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From the Department of Medicine (Neurology) (Drs. Scheffer and Berkovic, F.L. Phillips, and G. Parasivam), University of Melbourne, Epilepsy Research Institute, Austin & Repatriation Medical Centre; Department of Neurology (Drs. Scheffer and Berkovic), Royal Children’s Hospital; Neurosciences (Dr. Scheffer), Monash Medical Centre, Melbourne; Cytogenetics and Molecular Genetics (Drs. Wallace, Stromme, Gecz, and Mulley), Women’s and Children’s Hospital, Adelaide, South Australia; Paediatrics (Dr. Hewson), Barwon Health The Geelong Hospital, Geelong, Victoria; Neurology (K. Reardon), St. Vincent’s Hospital, Melbourne, Victoria; and Paediatrics (Dr. Gecz), The University of Adelaide, Australia.
Address correspondence and reprint requests to Associate Professor Ingrid Scheffer, Epilepsy Research Institute, Austin & Repatriation Medical Centre, Level 1, Neurosciences Building, Repatriation Campus, Banksia Street, West Heidelberg VIC 3081, Australia; e-mail: scheffer{at}unimelb.edu.au
Objective: To describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder.
Methods: The authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach.
Results: All six affected boys had myoclonic seizures and TCS; two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2–22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX).
Conclusions: XMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX; MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.
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