Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

Background: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability.

Methods: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor.

Huntington's Disease with Small CAG Repeat Expansions.

Background: Carriers of small cytosine-adenine-guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied.

Objective: To study the phenotype of CAG repeat carriers.

Methods: We included 35 patients and premanifest carriers of CAG repeats.

Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial.

Background: Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2.

Methods: We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases.

Motor neuron pathology in CANVAS due to RFC1 expansions.

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG.

Multiparametric characterization of white matter alterations in early stage Huntington disease.

Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology.

Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study.

Background: Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals.

Methods: In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6.

Significance of NT-proBNP and High-sensitivity Troponin in Friedreich Ataxia.

Background: Friedreich's ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum cardiac high-sensitivity troponin (hsTnT) concentrations, and the extent of genetic abnormality and cardiac parameters.

Methods: Between 2013 and 2015, 85 consecutive genetically confirmed FA adult patients were prospectively evaluated by measuring plasma hsTnT and NT-proBNP concentrations, electrocardiogram, and echocardiography.

Predictors of Left Ventricular Dysfunction in Friedreich's Ataxia in a 16-Year Observational Study.

Background: Friedreich's ataxia (FRDA) is a cerebellar ataxia due to GAA repeat expansions in the FXN gene, and in affected patients, lower left ventricular ejection fraction (LVEF) leads to poorer prognosis. We aimed to identify patients likely to develop worsening LVEF at an early stage.

Methods: We included 115 FRDA patients aged 30 ± 10 years with 620 ± 238 GAA repeats on the shorter allele and disease onset of 15 ± 7 years.

Oral mobility reflects rate of progression in advanced Friedreich's ataxia.

Our objective was to identify a sensitive marker of disease progression in Friedreich's ataxia. We prospectively evaluated speech, voice, and oromotor function in 40 patients at two timepoints. The mean disease duration was 20.

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with .

Objective: We took advantage of a large multinational recruitment to delineate genotype-phenotype correlations in a large, trans-European multicenter cohort of patients with spastic paraplegia gene 7 ().

Methods: We analyzed clinical and genetic data from 241 patients with , integrating neurologic follow-up data. One case was examined neuropathologically.

Contemporary Dance Practice Improves Motor Function and Body Representation in Huntington's Disease: A Pilot Study.

Background: Physical exercise improves neurological conditions, but adherence is hard to establish. Dance might be a promising alternative; however, since patients with Huntington's disease (HD) suffer from rhythmic movement execution deficits, any metric dance practice must be avoided.

Objective: Here we asked, if contemporary dance, a lyrical dance form, practiced for two hours per week over five months, might improve motor function, neuropsychiatric variables, cognition and brain volume of HD patients.

Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex.

Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by progressive distal degeneration of the corticospinal tracts. Among the 79 loci and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST, which encodes spastin, responsible for SPG4, are the most frequent cause of both familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype associated with restricted involvement of the corticospinal tracts and posterior columns of the spinal cord.

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.

Importance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion.

Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence.

Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy.

The striatum is a well-known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using P magnetic resonance spectroscopy ( P MRS).

Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5.

The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism.

A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.

Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature.

Background: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism.

Objectives: To better characterise the natural history of PMM2-CDG.

Methods: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed.

Mutations in TGM6 induce the unfolded protein response in SCA35.

Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations in TG6 induce cerebellar degeneration by an unknown mechanism. We identified seven patients bearing new mutations in TGM6.

A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias.

Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series.

A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.

Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases.

A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia.

Importance: Friedreich ataxia (FRDA) is the most common genetic sensory ataxia, and myocardial involvement is a major determinant of survival.

Objective: To assess FRDA survival and cardiac outcome to adapt future therapeutic trials.

Design, Setting, And Participants: In a longitudinal follow-up study, all patients with genetically confirmed FRDA seen in the reference center and referred for cardiac evaluation (standard 12-lead electrocardiogram and transthoracic echocardiography) to the cardiology department were enrolled and followed up from April 27, 1990, to July 31, 2013.