Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach

We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non‐pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX‐related disorders is crucial for an adequate clinical follow‐up and accurate genetic counseling of at‐risk family members. Molecular screening of ARX gene is frequent in patients with intellectual disability (ID) presenting with infantile epilepsy or m...
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: Original Article Source Type: research

Related Links:

We report a 6-year-old girl with GLUT1-DS, which is caused by a novel heterozygous variant c.109dupC of the SLC2A1 gene. The dominating clinical features were ataxia, epilepsy started at 4 years, acquired microcephaly, and mild intellectual disability. Treatment with ketogenic diet showed clinical improvement with the reduction of ataxia and seizure control in a 10-month follow-up period.
Source: Journal of Pediatric Neurosciences - Category: Neuroscience Authors: Source Type: research
Mutations of the ATP1A3 gene are associated with a wide spectrum of neurological disorders including rapid onset dystonia-parkinsonism and alternating hemiplegia of childhood (AHC). The genotype-phenotype correlations in these cases remain unclear however. We here report a pediatric case of catastrophic early life epilepsy, respiratory failure, postnatal microcephaly, and severe developmental disability associated with a novel heterozygous ATP1A3 mutation.
Source: Brain and Development - Category: Neurology Authors: Tags: Case Report Source Type: research
Abstract PURPOSE OF REVIEW: Hyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions. RECENT FINDINGS: Mutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN...
Source: Epilepsy Curr - Category: Neurology Authors: Tags: Curr Neurol Neurosci Rep Source Type: research
AbstractPurpose of ReviewHyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.Recent FindingsMutations inADCY5 andPDE10A have been identified as important causes of childhood-onset dyskinesias andKMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations inATP1A3,FOXG1,GNAO1,GRIN1,FRRS1L, andTBC1D24 is rev...
Source: Current Neurology and Neuroscience Reports - Category: Neuroscience Source Type: research
We report a 3-year-old girl with short stature, mild developmental delay and intellectual disability, minor brain anomalies and very few dysmorphic features including unusual stroma of the irises and corectopia. Exome sequencing reported a de novo pathogenic variant on the ACTB gene. The present report adds a new ocular finding to the phenotypic spectrum which may be mild. PMID: 29024830 [PubMed - as supplied by publisher]
Source: European Journal of Medical Genetics - Category: Genetics & Stem Cells Authors: Tags: Eur J Med Genet Source Type: research
We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45, which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and bra...
Source: European Journal of Medical Genetics - Category: Genetics & Stem Cells Authors: Tags: Eur J Med Genet Source Type: research
This article provides an overview of burden of neurological diseases in Canada to set the stage for the in-depth systematic reviews of the 14 priority neurological conditions presented in subsequent articles in this issue. PMID: 27153747 [PubMed - as supplied by publisher]
Source: Neurotoxicology - Category: Neurology Authors: Tags: Neurotoxicology Source Type: research
Conclusions: This cohort illustrates the expanding phenotypic and genotypic variability of ATP1A3 mutations even within the RDP diagnosis suggesting that systematic testing of a wider clinical spectrum of patients is warranted.Disclosure: Dr. Meijer has nothing to disclose. Dr. Lubarr has nothing to disclose. Dr. Greene has nothing to disclose. Dr. Frucht has received personal compensation for activities with Merz Pharmaceuticals as a consultant. Dr. Raymond has nothing to disclose. Dr. Severt has received personal compensation for activities with Teva, Allergan, Impax, and Lundbeck. Dr. Shanker has nothing to disclose. Dr...
Source: Neurology - Category: Neurology Authors: Tags: Movement Disorders: Ataxia and Dystonia Source Type: research
OBJECTIVE: To better characterize the clinical presentation of functional movement disorders. BACKGROUND: Functional (psychogenic) movement disorders are receiving greater attention as valid and treatable neurologic disorders. Unfortunately, the often long list of complaints with variable presentations may hamper timely diagnosis and treatment. METHODS: We reviewed 113 charts retrospectively of patients presenting to the National Institutes of Health. Patients were referred from 44 states and the District of Columbia, with the majority presenting from the local Washington D.C. metropolitan area. Most patients were diagnose...
Source: Neurology - Category: Neurology Authors: Tags: Movement Disorders: Miscellaneous Source Type: research
Abstract INTRODUCTION: Gabapentin has been used in the management of neuropathic pain, epilepsy and occasionally movement disorders. METHODS: A four-year retrospective, observational study analysed the use of gabapentin for severe dystonia in children at the Evelina London Children's Hospital. Motor severity was classified according to the Gross Motor Function Classification System (GMFCS), Dystonia Severity Assessment Plan (DSAP) and levels of impairment in activities of daily living were graded according to the WHO International Classification of Functioning, Disability and Health, Children &Youth versi...
Source: European Journal of Paediatric Neurology - Category: Neurology Authors: Tags: Eur J Paediatr Neurol Source Type: research
More News: Brain | Disability | Dystonia | Epilepsy | Genetics | Neurology | Study