Abstracts

RATIONALE: To characterise and map an Australian family with an infantile myoclonic epilepsy. To determine if the disorder is distinct from X-linked infantile spasms which maps to Xp22,and typically presents with infantile spasms and unaffected carrier females.
METHODS: All affected and unaffected family members in the main branch of the family underwent detailed characterisation including seizure questionnaire, medical history, neurological examination and EEG studies. Molecular genetic analysis included linkage studies to confirm mapping of the disorder to the X chromosome and a search for appropriate candidate genes.
RESULTS: A history was obtained on 271 family members. The main family comprised 6 affected males and three obligate female carriers. The mean age of onset of seizures was 7 months. All affected boys had tonic-clonic seizures and in 5 boys (information was not available on 1), myoclonus was prominent. Tonic seizures occurred in 2, and atonic seizures in 1. Infantile spasms may have occurred in one boy but did not occur in 4. Intellectual disability varied from moderate (1), severe (3), to profound (2); the latter two boys died by 4 years. All living affected males had generalized spasticity. EEG studies showed generalized spike wave activity in 3 living affected males, and all 4 living affected males had diffuse background slowing.
All obligate carrier women had hyperreflexia. The matriarch of the family, aged 68 years, had onset of progressive myoclonus, ataxia and spasticity at 58 years for which no aetiology could be found.
Mapping studies were consistent with X-linkage with a maximum lod score of 1.8 to a 25cM interval on Xp. Five candidate genes were screened negative for mutations in this family. These were: STK9 (a serine-threonine kinase 9); AOE372 (a thioredoxin peroxidase); PCYT1B (a choline esterase); Hs.40065 (unknown function); and IL1RAPL1 (interleukin receptor accessory protein like 1). Among these, disease-causing mutations were previously found only in the IL1RAPL1 gene in cases with non-specific mental retardation. Apart from several single nucleotide polymorphisms (SNPs), no disease causing mutations have yet been identified.
CONCLUSIONS: We describe a new syndrome of infantile myoclonic epilepsy with spasticity and severe intellectual disability in males. This syndrome is clinically distinct from X-linked infantile spasms. The occurrence of hyperreflexia in carrier females may be a useful clinical marker, and they may be at risk of late onset progressive neurological disease with myoclonus. The gene is presently localized to a very large region on the X chromosome and it is unclear whether it is allelic with X-linked infantile spasms or is genetically heterogeneous.
Support: National Health and Medical Research Council of Australia, Epilepsy Foundation of Victoria, Bionomics
Disclosure: Salary - Australian Biotechnology company Bionomics provides salaries for some workers. Grant - Bionomics provides research grants to the laboratories. Equity - Nil. Consulting - Prof. Berkovic is on the Bionomics Scientific Advisory Board. Ownership - Nil. Materials - Nil. Stock - Bionomics share options are held by some authors. Royalties - Nil. Honoraria - Nil. Other - Nil.