabolism
-Rare genetic disease
Comment:
Case study with 6 patients in 3 consanguineous families identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) . The encoded protein is responsible for phosphorylation-mediated inactivation of the E1a subunit of branched-chain ketoacid dehydrogenase (BCKDH)(PMID: 22956686). Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome (PMID:22956686).
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 ... 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.
In 3 consanguineous families with autism, epilepsy, and intellectual disability, Novarino et al. (2012) detected homozygosity for mutation in the branched-chain ketoacid dehydrogenase kinase (BCKDK) gene (614901.0001-614901.0003). Two families carried null mutations (nonsense and frameshift) and 1 family ... In 3 consanguineous families with autism, epilepsy, and intellectual disability, Novarino et al. (2012) detected homozygosity for mutation in the branched-chain ketoacid 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.