Spinocerebellar Ataxia 19

A number sign (#) is used with this entry because autosomal dominant spinocerebellar ataxia-19 (SCA19), also known as SCA22, is caused by heterozygous mutation in the KCND3 gene (605411) on chromosome 1p13.

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

Clinical Features

Schelhaas et al. (2001) reported a 4-generation Dutch family with a distinct form of autosomal dominant cerebellar ataxia (ADCA) type I. Affected members showed a relatively mild ataxia syndrome with cognitive impairment, poor performance on the Wisconsin Card Sorting Test, myoclonus, and a postural irregular tremor of low frequency. There was no indication of sex-limited transmission. Genetic loci implicated in other forms of spinocerebellar ataxia were excluded by mutation analysis or linkage studies. By neuropathologic examination, Duarri et al. (2012) found loss of Purkinje cells in the cerebellum of 1 of the patients reported by Schelhaas et al. (2001). The anterior part of the vermis was most severely affected, followed by the posterior vermis and the cerebellar hemispheres. There was also degeneration and atrophy in both the molecular and internal granular layers. Purkinje cell bodies showed intense staining for KCND3 within large puncta.

Chung et al. (2003) reported a 4-generation Han Chinese family with autosomal dominant cerebellar ataxia. The proband (in generation II) was a 68-year-old man with a 23-year history of gait and limb ataxia. He also had hyporeflexia, dysphagia, dysarthria, and gaze-evoked horizontal nystagmus. MRI showed cerebellar atrophy. Examination of 8 other affected family members revealed a mean age at onset of 40.5 years in generation II, 20.7 years in generation III, and 12.5 years in generation IV, suggesting genetic anticipation. The initial symptom in all affected members was gait ataxia, followed by trunk and limb ataxia, dysarthria, and 'cogwheel' pursuits of the eyes. No patients, including the proband who was most severely affected, showed cogwheel rigidity, myoclonus, tremor, akinesia, sensory deficits, seizures, or cognitive impairment. Chung et al. (2003) noted that the lack of additional signs in these patients indicated a pure form of ADCA that is best classified as ADCA III. Lee et al. (2012) reported follow-up of the Han Chinese family reported by Chung et al. (2003), which had 13 affected individuals. The age at onset ranged from 13 to 46 years. All had a slowly progressive form of cerebellar ataxia with mild oculomotor abnormalities, such as nystagmus and saccadic pursuits, dysarthria, and decreased reflexes in the lower limbs. Three patients showed mild cerebellar atrophy on brain MRI.

Lee et al. (2012) reported a French family in which 8 individuals presented with slowly progressive cerebellar ataxia with onset between 24 and 51 years. Additional variable features included impaired vibration sense at the ankles (3 patients), hyperreflexia (3), mild cogwheel rigidity (2) urinary urgency or incontinence (5), and eye movement abnormalities (6). Six patients had cerebellar atrophy on brain imaging. Only 1 patient was wheelchair-bound after 43 years of disease.

Inheritance

The transmission pattern of SCA19 in the families reported by Schelhaas et al. (2001) and Chung et al. (2003) was consistent with autosomal dominant inheritance.

Mapping

Using a genomewide screen in the large Dutch ADCA family studied by Schelhaas et al. (2001), Verbeek et al. (2002) mapped the disorder, designated SCA19, to chromosome 1p21-q21 (maximum 2-point lod score of 3.82 at theta = 0.0 with marker D1S534). Multipoint and haplotype analysis defined a candidate interval of about 35 cM.

By genomewide analysis of a Han Chinese family with ADCA, Chung et al. (2003) identified a candidate disease locus, termed SCA22, at chromosome 1p21-q23 (maximum multipoint lod score of 3.78 at marker D1S1167). Haplotype analysis defined a 43.7-cM interval flanked by D1S206 and D1S2878.

Schelhaas et al. (2004) asserted that the SCA19 and SCA22 loci represented the same disease-causing gene. Chung and Soong (2004) stated that the features in their family were different from those reported by Schelhaas et al. (2001), but also noted that it is unlikely that there are 2 different genes causing SCA within the candidate region.

Molecular Genetics

In affected members of a Han Chinese family with SCA, originally reported by Chung et al. (2003), Lee et al. (2012) identified a heterozygous 3-bp deletion in the KCND3 gene (605411.0001). The same heterozygous deletion was found in affected members of a French family with autosomal dominant SCA. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. In HEK293 cells, the mutant protein showed no discernible surface expression and appeared to be abnormally retained within the endoplasmic reticulum. Voltage-clamp recordings showed decreased outward potassium currents compared to wildtype cells in response to voltage. Three additional heterozygous missense variants were found in the KCND3 gene (G345V, V338E, or T377M) in an Ashkenazi Jewish family and in 3 of 55 Japanese families with late-onset SCA, but segregation of the variants with the phenotype was unclear and no functional studies were performed on these variants. No KCND3 mutations were found in probands from 105 Chinese families with hereditary ataxia.

In affected members of a large Dutch family with SCA, originally reported by Schelhaas et al. (2001), Duarri et al. (2012) identified a heterozygous mutation in the KCND3 gene (T352P; 605411.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transfection of the mutation into HeLa cells showed that the mutant protein had almost no cell surface expression, but rather accumulated in the endoplasmic reticulum, consistent with a trafficking defect. The mutant protein was more rapidly degraded compared to the wildtype protein, suggesting that it was misfolded. The trafficking and degradation defects could be rescued by coexpression with the active isoform of KCHIP2 (604661). Patch-clamp recordings showed that the mutant channel had almost no detectable current activity (1% compared to wildtype). Duarri et al. (2012) suggested a dominant-negative effect and hypothesized that abnormal channel function may cause cellular toxicity due to abnormal intracellular calcium homeostasis, defects in long-term potentiation or depression, or chronic activation of the ER stress response. Two additional missense variants were identified in 2 probands, but segregation of the variants within the families was unclear.