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BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

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BackgroundThe European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich ataxia (FRDA). We report one-and two-year longitudinal data to delineate potential outcomes for clinical trials. MethodsWe enrolled genetically confirmed FRDA patients from eleven European study sites. Patients were seen on an annual basis at three visits. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF) and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. Disease progression was analyzed with linear mixed effect models. This study is registered with ClinicalTrials.gov, number NCT02069509. Patients with more than 353 GAA repeats on the shorter allele had a higher SARA progression rate (by 0·09 [0·02] per additional 100 repeats). Annual worsening for INAS was 0·10 (0·03), for SCAFI -0·04 (0·01), for ADL 0·93 (0·06) and for EQ-5D-3L -0·02 (0·004). PVF performance improved by 0·99 [0·14] words per year. 548 or 184 patients would be needed to detect a 50% reduction in SARA progression at 80% power in a one-year or two-year clinical trial, respectively. InterpretationThe EFACTS longitudinal analysis provides suitable outcome measures and sample size calculation for upcoming clinical trial designs in FRDA.

BackgroundThe most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset.MethodsWe combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age.ResultsFor SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age.ConclusionsThese estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.ClinicalTrials.gov, numberNCT01037777 and NCT00136630 for the French patients.

Hereditary spastic paraplegias are a heterogeneous group of neurodegenerative disorders, clinically classified in pure and complex forms. Genetically, more than 70 different forms of spastic paraplegias have been characterized. A subgroup of complicate recessive forms has been distinguished for the presence of thin corpus callosum and white matter lesions at brain imaging. This group includes several genetic entities, but most of the cases are caused by mutations in the KIAA1840 (SPG11) and ZFYVE26 genes (SPG15). We studied a cohort of 61 consecutive patients with complicated spastic paraplegias, presenting at least one of the following features: mental retardation, thin corpus callosum and/or white matter lesions. DNA samples were screened for mutations in the SPG11/KIAA1840, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG48/AP5Z1 and SPG54/DDHD2 genes by direct sequencing. Sequence variants were found in 30 of 61 cases: 16 patients carried SPG11/KIAA1840 gene variants (26.2%), nine patients carried SPG15/ZFYVE26 variants (14.8%), three patients SPG35/FA2H (5%), and two patients carried SPG48/AP5Z1 gene variants (3%). Mean age at onset was similar in patients with SPG11 and with SPG15 (range 11-36), and the phenotype was mostly indistinguishable. Extrapyramidal signs were observed only in patients with SPG15, and epilepsy in three subjects with SPG11. Motor axonal neuropathy was found in 60% of cases with SPG11 and 70% of cases with SPG15. Subjects with SPG35 had intellectual impairment, spastic paraplegia, thin corpus callosum, white matter hyperintensities, and cerebellar atrophy. Two families had a late-onset presentation, and none had signs of brain iron accumulation. The patients with SPG48 were a 5-year-old child, homozygous for a missense SPG48/AP5Z1 variant, and a 51-year-old female, carrying two different nonsense variants. Both patients had intellectual deficits, thin corpus callosum and white matter lesions. None of the cases in our cohort carried mutations in the SPG21/ACP33 and SPG54/DDH2H genes. Our study confirms that the phenotype of patients with SPG11 and with SPG15 is homogeneous, whereas cases with SPG35 and with SPG48 cases present overlapping features, and a broader clinical spectrum. The large group of non-diagnosed subjects (51%) suggests further genetic heterogeneity. The observation of common clinical features in association with defects in different causative genes, suggest a general vulnerability of the corticospinal tract axons to a wide spectrum of cellular alterations.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.