Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause autosomal recessive cerebellar ataxia (ARCA) type 1 with highly variable clinical phenotypes. The aim of this study was to describe the phenotypic-genetic spectrum of SYNE1-related ARCA1 patients in the Chinese population. We screened 158 unrelated patients with autosomal recessive or sporadic ataxia for variants in SYNE1 using next-generation sequencing. Pathogenicity assessment of SYNE1 variants was interpreted according to the American College of Medical Genetics standards and guidelines. We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families, including nine novel variants and one reported variant. Of the six index patients, two patients showed the classical pure cerebellar ataxia, while four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation. The variants associated with motor neuron or cognition involvement tend to be located in the C-terminal region of SYNE1 protein, compared with the variants related to pure cerebellar ataxia. Our data indicating SYNE1 mutation is one of the more common causes of recessive ataxia in the Chinese population. The use of next-generation sequencing has enabled the rapid analysis of recessive ataxia and further expanded our understanding of genotype-phenotype correlation.

Autosomal Recessive Cerebellar Ataxia 1: First Case Report Depicting a Variant in SYNE1 Gene in a Chilean Patient.

Autosomal recessive cerebellar ataxia type 1 (ARCA-1) or spinocerebellar ataxia autosomal recessive type 8 (SCAR8) is a slowly progressive neurodegenerative disorder that occurs due to mutations in the spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene. Previously considered a rare cause of ARCA, related to French-Canadian patients from Beauce, Quebec, Canada, SYNE1 ataxia is now known to be of worldwide distribution. We present the case report of a 54-year-old male patient with the genetic diagnosis of SYNE1 ataxia, presenting with a SYNE1 gene mutation never described in Chilean population before.

The KASH-containing isoform of Nesprin1 giant associates with ciliary rootlets of ependymal cells.

Biallelic nonsense mutations of SYNE1 underlie a variable array of cerebellar and non-cerebellar pathologies of unknown molecular etiology. SYNE1 encodes multiple isoforms of Nesprin1 that associate with the nuclear envelope, with large cerebellar synapses and with ciliary rootlets of photoreceptors. Using two novel mouse models, we determined the expression pattern of Nesprin1 isoforms in the cerebellum whose integrity and functions are invariably affected by SYNE1 mutations. We further show that a giant isoform of Nesprin1 associates with the ciliary rootlets of ependymal cells that line brain ventricles and establish that this giant ciliary isoform of Nesprin1 harbors a KASH domain. Whereas cerebellar phenotypes are not recapitulated in Nes1gSTOP/STOP mice, these mice display a significant increase of ventricular volume. Together, these data fuel novel hypotheses about the molecular pathogenesis of SYNE1 mutations and support that KASH proteins may localize beyond the nuclear envelope in vivo.

A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I.

Nonsense mutations across the whole coding sequence of Syne1/Nesprin1 have been linked to autosomal recessive cerebellar ataxia Type I (ARCA1). However, nothing is known about the molecular etiology of this late-onset debilitating pathology. In this work, we report that Nesprin1 giant is specifically expressed in CNS tissues. We also identified a CNS-specific splicing event that leads to the abundant expression of a KASH-LESS variant of Nesprin1 giant (KLNes1g) in the cerebellum. KLNes1g displayed a noncanonical localization at glomeruli of cerebellar mossy fibers whereas Nesprin2 exclusively decorated the nuclear envelope of all cerebellar neurons. In immunogold electron microscopy, KLNes1g colocalized both with synaptic vesicles within mossy fibers and with dendritic membranes of cerebellar granule neurons. We further identified vesicle- and membrane-associated proteins in KLNes1g immunoprecipitates. Together, our results suggest that the loss of function of KLNes1g resulting from Nesprin1 nonsense mutations underlies the molecular etiology of ARCA1.

Autosomal recessive spinocerebellar ataxia SCAR8/ARCA1: first families detected in Spain.

