A BS TRACT: This comprehensive MDSGene review is devoted to 7 genes -TOR1A, THAP1, GNAL, ANO3, PRKRA, KMT2B, and HPCAmutations in which may cause isolated dystonia. It followed MDSGene's standardized data extraction protocol and screened a total of~1200 citations. Phenotypic and genotypic data on~1200 patients with 254 different mutations were curated and analyzed. There were differences regarding age at onset, site of onset, and distribution of symptoms across mutation carriers in all 7 genes. Although carriers of TOR1A, THAP1, PRKRA, KMT2B, or HPCA mutations mostly showed childhood and adolescent onset, patients with GNAL and ANO3 mutations often developed first symptoms in adulthood. GNAL and KMT2B mutation carriers frequently have 1 predominant site of onset, that is, the neck (GNAL) or the lower limbs (KMT2B), whereas site of onset in DYT-TOR1A, DYT-THAP1, DYT-ANO3, DYT-PRKRA, and DYT-HPCA was broader. However, in most DYT-THAP1 and DYT-ANO3 patients, dystonia first manifested in the upper half of the body (upper limb, neck, and craniofacial/laryngeal), whereas onset in DYT-TOR1A, DYT-PRKRA and DYT-HPCA was frequently observed in an extremity, including both upper and lower ones. For ANO3, a segmental/multifocal distribution was typical, whereas TOR1A, PRKRA, KMT2B, and HPCA mutation carriers commonly developed generalized dystonia. THAP1 mutation carriers presented with focal, segmental/multifocal, or generalized dystonia in almost equal proportions. GNAL mutation carriers rarely showed generalization. This review provides a comprehensive overview of the current knowledge of hereditary isolated dystonia. The data are also available in an online database (http://www.mdsgene.org), which additionally offers descriptive summary statistics.

ObjectiveIsolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients.MethodsPatients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread.Results487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009).ConclusionsInitial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.

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ObjectivesTo determine the possible interactions between levodopa therapy and plasma levels of B vitamins in patients with advanced idiopathic Parkinson's disease (IPD) in the context of either oral levodopa therapy or levodopa/carbidopa intestinal gel (LCIG). Secondly, to determine the prevalence of neuropathy and its relation to plasma levels of B vitamins and homocysteine.MethodsMedication doses, neurographies, and serum levels of pyridoxine, cobalamin, folate, and homocysteine of eight LCIG and 13 orally treated advanced IPD patients matched for age, Hoehn & Yahr stage, and UPRDS III were collected. This data was analyzed for correlation with daily levodopa dose (LDD).Results LICG patients had a longer disease duration and higher LDD. All LCIG patients and most orally treated patients had sensorimotor axonal polyneuropathy. Of all plasma vitamin levels, pyridoxine was decreased most and significantly lower in the LCIG group. Cobalamin and folate, however, were within the lower reference range, and homocysteine highly elevated, all without any significant difference between both groups. LDD correlated significantly with pyridoxine deficiency (p = .02) irrespective of the route of application and with hyperhomocysteinemia in the LCIG group (p = .03). At LDDs above 2,000 mg, pyridoxine deficiency was almost always detectable.ConclusionsPyridoxine deficiency and hyperhomocysteinemia are dependent on the daily levodopa/carbidopa dose, while levels of cobalamin and folate are not. The mode of application of levodopa/carbidopa has no impact on B‐vitamin levels. Neuropathy is very frequent in advanced IPD; however, it remains to be investigated further whether neuropathy is more frequent in LCIG than in orally levodopa/carbidopa‐treated advanced IPD patients.

Monitoring one’s actions is essential for goal-directed performance. In the event-related potential (ERP), errors are followed by fronto-centrally distributed negativities. These error(-related) negativity (Ne/ERN) amplitudes are often found to be attenuated in patients with Parkinson’s disease (PD) compared to healthy controls (HC). Although Ne/ERN has been proposed to be related to dopaminergic neuronal activity, previous research did not find evidence for effects of dopaminergic medication on Ne/ERN amplitudes in PD. We examined 13 PD patients “on” and “off” dopaminergic medication. Their response-locked ERP amplitudes (obtained on correct [Nc/CRN] and error [Ne/ERN] trials of a flanker task) were compared to those of 13 HC who were tested twice as well, without receiving dopaminergic medication. While PD patients committed more errors than HC, error rates were not significantly modulated by dopaminergic medication. PD patients showed reduced Ne/ERN amplitudes relative to HC; however, this attenuation of response-locked ERP amplitudes was not specific to errors in this study. PD-related attenuation of response-locked ERP amplitudes was most pronounced when PD patients were on medication. These results suggest overdosing of dopaminergic pathways that are relatively spared in PD, but that are related to the generation of the Ne/ERN, notably pathways targeted on the medial prefrontal cortex.