A Longer Polyalanine Expansion Mutation in the ARX Gene Causes Early Infantile Epileptic Encephalopathy with Suppression-Burst Pattern (Ohtahara Syndrome)

Abstract

Early infantile epileptic encephalopathy with suppression-burst pattern (EIEE) is one of the most severe and earliest forms of epilepsy, often evolving into West syndrome; however, the pathogenesis of EIEE remains unclear. ARX is a crucial gene for the development of interneurons in the fetal brain, and a polyalanine expansion mutation of ARX causes mental retardation and seizures, including those of West syndrome, in males. We screened the ARX mutation and found a hemizygous, de novo, 33-bp duplication in exon 2, 298_330dupGCGGCA(GCG)9, in two of three unrelated male patients with EIEE. This mutation is thought to expand the original 16 alanine residues to 27 alanine residues (A110_A111insAAAAAAAAAAA) in the first polyalanine tract of the ARX protein. Although EIEE is mainly associated with brain malformations, ARX is the first gene found to be responsible for idiopathic EIEE. Our observation that EIEE had a longer expansion of the polyalanine tract than is seen in West syndrome is consistent with the findings of earlier onset and more-severe phenotypes in EIEE than in West syndrome.

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

“…To our knowledge, this is only the second report of an ARX gene mutation causing OS and the first with an inherited mutation. Interestingly, in the cases reported by Kato et al, 19 both had a 33-bp duplication in exon 2 of ARX rather than a protein truncating mutation. This supports the conclusion that modified function rather than complete loss of function of the ARX protein may be the cause of OS in our family.…”

“…Similar to mental retardation, there is a 30% excess of males with OS, indicative of the involvement of genes located on the X chromosome, 18 and an ARX polyalanine expansion mutation has recently been described as a cause of OS in two out of three sporadic male cases. 19 ARX is expressed in GABAergic neurons, and Kato et al 19 hypothesized that dysfunction of the GABAergic system is critical to the neuropathology of EIEE and WS. In addition, heterozygous mutations in the STXBP1 gene seem to cause OS in both males and females.…”

Two Distinct De novo Pathogenic Sequence Variants in the SCN2A Gene in Children with Early Infantile Epileptic Encephalopathy/Ohtahara Syndrome

“…EIEE/OS belongs to a group of genetically and clinically distinct epileptic encephalopathies. Approximately 75% of EIEE may progress to West syndrome, a diagnosis with an adverse prognosis including the arrest of psychomotor development and abnormal EEG pattern negatively affecting brain functions [42]. Wolff et al defined two groups of patients with distinct seizure onset (before or after three months of age).…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…Nonmalformation phenotypes are associated with missense mutations outside of the homeobox or expansion of the second polyA tract, and include X-linked infantile spasms (ISSX)/West syndrome, Partington syndrome (mental retardation with mild distal dystonia), and nonspecific X-linked mental retardation [89,92]. Expansions in the first polyA tract cause ISSX/West syndrome (tonic spasms with clustering, severe psychomotor delay, and hypsarrhythmia on EEG) [93,94], a severe epileptic-dyskinetic encephalopathy [90], tonic seizures and dystonia without infantile spasms [95], and Ohtahara syndrome (Table 1) [96]. No neuropathologic studies of the brain of patients with "nonmalformation" phenotypes are available to confirm that structural abnormalities are, in fact, absent at the microscopic level.…”