INTRODUCTION: Autosomal recessive spinocerebellar ataxia type 8 (ARCA1/SCAR8) is caused by mutations of the SYNE1 gene. The disease was initially described in families from Quebec (Canada) with a phenotype of pure cerebellar syndrome, but in recent years has been reported with a more variable clinical phenotype in other countries. Cases have recently been described of muscular dystrophy, arthrogryposis, and cardiomyopathy due to SYNE1 mutations. OBJECTIVE: To describe clinical and molecular findings from 4 patients (3 men and one woman) diagnosed with ARCA1/SCAR8 from 3 Spanish families from different regions. MATERIAL AND METHODS: We describe the clinical, paraclinical, and genetic results from 4 patients diagnosed with ARCA1/SCAR8 at different Spanish neurology departments. RESULTS: Onset occurred in the third or fourth decade of life in all patients. After 15 years of progression, 3 patients presented pure cerebellar syndrome, similar to the Canadian patients; the fourth patient, with over 30 years' progression, presented vertical gaze palsy, pyramidal signs, and moderate cognitive impairment. In all patients, MRI studies showed cerebellar atrophy. The genetic study revealed distinct pathogenic SYNE1 mutations in each family. CONCLUSIONS: ARCA1/SCAR8 can be found worldwide and may be caused by many distinct mutations in the SYNE1 gene. The disease may manifest with a complex phenotype of varying severity.

Case Report: Late-Onset Autosomal Recessive Cerebellar Ataxia Associated With SYNE1 Mutation in a Chinese Family.

Autosomal recessive cerebellar ataxia type 1 (ARCA-1), also known as autosomal recessive spinocerebellar ataxia type 8 (SCAR8), is caused by spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene mutation. Nesprin-1, encoded by SYNE1, is widely expressed in various tissues, especially in the striated muscle and cerebellum. The destruction of Nesprin-1 is related to neuronal and neuromuscular lesions. It has been reported that SYNE1 gene variation is associated with Emery-Dreifuss muscular dystrophy type 4, arthrogryposis multiplex congenita, SCAR8, and dilated cardiomyopathy. The clinical manifestations of SCAR8 are mainly characterized by relatively pure cerebellar ataxia and may be accompanied by upper and/or lower motor neuron dysfunction. Some affected people may also display cerebellar cognitive affective syndrome. It is conventionally held that the age at the onset of SCAR8 is between 6 and 42 years (the median age is 17 years). Here, we report a pedigree with SCAR8 where the onset age in the proband is 48 years. This case report extends the genetic profile and clinical features of SCAR8. A new pathogenic site (c.7578del; p.S2526Sfs*8) located in SYNE1, which is the genetic cause of the patient, was identified via whole exome sequencing (WES).

Focal dystonia in a case of SYNE1 spastic-ataxia: Expanding the phenotypic spectrum.

Synaptic nuclear envelope protein-1 (SYNE1) related cerebellar ataxia also called ARCA1 or SCAR8, manifests as a relatively pure cerebellar ataxia or with additional neurological involvement. Dystonia is rarely seen in SYNE1 ataxia and to the best of our knowledge, there are only three reports of dystonia in patients with SYNE1 ataxia. This report describes a 22-year-old woman with chronic progressive spastic-ataxia of 3-year duration with additional focal dystonia of the right upper limb. Patient had cerebellar atrophy on MRI brain and a novel pathogenic homozygous variant in exon 74 of the SYNE1 gene (p.Gln4047Ter).

Autosomal recessive spinocerebellar ataxia SCAR8/ARCA1: First families detected in Spain. / Heredoataxia cerebelosa recesiva ARCA1/SCAR8: primeras familias detectadas en España.

INTRODUCTION: Autosomal recessive spinocerebellar ataxia type 8 (ARCA1/SCAR8) is caused by mutations of the SYNE1 gene. The disease was initially described in families from Quebec (Canada) with a phenotype of pure cerebellar syndrome, but in recent years has been reported with a more variable clinical phenotype in other countries. Cases have recently been described of muscular dystrophy, arthrogryposis, and cardiomyopathy due to SYNE1 mutations. OBJECTIVE: To describe clinical and molecular findings from 4 patients (3 men and one woman) diagnosed with ARCA1/SCAR8 from 3 Spanish families from different regions. MATERIAL AND METHODS: We describe the clinical, paraclinical, and genetic results from 4 patients diagnosed with ARCA1/SCAR8 at different Spanish neurology departments. RESULTS: Onset occurred in the third or fourth decade of live in all patients. After 15 years of progression, 3 patients presented pure cerebellar syndrome, similar to the Canadian patients; the fourth patient, with over 30 years' progression, presented vertical gaze palsy, pyramidal signs, and moderate cognitive impairment. In all patients, MRI studies showed cerebellar atrophy. The genetic study revealed distinct pathogenic SYNE1 mutations in each family. CONCLUSIONS: ARCA1/SCAR8 can be found worldwide and may be caused by many distinct mutations in the SYNE1 gene. The disease may manifest with a complex phenotype of varying severity.