A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).
Specific mutations in at least four genes (whose protein products are essential in lower brain's neuronal and interneuronal functions, including mitochondrial respiratory chains have been identified in unrelated individuals with EIEE and include: (a) the ARX (aristaless-related) homeobox gene at Xp22.13 (EIEE-1 variant); (b) the CDKL5 (SYK9) gene at Xp22 (EIEE-2 variant); (c) the SLC25A22 (GC1) gene at 11p15.5 (EIEE-3 variant); and (d) the Stxbp1 (MUNC18-1) gene at 9q34-1 (EIEE-4 variant).
ARX mutation testing should be undertaken in children aged less than 1 year with Ohtahara syndrome and a movement disorder, and in infants with unexplained neurodegeneration, progressive white matter loss, and cortical atrophy.
Analysis of mutations in 7 genes associated with neuronal excitability and synaptic transmission in a cohort of children with non-syndromic infantile epileptic encephalopathy.
Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern.
This study confirms that ARX is involved in the pathogenesis of cryptogenic early onset epileptic encephalopathy, such as OS, and suggests that the severity of the electroclinical picture is likely to not exclusively correlate with the extent of expansions of the polyalanine tracts, but rather with the functional effect of different pathogenetic mutations.
The Aristaless-related homeobox gene (ARX) is a known intellectual disability (ID) gene that frequently presents with X-linked infantile spasm syndrome as a comorbidity.
Mutations in the Aristaless-related homeobox gene (ARX) have been recognized as a cause of X-linked infantile spasms and sporadic cryptogenic infantile spasms.
The etiology of Ohtahara syndrome is heterogeneous; however, the molecular analysis of ARX should be considered in sporadic or familial male patients with Ohtahara syndrome.
Mutations in the ARX gene have been found in X-linked infantile spasms syndrome, Partington syndrome (mental retardation with dystonic movements of the hands), X-linked lissencephaly with abnormal genitalia, X-linked myoclonus epilepsy with spasticity and intellectual disability, and in nonsyndromic X-linked mental retardation.
Reviewing records of patients with ARX mutations, infantile epilepsies, and psychomotor retardation, we analyzed a family harboring a novel ARX mutation with different phenotypes in males and females, including Ohtahara syndrome.
This disorder is allelic with X-linked infantile spasms (ISSX; MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect.