SNOMEDCT: 722435003; ORPHA: 210571; DO: 0090048;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.2 | Dystonia 16 | 612067 | Autosomal recessive | 3 | PRKRA | 603424 |
A number sign (#) is used with this entry because of evidence that dystonia-16 (DYT16) is caused by homozygous mutation in the PRKRA gene (603424) on chromosome 2q31.
Camargos et al. (2008) reported 2 unrelated consanguineous families from Brazil in which a total of 6 individuals had early-onset dystonia-parkinsonism. Patients had onset of gait abnormalities and leg pain around age 12 years, followed by dysphagia, spasmodic dysphonia generalized dystonia, torticollis, upper limb dystonia, and opisthotonic posturing. Orofacial dystonia and facial grimacing were prominent features. Four patients had bradykinesia, 1 of whom also had tremor. Two patients had delayed development, and several had speech and language impairment.
Zech et al. (2014) reported 2 adult brothers of Polish descent who developed limb dystonia at ages 16 and 11 years, respectively. The disorder was slowly progressive in both patients, resulting in difficulties in fine motor tasks, walking, and speech. The symptoms were not responsive to medication. Cognition was unaffected in 1 patient at age 58 years. The other patient, who was more severely affected, underwent pallidotomy and later had a severe ischemic stroke resulting in complete loss of walking ability. This patient also had significant cognitive deficits at age 64 years. Both patients had mild parkinsonian features, including akinesia and rigidity.
The transmission pattern of DYT16 in the families reported by Camargos et al. (2008) and Zech et al. (2014) was consistent with autosomal recessive inheritance.
By genomewide linkage analysis of 2 Brazilian families with early-onset dystonia, Camargos et al. (2008) identified a locus, designated DYT16, on chromosome 2q31.2.
In affected members of 2 unrelated Brazilian families with early-onset dystonia-16, Camargos et al. (2008) identified a homozygous mutation in the PRKRA gene (P222L; 603424.0001). The mutation was found by linkage analysis and candidate gene sequencing. Haplotype analysis suggested a founder effect.
Seibler et al. (2008) identified a heterozygous 2-bp deletion in the PRKRA gene (603424.0002) in a 9-year-old German boy with early-onset dystonia of the legs that spread gradually over a few years. There was no family history of movement disorders. Although a second pathogenic PRKRA mutation was not identified, Seibler et al. (2008) postulated that there may be a mutation in noncoding gene regions or that there may be a gene dosage effect. Alternatively, the heterozygous mutation may be pathogenic in itself.
Zech et al. (2014) identified a homozygous P222L mutation in the PRKRA gene in 2 Polish brothers with DYT16. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Haplotype analysis indicated identity by state with the Brazilian patients who carried this mutation (Camargos et al., 2008), consistent with a founder effect. Functional studies of the variant were not performed. No additional PRKRA mutations were found in 10 German patients with generalized dystonia. Three heterozygous variants (T34S, N102S, and c.-14A-G) in the PRKRA gene were found in 3 of 329 patients with mainly adult-onset focal or segmental dystonia, but the pathogenicity of these heterozygous variants was unclear.
Camargos, S., Scholz, S., Simon-Sanchez, J., Paisan-Ruiz, C., Lewis, P., Hernandez, D., Ding, J., Gibbs, J. R., Cookson, M. R., Bras, J., Guerreiro, R., Oliveira, C. R., Lees, A., Hardy, J., Cardoso, F., Singleton, A. B. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 7: 207-215, 2008. [PubMed: 18243799] [Full Text: https://doi.org/10.1016/S1474-4422(08)70022-X]
Seibler, P., Djarmati, A., Langpap, B., Hagenah, J., Schmidt, A., Bruggemann, N., Siebner, H., Jabusch, H.-C., Altenmuller, E., Munchau, A., Lohmann, K., Klein, C. A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalised dystonia in a German patient. Lancet Neurol. 7: 380-381, 2008. [PubMed: 18420150] [Full Text: https://doi.org/10.1016/S1474-4422(08)70075-9]
Zech, M., Castrop, F., Schormair, B., Jochim, A., Wieland, T., Gross, N., Lichtner, P., Peters, A., Gieger, C., Meitinger, T., Strom, T. M., Oexle, K., Haslinger, B., Winkelmann, J. DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family. Mov. Disord. 29: 1504-1510, 2014. [PubMed: 25142429] [Full Text: https://doi.org/10.1002/mds.25981]