Anne Weissbach

A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.

Prominent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus-dystonia

BACKGROUND Neurological and psychiatric disorders show clinical overlap suggesting a shared pathophysiological background. We evaluated myoclonus-dystonia, a monogenic movement disorder as a disease model for inherited psychopathology. METHOD We investigated 12 SGCE mutation carriers using standardized neurological and psychiatric examinations to assign DSM-IV diagnoses. Furthermore, we analyzed all studies in the Medline database which included psychiatric information on SGCE mutation-positive patients. RESULTS Of our twelve SGCE mutation carriers, 10 were older than 16 years. Two of them (20%) reported psychiatric diagnoses before our examination, which resulted in at least one psychiatric diagnosis in seven (70%) patients, most frequently anxiety (60%), depression (30%) or both. Substance abuse was observed in 20%, whereas obsessive-compulsive disorders were absent. One mutation carrier showed Axis 2 features. In the literature analysis, the ten studies using standardized tools covering DSM-IV criteria reported prevalences similar to those in our sample. This was three times the frequency of psychiatric disorders detected in 13 studies using clinical history or patient report only. CONCLUSION About two thirds of SGCE mutation carriers develop psychiatric comorbidity and >80% are previously undiagnosed.

Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

Objectives: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinsons Disease (GEO-PD) cohort. Methods: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. Results: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low. Conclusions: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

Exome sequencing in a family with restless legs syndrome

Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found.

Alternating Hemiplegia of Childhood as a New Presentation of Adenylate Cyclase 5-Mutation-Associated Disease: A Report of Two Cases

&NA; Mutations in the adenylate cyclase 5 (ADCY5) gene recently have been identified as the cause of a childhood‐onset disorder characterized by persistent or paroxysmal choreic, myoclonic, and/or dystonic movements. The 2 novel mutations we identified expand the clinical spectrum of ADCY5 mutations to include alternating hemiplegia of childhood.

A nonsense mutation in CHCHD2 in a patient with Parkinson disease.

While Parkinson disease (PD) was for many years regarded as a textbook example of a nongenetic disease, this view has dramatically changed over the past 2 decades with the identification of a number of genes, mutations in which cause monogenic PD. In recent years, the identification of disease genes was facilitated due to the advent of next-generation sequencing (NGS) resulting in an exponential increase in the number of reported disease genes.1 These observations require independent confirmation since the number of false-positive results has likewise considerably increased.2

The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30–50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D.

Hereditary dystonia and parkinsonism: two sides of the same coin?

This scientific commentary refers to ‘Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers’, by Mencacci et al. (doi:10/1093/brain/awu179). A number of inherited disorders are marked by combined dystonia and parkinsonism, and the genetic basis of many of these has now been identified. They include putative ‘neurofunctional’ conditions with dystonia-parkinsonism, such as DOPA-responsive dystonia caused by mutations in the GTP cyclohydrolase 1 ( GCH1 ) gene, as well as neurodegenerative diseases that present with predominant parkinsonism, frequently accompanied by dystonic features, i.e. ‘parkinsonism-dystonia’, as seen in carriers of parkin ( PARK2 ) and PINK1 mutations. Because dystonia can be the presenting sign in parkinsonism-dystonias (Grunewald et al. , 2013) and, conversely, patients with DOPA-responsive dystonia can present with isolated parkinsonism (Grimes et al. , 2002; Tadic et al. , 2012), it can be difficult to categorize individual patients solely on clinical grounds. The boundaries between dystonia and parkinsonism may thus be less well defined than previously thought, and this calls for detailed longitudinal phenotyping of patients. Indeed, despite the advent of next-generation sequencing and increased availability of diagnostic testing—resulting in a wealth of genetic data—systematic genotype–phenotype evaluations lag behind advances in genetics and have largely yet to be translated into clinical practice (Grunewald et al. , 2013). In this issue of Brain , Mencacci et al. elegantly address the phenomenon of prominent parkinsonism in carriers of GCH1 mutations (Mencacci et al. , 2014). Prompted by their observation that relatives of patients with DOPA-responsive dystonia can present with pure ‘Parkinson’s disease’, they systematically collected and examined four such unrelated pedigrees harbouring GCH1 mutations and reviewed the literature for similar reports. This resulted in a total of eight cases from different ethnic backgrounds with predominant parkinsonism, all of whom had a mostly asymmetrical reduction in dopamine transporter density or fluorodopa uptake, in …

Alcohol improves cerebellar‐learning deficit in myoclonus‐dystonia ‐ a clinical and electrophysiological investigation

To characterize neurophysiological subcortical abnormalities in myoclonus–dystonia and their modulation by alcohol administration.

Premotor–motor excitability is altered in dopa‐responsive dystonia

Dopa‐responsive dystonia is clinically dominated by a combination of dystonia and parkinsonism, both known to be associated with abnormal activity in premotor‐motor circuits.