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.
- SourceAvailable from: Mario Mastrangelo
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- "X-linked myoclonic seizures, spasticity, and intellectual disability syndrome was mainly related to a missense mutation (1058C>T/P353L) within the homeodomain of the Aristaless-related homeobox gene, and an X-linked recessive transmission was observed. The obligate female typically presented osteotendineous hyperreflexia . "
ABSTRACT: Early-onset epileptic encephalopathies are severe disorders in which seizure recurrence impairs motor, cognitive, and sensory development. In recent years, next-generation sequencing technologies have led to the detection of several pathogenic new genes. A PubMed search was carried out using the entries "early onset epileptic encephalopathies," "early infantile epileptic encephalopathies," and "next generation sequencing." The most relevant articles written on this subject between 2000 and 2015 were selected. Here we summarize the related contents concerning the pathogenic role and the phenotypic features of 20 novel gene-related syndromes involved in the pathogenesis of early-onset epileptic encephalopathy variants. Despite the increasing number of single early-onset epileptic encephalopathy genes, the clinical presentations of these disorders frequently overlap, making it difficult to picture a systematic diagnostic workup. In any case, a progressive approach should guide the choice of molecular genetic investigations. It is suggested that clinicians pay particular attention to mutated genes causing potentially treatable conditions in order to take advantage of expert counseling. Copyright © 2015 Elsevier Inc. All rights reserved.Pediatric Neurology 01/2012; 46(1):24-31. DOI:10.1016/j.pediatrneurol.2011.11.003 · 1.70 Impact Factor
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- "Discovery of the gene for action myoclonus renal failure syndrome (AMRF)96 led on to its role as a gene for progressive myoclonus epilepsy (PME) without renal failure.97 Similarly, identification of the ARX gene for intellectual disability frequently associated with seizures112 led to its link to a myoclonic epilepsy with spasticity and intellectual disability.113 The ARX spectrum disorders proliferated from that point and we refer the reader to recent reviews in that area.119,120 "
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
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- "Diseases caused by mutations in this gene include: West syndrome (Stromme et al. 2002a), Partington syndrome (Stromme et al. 2002b), XLAG (Kitamura et al. 2002), XLMR (Bienvenu et al. 2002), Proud Syndrome (Kato et al. 2004), and various forms of epilepsy (Stromme et al. 2002a, b; Scheffer et al. 2002). There seems to be a genotype/phenotype correlation between the location and nature of the mutation and the severity of the phenotype. "
ABSTRACT: Intellectual disability (ID), also referred to as mental retardation (MR), is frequently the result of genetic mutation. Where ID is present together with additional clinical symptoms or physical anomalies, there is often sufficient information available for the diagnosing physician to identify a known syndrome, which may then educe the identification of the causative defect. However, where co-morbid features are absent, narrowing down a specific gene can only be done by 'brute force' using the latest molecular genetic techniques. Here we attempt to provide a systematic review of genetic causes of cases of ID where no other symptoms or co-morbid features are present, or non-syndromic ID. We attempt to summarize commonalities between the genes and the molecular pathways of their encoded proteins. Since ID is a common feature of autism, and conversely autistic features are frequently present in individuals with ID, we also look at possible overlaps in genetic etiology with non-syndromic ID.Journal of Neurodevelopmental Disorders 12/2010; 2(4):182-209. DOI:10.1007/s11689-010-9055-2 · 3.27 Impact Factor