Dystonia-25 is an autosomal dominant neurologic disorder characterized by adult onset of focal dystonia, usually involving the neck. The dystonia most often progresses to involve other regions, particularly the face and laryngeal muscles, and less commonly the trunk ... Dystonia-25 is an autosomal dominant neurologic disorder characterized by adult onset of focal dystonia, usually involving the neck. The dystonia most often progresses to involve other regions, particularly the face and laryngeal muscles, and less commonly the trunk and limbs (summary by Fuchs et al., 2013).
Bressman et al. (1994) reported a large multigenerational non-Jewish family of German ancestry in which 7 individuals had primary torsion dystonia. The mean age at onset was 28.4 years (range, 7 to 50). Six of the 7 had ... Bressman et al. (1994) reported a large multigenerational non-Jewish family of German ancestry in which 7 individuals had primary torsion dystonia. The mean age at onset was 28.4 years (range, 7 to 50). Six of the 7 had onset in the neck; the seventh had onset in the toes at age 7, but later had more severe neck involvement at age 17. All patients noted progression of dystonia to involve other body regions, most commonly the face, but also the tongue, larynx, jaw, and trunk. Five had abnormal speech. Some patients had mild limb involvement, resulting in abnormal writing. Treatment with levodopa was not beneficial. Fuchs et al. (2013) reported 28 patients from 8 families with autosomal dominant primary torsion dystonia, including the family reported by Bressman et al. (1994), which was referred to as family D1. The average age of onset was 31.3 years (range, 7 to 54 years), and most (82%) had focal onset in the neck. However, progression of dystonia usually spread to other sites. Cranial involvement was present in 57%, and 44% had speech involvement. About a third of patients eventually had limb involvement.
By exome sequencing of 2 large families with autosomal dominant dystonia, Fuchs et al. (2013) identified 2 different heterozygous mutations in the GNAL gene (139312.0001 and 139312.0002, respectively) that segregated with the disorder. Screening of the GNAL gene ... By exome sequencing of 2 large families with autosomal dominant dystonia, Fuchs et al. (2013) identified 2 different heterozygous mutations in the GNAL gene (139312.0001 and 139312.0002, respectively) that segregated with the disorder. Screening of the GNAL gene identified heterozygous pathogenic mutations (see, e.g., 139312.0003-139312.0006) in 6 of 39 additional families with a similar disorder. The GNAL gene encodes a stimulatory alpha-subunit of G proteins with high expression in the basal ganglia. In vitro functional expression studies in a cell-based bioluminescence reporter system indicated that a nonsense mutation (S293X; 139312.0002) did not support any DRD1 (126449)-driven responses, whereas wildtype GNAL caused a rapid increase in the signal. A V137M missense mutation (139312.0001) showed an intermediate phenotype, consistent with impaired association of G(s)-olf with the G-beta-gamma subunits. The findings suggested that the mutations resulted in a loss of function. The identification of GNAL mutations indicated that primary abnormalities in postsynaptic DRD1 and/or ADORA2A (102776) transmission in the basal ganglia may lead to dystonia.