Our data in an Eastern Slavic (Russian) population correspond well to results of other studies from different countries and confirm that certain TOR1A genotypes may be regarded as factors predisposing to focal and segmental dystonia.
A novel TOR1A mutation (c.581A>T, p.Asp194Val) was found in a patient with early-onset segmental dystonia harboring a THAP1 mutation (c.539T>C, p.Leu180Ser).
The following groups of patients were included in the study: 1) patients with early-onset (<30 years) generalized dystonia and those patients with onset after age 30 years who have relatives with early-onset dystonia, 2) patients with writer's cramp (focal or as part of segmental dystonia) independently of age of onset, 3) asymptomatic (adult only) relatives of the diagnosed DYT1 carriers.
Here, we report the course of clinical improvement for up to 11 years of pallidal DBS in three male patients belonging to the same family with early-onset generalized or segmental dystonia due to a heterozygous THAP1 gene mutation (DYT6).
A novel TOR1A mutation (c.581A>T, p.Asp194Val) was found in a patient with early-onset segmental dystonia harboring a THAP1 mutation (c.539T>C, p.Leu180Ser).
The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writer's dystonia and then developing segmental dystonia.
PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia.
Genome-wide significance with MD was observed for an intronic variant in the arylsulfatase G (ARSG) gene (rs11655081; P = 3.95 × 10(-9) ; odds ratio [OR], 4.33; 95% confidence interval [CI], 2.66-7.05). rs11655081 was also associated with WD (P = 2.78 × 10(-2) ) but not with any other focal or segmental dystonia.
Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia.
Two clinical patterns of deafness-dystonia syndrome were observed: patients who had an onset in childhood had generalized dystonia (10 of 13 patients) with frequent bulbar involvement, whereas patients who had a dystonia onset in adulthood had segmental dystonia (3 of 13 patients) with the invariable presence of laryngeal dystonia.
Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls.
Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls.
Myoclonus-dystonia (M-D, DYT11) is a dystonia plus syndrome characterized by brief myoclonic jerks predominantly of neck and upper limbs in combination with focal or segmental dystonia.