SNOMEDCT: 718772002; ORPHA: 101108; DO: 0050973;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p13 | Spinocerebellar ataxia 23 | 610245 | Autosomal dominant | 3 | PDYN | 131340 |
A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-23 (SCA23) is caused by heterozygous mutation in the PDYN gene (131340) on chromosome 20p13.
Spinocerebellar ataxia-23 (SCA23) is an adult-onset autosomal dominant neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, with variable additional features, including peripheral neuropathy and dysarthria (Bakalkin et al., 2010).
For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).
Verbeek et al. (2004) reported a Dutch family with autosomal dominant late-onset spinocerebellar ataxia affecting at least 13 members spanning 3 generations. In the 5 affected family members who were examined, age at onset ranged from 43 to 56 years, and the disorder was slowly progressive. Clinical features included gait and limb ataxia, with variable dysarthria, slow saccades, ocular dysmetria, and decreased vibratory sense below the knees. Four affected individuals showed hyperreflexia, 2 of whom also had extensor plantar responses. Only 1 patient, with a disease duration of 23 years, was wheelchair-bound. MRI of that patient showed severe cerebellar atrophy. Postmortem examination of 1 patient showed frontotemporal atrophy, atrophy of the cerebellar vermis, pons, and spinal cord. There was neuronal loss in the cerebellar vermis, dentate nuclei, and inferior olives, but not in the pons. There was also thinning of the cerebellopontine tracts and demyelination of the posterior and lateral columns of the spinal cord.
Bakalkin et al. (2010) reported 2 Dutch sibs with SCA23. The sister was initially diagnosed with essential tremor of head and postural arms in mid-adulthood and showed memory deficits beginning around age 50. Neurologic exam at age 53 showed slowed mental processes, slight dysarthria, mild ataxia of upper and lower limbs, postural arm and head tremor, proximal paresis of the legs with mild signs of sensory neuropathy, and bilateral pes cavus. Her 54-year-old brother, who had always been clumsy, showed gait impairment and slowing, head tremor, gaze fixation instability, very mild dysarthria, action tremor of the hands, and a subtle ataxia of the hands and arms. The mother, who was not examined, had mild late-onset ataxia and tremor, and probably had dementia. Two additional unrelated affected individuals had slowly progressive gait and upper limb ataxia and distal sensory neuropathy. One had oculomotor abnormalities, pyramidal signs of the legs, and parkinsonian features; brain MRI of the other patient showed generalized cerebral cortical and subcortical atrophy, agenesis of the corpus callosum, and prominent atrophy of the cerebellar vermis, the pons, and the inferior olivary nucleus.
By genomewide linkage analysis of a large Dutch family, Verbeek et al. (2004) identified a candidate disease locus, termed SCA23, on chromosome 20p13-p12.3 (maximum 2-point lod score of 3.46 at marker D20S199). Haplotype analysis identified a 18.2-cM region between the tip of the short arm of chromosome 20 and D20S194. Molecular analysis excluded mutations in the SKIP3 (607898), PRNP (176640), and PRND (604263) genes.
The transmission pattern of SCA23 in the families reported by Bakalkin et al. (2010) was consistent with autosomal dominant inheritance.
In affected members of the family with SCA23 reported by Verbeek et al. (2004), Bakalkin et al. (2010) identified a heterozygous mutation in the PDYN gene (R138S; 131340.0001). Screening of 1,100 additional Dutch ataxia patients revealed 3 more PDYN mutations: 1 in 2 sibs (R215C; 131340.0002) and 1 each in 2 additional unrelated patients with no family history of the disorder (L211S, 131340.0003 and R212W, 131340.0004, respectively). These findings indicated that SCA23 is an uncommon cause of SCA (0.5%) in the Dutch population. Cellular studies and studies on patient cerebellar tissue implicated 2 possible pathogenic mechanisms: upregulation of dynorphin A, which may have neurodegenerative effects or cause changes in opioid activity, or accumulation of mutant PDYN that cannot be properly processed and is toxic to Purkinje cells.
Schicks et al. (2011) did not identify mutations in the PDYN gene in 104 German families with autosomal dominant SCA who were negative for common SCA-causing repeat expansions and SCA-associated mutations in other genes, suggesting that SCA23 is rare in central European populations.
Bakalkin, G., Watanabe, H., Jezierska, J., Depoorter, C., Verschuuren-Bemelmans, C., Bazov, I., Artemenko, K. A., Yakovleva, T., Dooijes, D., Van de Warrenburg, B. P. C., Zubarev, R. A., Kremer, B., Knapp, P. E., Hauser, K. F., Wijmenga, C., Nyberg, F., Sinke, R. J., Verbeek, D. S. Prodynorphin mutations cause the neurodegenerative disorder spinocerebellar ataxia type 23. Am. J. Hum. Genet. 87: 593-603, 2010. Note: Erratum: Am. J. Hum. Genet. 87: 736 only, 2010. [PubMed: 21035104] [Full Text: https://doi.org/10.1016/j.ajhg.2010.10.001]
Schicks, J., Synofzik, M., Beetz, C., Shiele, F., Schols, L. Mutations in the PDYN gene (SCA23) are not a frequent cause of dominant ataxia in Central Europe. (Letter) Clin. Genet. 80: 503-504, 2011. [PubMed: 22243190] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01651.x]
Verbeek, D. S., van de Warrenburg, B. P., Wesseling, P., Pearson, P. L., Kremer, H. P., Sinke, R. J. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3. Brain 127: 2551-2557, 2004. [PubMed: 15306549] [Full Text: https://doi.org/10.1093/brain/awh276]