A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-8 (SCAR8) is caused by homozygous or compound heterozygous mutation in the SYNE1 gene (608441) on chromosome 6q25.

Autosomal recessive spinocerebellar ataxia-8 (SCAR8) is a slowly progressive neurodegenerative disorder characterized by gait ataxia and other cerebellar signs, such as nystagmus and dysarthria. The age at onset is highly variable, and but most often is in the second or third decades. The disorder was initially identified in patients of French Canadian descent, most of whom have a relatively 'pure' form of the disorder. However, subsequent studies have shown that SCAR8 occurs worldwide and most commonly manifests with additional features, including spasticity, secondary musculoskeletal abnormalities, and ocular movement anomalies, consistent with a 'complicated' phenotype. Brain imaging typically shows cerebellar atrophy, sometimes with pontine involvement. Rare patients may have an early-onset multisystemic disorder with impaired intellectual development and respiratory dysfunction (summary by Synofzik et al., 2016).

Gros-Louis et al. (2007) identified a geographically defined group of 26 French Canadian families, including 53 affected family members, most of which originated from the Beauce and Bas-St-Laurent regions of the province of Quebec, Canada. All of the affected family members had a similar phenotype, which consisted of late-onset cerebellar ataxia with slow progression accompanied by dysarthria, with few associated features other than dysmetria, occasional brisk lower-extremity tendon reflexes, and minor abnormalities in saccades and smooth pursuit. Gros-Louis et al. (2007) remarked that none of the subjects showed optic atrophy, auditory loss, sensory abnormalities, autonomic disturbances, or extrapyramidal signs. Nerve conduction studies carried out in 18 affected individuals were all within normal limits. Imaging by computed tomography (CT) or magnetic resonance imaging (MRI) invariably showed diffuse pure cerebellar atrophy. Therefore this disorder represented the first 'pure' autosomal recessive cerebellar ataxia mapped to that time. Gros-Louis et al. (2007) designated this phenotype autosomal recessive cerebellar ataxia type 1 (ARCA1), also known as recessive ataxia of Beauce.

Izumi et al. (2013) reported 2 unrelated Japanese patients, each born of consanguineous parents, with onset of pure cerebellar ataxia at ages 36 and 27 years, respectively. Brain imaging in both patients showed cerebellar atrophy. The phenotype was similar to that reported by Gros-Louis et al. (2007). Izumi et al. (2013) noted that these were the first published patients with genetically confirmed SCAR8 outside of the French Canadian population.

Clinical Variability

Izumi et al. (2013) reported a Japanese woman, born of consanguineous parents, with a severe variant of SCAR8. She presented at age 8 years with difficulty running, followed by distal dominant limb weakness and muscular atrophy, hyperreflexia, spastic ataxia, pes cavus, decreased Achilles tendon reflex, and decreased vibration sense. Brain MRI at age 19 showed cerebellar and brainstem atrophy. Other features included tongue fasciculation, tongue atrophy, and dysarthria. As an adult, her respiratory function was compromised, necessitating a tracheotomy. She died suddenly at age 44. The diagnosis was SCA with motor neuron disease; autopsy was not performed. Genetic analysis identified a homozygous truncating mutation in the SYNE1 gene and a homozygous missense variant (G185R) in the N-terminal region of SYNE1. Functional studies were not performed, but Izumi et al. (2013) suggested that both mutations contributed to the more complex motor neuron phenotype in this patient.

Synofzik et al. (2016) reported 23 probands of European descent, none of whom were French Canadian, with SCAR8. Twenty-two of the patients had biallelic truncating alleles, and 1 was compound heterozygous for a missense and a truncating allele. Five probands were from multiplex families, whereas 18 were simplex cases with no family history of the disorder. Most patients had onset in the second or third decades, although a few had onset as early as 6 years or as late as 40. All had cerebellar ataxia with gait disturbances, and most (81%) had additional upper motor neuron signs, most often spasticity of the lower limbs and/or lower limb weakness and muscle atrophy. Additional common features included urinary urge incontinence, scoliosis, kyphosis, pes cavus, and ocular anomalies such as slow saccades, ophthalmoparesis, ptosis, and strabismus. A few patients had mild axonal sensory or motor peripheral neuropathy, and some had dystonia of the upper limbs. Three patients, including 2 sibs, had a multisystem disorder with impaired intellectual development (IQ of 49 in 1 patient) and respiratory dysfunction, which resulted in death at age 36 years in 1. EMG, when performed, showed neurogenic changes, and muscle biopsy showed neurogenic atrophy without evidence of a primary muscle disorder. Brain imaging showed cerebellar atrophy in all patients, and PET imaging in 2 patients showed decreased metabolism in the pontine brainstem.

The transmission pattern of SCAR8 in the families reported by Gros-Louis et al. (2007) and Izumi et al. (2013) was consistent with autosomal recessive inheritance.

Gros-Louis et al. (2007) performed genomewide linkage analysis of selected families, which showed only 1 marker, D6S476, with a maximum lod score above 3.0. Mapping studies established a minimum candidate interval of about 0.5 Mb on chromosome 6q.

The candidate interval established by Gros-Louis et al. (2007) in French Canadian families with pure cerebellar ataxia contained only 1 gene, SYNE1 (608441), which spans over 0.5 Mb of genomic DNA. Screening of all exons and flanking intronic sequences of SYNE1 led to the identification of 2 disease-segregating SNPs that were not detected among 380 age- and ethnicity-matched control chromosomes. Gros-Louis et al. (2007) concluded that these 2 variants may be causative mutations for ARCA1: 310067A-G (608441.0001) and 306434A-G (608441.0002). Both of these were intronic mutations shown to have functional consequences on the proper splicing of the gene and resulting in premature termination of the protein. Based on haplotype reconstructions of affected individuals from all of the other families, Gros-Louis et al. (2007) identified 3 other different disease haplotypes, suggesting that other mutations could be associated with the disease. A second mutational screen by direct sequencing uncovered 3 additional mutations that segregated with their respective haplotypes and were all predicted to lead to premature termination of the protein: R2906X (608441.0003), a 5-bp del (608441.0004), and Q7640X (608441.0005). These additional mutations were likewise not detected among 380 age- and ethnicity-matched control chromosomes. The finding of 5 different mutations in a relatively homogeneous population led Gros-Louis et al. (2007) to predict that mutations in the SYNE1 gene may be responsible for a substantial fraction of all adult-onset autosomal recessive ataxia syndromes with cerebellar atrophy.

Dupre et al. (2007) identified 2 additional SYNE1 mutations (608441.0006; 608441.0007) in French Canadian patients with SCAR8. A splice site mutation (608441.0002) was the most common mutation, occurring at a frequency of 50.8% among 124 patients.

In 2 unrelated Japanese patients with adult-onset SCAR8, Izumi et al. (2013) identified different homozygous truncating mutations in the SYNE1 gene (see, e.g., 608441.0015).

Among 23 non-French-Canadian probands with SCAR8, Synofzik et al. (2016) identified 35 different homozygous or compound heterozygous mutations in the SYNE1 gene (see, e.g., 608441.0016-608441.0017). There were 20 nonsense, 7 frameshift, and 7 splice site mutations, and only 1 missense mutation; mutations occurred throughout the gene. Twenty-two of the patients had biallelic truncating alleles, and 1 was compound heterozygous for a missense and a truncating allele. Five probands were from multiplex families, whereas 18 were simplex cases with no family history of the disorder. All mutations were confirmed by Sanger sequencing, and the mutations segregated with the disorder in families from whom DNA was available. Most of the mutations were absent in the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, although a few were observed at low frequencies. The missense variant (F220S) occurred at a highly conserved residue in the actin-binding domain and was absent from public databases. Analysis of patient cells from 1 family with a truncating and a frameshift mutation showed that the mutations resulted in nonsense-mediated mRNA decay, consistent with a loss of function. Muscle biopsy samples from 3 unrelated patients showed severely decreased or absent SYNE1 immunostaining, also consistent with a loss of protein. Functional studies of the variants and additional studies of patient cells were not performed, but all of the variants were predicted to result in a loss of function. The patients were ascertained from a cohort of 434 index patients from 36 different countries with autosomal recessive ataxia compiled from 7 different European ataxia centers. Those with genetically confirmed SCAR8 accounted for almost 5%, indicating that SCAR8 is more common than previously thought. The findings also indicated that the phenotype of SCAR8 more often than not includes additional complicating features.