X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX.
ABSTRACT 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.
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.
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).
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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ABSTRACT: Background Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in approximately 40% of patients. We hypothesised that unexplained IS cases represent a large collection of rare single-gene disorders.Methods We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n=44) followed by targeted sequencing of 35 known epilepsy genes (n=8) or whole-exome sequencing (WES) of familial trios (n=18) to search for rare inherited or de novo mutations.ResultsaCGH analysis revealed de novo variants in 7% of patients (n=3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n=1/14) and STXBP1 (n=1/8). By contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n=8) did not identify further mutations. Finally, WES (n=18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK, and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes.InterpretationOur results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS.Human Molecular Genetics 04/2014; DOI:10.1093/hmg/ddu199 · 6.68 Impact Factor
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ABSTRACT: The genomic era has enabled the application of molecular tools to the solution of many of the genetic epilepsies, with and without comorbidities. Massively parallel sequencing has recently reinvigorated gene discovery for the monogenic epilepsies. Recurrent and novel copy number variants have given much-needed impetus to the advancement of our understanding of epilepsies with complex inheritance. Superimposed upon that is the phenotypic blurring by presumed genetic modifiers scattering the effects of the primary mutation. The genotype-first approach has uncovered associated syndrome constellations, of which epilepsy is only one of the syndromes. As the molecular genetic basis for the epilepsies unravels, it will increasingly influence the classification and diagnosis of the epilepsies. The ultimate goal of the molecular revolution has to be the design of treatment protocols based on genetic profiles, and cracking the 30% of epilepsies refractory to current medications, but that still lies well into the future. The current focus is on the scientific basis for epilepsy. Understanding its genetic causes and biophysical mechanisms is where we are currently positioned: prizing the causes of epilepsy "out of the shadows" and exposing its underlying mechanisms beyond even the ion-channels.The Application of Clinical Genetics 08/2011; 4:113-25. DOI:10.2147/TACG.S7407