Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

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The DYT6 gene for primary torsion dystonia (PTD) was mapped to chromosome 8p21-q22 in two Amish-Mennonite families who shared a haplotype of marker alleles across a 40 cM linked region. The objective of this study was to narrow the DYT6 region, clinically characterize DYT6 dystonia in a larger cohort, and to determine whether DYT6 is associated with dystonia in newly ascertained multiplex families. We systematically examined familial Amish-Mennonite dystonia cases, identifying five additional members from the original families, as well as three other multiplex Amish-Mennonite families, and evaluated the known DYT6 haplotype and recombination events. One of the three new families carried the shared haplotype, whereas the region was excluded in the two other families, suggesting genetic heterogeneity for PTD in the Amish-Mennonites. Clinical features in the five newly identified DYT6 carriers were similar to those initially described. In contrast, affected individuals from the excluded families had a later age of onset (46.9 years vs. 16.1 years in the DYT6), and the dystonia was both more likely to be of focal distribution and begin in the cervical muscles. Typing of additional markers in the DYT6-linked families revealed recombinations that now place the gene in a 23 cM region surrounding the centromere. In summary, the DYT6 gene is in a 23 cM region on chromosome 8q21-22 and does not account for all familial PTD in Amish-Mennonites.

Although myoclonus and dystonia are the hallmarks of myoclonus-dystonia (M-D), psychiatric features, particularly obsessive-compulsive disorder and alcohol dependence, have been reported in three families linked to chromosome 7q21. As the epsilon sarcoglycan (SGCE) gene for M-D was subsequently identified, we evaluated the relationship between psychiatric features and SGCE mutations in these original and two additional families and confirm that OCD and alcohol dependence are associated with manifesting mutated SGCE.

Myoclonus-dystonia is a movement disorder associated with mutations in the epsilon-sarcoglycan gene (SGCE) in most families and in the DRD2 and DYT1 genes in two single families. In both of the latter families, we also found a mutation of SGCE. The molecular mechanisms through which the detected mutations may contribute to myoclonus-dystonia remain to be determined.

Myoclonus-dystonia (M-D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys (P < 0.0097). We found no association between mutation type and phenotype.

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