Emerging topics in FXTAS

This paper summarizes key emerging issues in fragile X-associated tremor/ataxia syndrome (FXTAS) as presented at the First International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2013

EIF4G1 in familial Parkinson's disease: pathogenic mutations or rare benign variants?

International audienceMutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene, encoding a component of the eIF4F translation initiation complex, were recently reported as a possible cause for the autosomal dominant form of Parkinson's disease (PD). Here, we describe the screening of all 31 EIF4G1 coding exons in a series of 251 index cases with autosomal dominant PD, mostly of French origin and in 236 European control subjects. We identified 12 rare coding variants (either nonsynonymous amino acid substitutions or in frame deletions/insertions), including 6 variants present only in cases and 3 in controls. Segregation was possible only for 1 variant (p.E462delInsGK) that was found in 2 affected siblings. In addition, we found 2 previously reported pathogenic variants in 2 isolated patients (p.G686C) and in a control subject (p.R1197W). These data do not support the pathogenicity of several EIF4G1 variants in PD, at least in the French population

Type I interferonopathy due to a homozygous loss-of-inhibitory-function mutation in STAT2

International audiencePurpose STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. Methods Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. Results WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. Conclusion Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients

The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes.While SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20-25%.This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. This article is protected by copyright. All rights reserved

Correction: Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

[This corrects the article DOI: 10.5334/tohm.464.]

Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy

BACKGROUND: Intronic GAA repeat expansions in the fibroblast growth factor 14 gene (FGF14) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic FGF14 GAA repeat expansions in patients with an unexplained CANVAS-like phenotype. METHODS: We recruited 45 patients negative for biallelic RFC1 repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP), and genotyped the FGF14 repeat locus. Phenotypic features of GAA-FGF14-positive versus GAA-FGF14-negative patients were compared. RESULTS: Frequency of FGF14 GAA repeat expansions was 38% (17/45) in the entire cohort, 38% (5/13) in the subgroup with cerebellar ataxia plus polyneuropathy, 43% (9/21) in the subgroup with cerebellar ataxia plus BVP and 27% (3/11) in patients with all three features. BVP was observed in 75% (12/16) of GAA-FGF14-positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA-FGF14-positive patients. Family history of ataxia (59% vs 15%; p=0.007) was significantly more frequent and permanent cerebellar dysarthria (12% vs 54%; p=0.009) significantly less frequent in GAA-FGF14-positive than in GAA-FGF14-negative patients. Age at onset was inversely correlated to the size of the repeat expansion (Pearson's r, -0.67; R2=0.45; p=0.0031). CONCLUSIONS: GAA-FGF14-related disease is a common cause of cerebellar ataxia with polyneuropathy and/or BVP, and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum

Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder