A number sign (#) is used with this entry because spinocerebellar ataxia-36 (SCA36) is caused by heterozygous expansion of an intronic GGCCTG hexanucleotide repeat in the NOP56 gene (614154) on chromosome 20p13. Unaffected individuals carry 3 to 14 repeats, whereas affected individuals carry 650 to 2,500 repeats (Kobayashi et al., 2011 and Garcia-Murias et al., 2012).

Spinocerebellar ataxia-36 (SCA36) is a slowly progressive neurodegenerative disorder characterized by adult-onset gait ataxia, eye movement abnormalities, tongue fasciculations, and variable upper motor neuron signs. Some affected individuals may develop hearing loss (summary by Garcia-Murias et al., 2012).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Kobayashi et al. (2011) reported 5 unrelated Japanese families with an autosomal dominant form of spinocerebellar ataxia. The mean age at onset of gait ataxia, truncal instability, dysarthria, and limb incoordination was 52.8 years. An unusual feature for SCA was the late onset of motor neuron involvement in those with longer disease duration. Affected individuals developed tongue atrophy with fasciculation, although swallowing function was relatively preserved. Skeletal muscle atrophy and fasciculation in the limbs and trunk were observed in advanced cases. Most patients had hyperreflexia, but none had severe lower limb spasticity or extensor plantar responses. Brain MRI showed mild cerebellar atrophy. Nerve conduction studies were normal, whereas EMG showed neurogenic changes only in cases with skeletal muscle atrophy, indicating a lower motor neuropathy. The pattern of muscle involvement and progression differed from that seen in amyotrophic lateral sclerosis (ALS; 105400).

Ikeda et al. (2012) studied in detail 14 of 18 individuals from 9 Japanese families with genetically confirmed SCA36. The mean age at onset was 53.1 years, and most presented with truncal ataxia. All affected patients showed cerebellar ataxia manifest as ataxic dysarthria, limb ataxia, and dysdiadochokinesis. Many had hyperreflexia (79%) and increased muscle tone (29%), but none had extensor plantar responses. Impaired smooth pursuit and horizontal gaze nystagmus were found in 93% and 29%, respectively, and tongue atrophy or fasciculation was found in 10 patients (71%). Dysphagia was observed, but did not impair oral intake for at least 10 years after disease onset. Nine patients (64%) had skeletal muscle atrophy in the distal limbs and trunk, with fasciculations in 8. None had sensory disturbance, parkinsonism, or urinary disturbance. Skeletal muscle biopsy of 1 patient showed grouped atrophy of the fibers, small angular fibers, and pyknotic nuclear clumps, consistent with neurogenic atrophy and chronic denervation. Brain imaging showed atrophy of the cerebellar vermis and hemispheres and dilation of the fourth ventricle. Neuropathologic examination of 1 patient showed marked neuronal loss in the Purkinje cell layer of the cerebellum. There was also loss of motor neurons in the hypoglossal nucleus and the anterior horn of the upper cervical spinal cord. No NOP56 aggregates or inclusions were found.

Garcia-Murias et al. (2012) identified 2 large SCA36 kindreds originating from Costa da Morte in Galicia, Spain, a historically isolated region. Extensive family interviews and document studies allowed the reconstruction of over 650 individuals spanning 7 generations in each of the 2 families. Eight additional families from the same geographic region with a similar disorder were subsequently identified. The phenotype was homogeneous, with onset of gait difficulties due to ataxia in the late forties or early fifties. Most patients had variable eye movement abnormalities, such as slow saccades, slow pursuit, and fixation instability. Some had vertical or horizontal gaze limitation, whereas only a few had nystagmus. In addition, almost all noticed progressive hearing loss, some even before the balance problems. Other features included limb ataxia, dysarthria, some dysphagia, tongue fasciculations, hyperreflexia, and occasional extensor plantar responses. Brain MRI showed atrophy of the cerebellar vermis in the initial stages, later evolving to olivopontocerebellar atrophy. Lower limb somatosensory evoked potentials were abnormal in all individuals in whom it was tested, suggesting involvement of the central sensory tracts. The disorder was slowly progressive, with most patients remaining ambulatory for 15 to 20 years after onset. There was some evidence of genetic anticipation.

The transmission pattern of SCA36 in the families reported by Kobayashi et al. (2011) was consistent with autosomal dominant inheritance. There was no negative association between age of onset and number of repeats and no obvious anticipation in the pedigrees.

By genomewide linkage analysis of 2 large kindreds originating from a historically isolated region in Galicia, Spain with autosomal dominant SCA, Garcia-Murias et al. (2012) found linkage to a 2-cM region on chromosome 20p between rs2422752 and D20S181 (maximum 2-point lod score of 9.8 at D20S842).

By genomewide linkage analysis followed by candidate gene sequencing and repeat analysis of 5 Japanese families with spinocerebellar ataxia-36, Kobayashi et al. (2011) identified a pathogenic heterozygous 6-bp repeat expansion (GGCCTG; rs68063608) in intron 1 of the NOP56 gene (614154.0001). Four additional patients with SCA carrying this repeat expansion were identified. Overall, 9 (3.6%) unrelated cases were found among 251 cohort patients. Fluorescence in situ hybridization of patient lymphoblastoid cells showed RNA foci, which were not found in controls, and double staining and gel-shift assays showed that the expanded GGCCUG repeat bound and sequestered the RNA-binding protein SFRS2 (600813), whereas (CUG)(6) did not. In addition, transcription of MIR1292 (614155), located within intron 1 of NOP56, was significantly decreased in lymphoblastoid cells of SCA patients. The findings indicated that SCA36 is caused by hexanucleotide repeat expansions through a toxic gain of function.

By linkage analysis followed by detailed examination of the candidate region on chromosome 20p in 2 large kindreds from northern Spain with SCA, Garcia-Murias et al. (2012) identified a pathogenic expanded GGCCTG repeat in intron 1 of the NOP56 gene. A similar genetic pattern was then observed in 8 additional probands with SCA from the same geographic region. The size of expanded alleles ranged from 650 to 2,500 repeats, and there was some evidence for genetic anticipation.

All the patients with SCA36 reported by Kobayashi et al. (2011) were from the Chugoku district in western Japan, and haplotype analysis indicated that the molecular basis for the disease was due to a founder effect.

Ikeda et al. (2012) reported 9 families with genetically confirmed SCA36, all of whom lived in the western part of Japan along the Asida River.

Garcia-Murias et al. (2012) determined that SCA36 was the most common form of SCA in Galicia, Spain. The founder repeat mutation in the NOP56 gene (614154.0001) was estimated to have occurred in that region about 1,275 years ago. Ten (6.3%) of 160 Galician families with SCA had SCA36, whereas 9.4% had other forms of routinely tested SCA types.