Alexander Schmidt

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family.

Etiology of musician’s dystonia: Familial or environmental?

Objective: To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician’s dystonia (MD) and to identify possible environmental triggers. Methods: The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia [FTSD] and 14 with no known family history [FH−]) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD. Results: A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias: n = 2), 5 of whom were members of FH− families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members. Conclusion: Our results suggest a genetic contribution to musician’s dystonia with phenotypic variability including focal task-specific dystonia. BIDS = Beth Israel Dystonia Screen; FH+ = reported positive family history of focal task-specific dystonia; FH− = no known family history of focal task-specific dystonia; FTSD = focal task-specific dystonia; MD = musician’s dystonia; WC = writer’s cramp.

A heterozygous frameshift mutation in PRKRA (DYT16) associated with generalised dystonia in a German patient

We have read with great interest the article in The Lancet Neurology by Camargos and colleagues who describe the fi nding of DYT16 dystonia, a novel, recessively inherited form of early-onset generalised dystonia that is associated with a missense mutation in the gene that encodes PPKRA. The homozygous mutation was found in seven aff ected members from three Brazilian families. In one family, the mother of a homozygous carrier was also aff ected but could not be genotyped. This raises the question of whether a heterozygous mutation might act as a susceptibility factor for dystonia. A similar scenario has been discussed for seemingly recessive genes that are linked to parkinsonism. To explore further the role of mutations in PRKRA, we screened patients with dystonia and controls for changes in the sequence of this gene. The phenotypic spectrum associated with mutations in PRKRA is, for the most part, unknown; on the basis of early onset (<25 years; mean 13·7 [SD 7·4] years), a positive family history (n=9), and limb involvement, we identifi ed 52 unrelated patients with dystonia: 22 patients presented with generalised dystonia, 11 with segmental dystonia, 15 with musician’s dystonia, and four with writer’s cramp. By use of published primer sequences, we sequenced all the coding exons and fl anking intronic sequences of PRKRA in these patients. The known and newly detected sequence variations were tested in a further 75 patients with dystonia (mean age of onset of 31·6 [6·4] years), of whom 15 had a positive family history of dystonia, and in 189 neurologically healthy controls (mean age: 57·7 [11·6] years). We identifi ed a novel heterozygous mutation (c.266_267delAT; p.H89fsX20) in exon 3 of PRKRA in patient 14741 (fi gure). This predicted frameshift mutation, which might cause premature truncation of the protein, was absent in the other patients and the controls. We did not detect any other mutations in PRKRA in this patient. Clinically, he presented with early-childhood-onset leg dystonia that spread gradually over the course of a few years. His family history was unremarkable for any movement disorder; secondary causes of dystonia were excluded; and brain MRI was normal. At his last examination, the patient, C C G

Structural imaging in the presymptomatic stage of genetically determined parkinsonism.

Several genes associated with monogenic forms of Parkinsons disease (PD) have been discovered, opening up new avenues for the investigation of presymptomatic stages of PD. Using voxel-based morphometry in 30 asymptomatic mutation carriers (MC) with mutations in four different genes for PD and 100 healthy controls, we identified an increase in gray matter volume (GMV) in the striatum in asymptomatic Parkin, PINK1, ATP13A2 and, to a much lesser extent, in LRRK2 MC. Moreover, an increase in GMV was found in the parieto-temporo-occipital association cortex in asymptomatic Parkin and ATP13A2 MC. The observed striatal GMV increase might be the common structural correlate of compensatory mechanisms due to the latent dopaminergic deficit, reflecting the different, but probably interrelated pathogenic pathways resulting in nigral cell death. Asymptomatic PINK1 and LRRK2 MC also revealed smaller GMV in the hippocampal region, which might play a role in the observed psychiatric disorders.

Challenges of Making Music: What Causes Musician’s Dystonia?

Challenges of Making Music: What Causes Musician’s Dystonia? Musician’s dystonia, a task-specific movement disorder, affects 1% to 2% of professional musicians and is thought to be environmentally acquired, related to years of practice.1,2 Indeed, professional musicians will have spent more than 10 000 hours on the instrument by the age of 20 years.3 Recently, a clustering of different types of dystonia was reported in the families of patients with musician’s dystonia, suggesting also a genetic contribution to the disease.4 However, the underlying molecular genetic factors are currently unknown. We here investigated in a case-control design whether intensive practice or other environmental factors are associated with musician’s dystonia in combination with genetic susceptibility.

Arm tremor in cervical dystonia—Is it a manifestation of dystonia or essential tremor?

The classification of arm tremor in cervical dystonia is a controversial issue. There have been many, at times passionate disputes in the movement disorder community about whether it should be classified as a manifestation of dystonia or essential tremor associated with dystonia. There are arguments in favor of both views. Settling the issue might be relevant to the understanding of the etiological, presumably genetic, background because phenomenological grouping is the starting point for genetic analyses. From this point of view, we outline this tremor debate and add some new clinical data.

Genome-wide association study in musician's dystonia: A risk variant at the arylsulfatase G locus?

Musicians dystonia (MD) affects 1% to 2% of professional musicians and frequently terminates performance careers. It is characterized by loss of voluntary motor control when playing the instrument. Little is known about genetic risk factors, although MD or writers dystonia (WD) occurs in relatives of 20% of MD patients. We conducted a 2‐stage genome‐wide association study in whites. Genotypes at 557,620 single‐nucleotide polymorphisms (SNPs) passed stringent quality control for 127 patients and 984 controls. Ten SNPs revealed P < 10−5 and entered the replication phase including 116 MD patients and 125 healthy musicians. A genome‐wide significant SNP (P < 5 × 10−8) was also genotyped in 208 German or Dutch WD patients, 1,969 Caucasian, Spanish, and Japanese patients with other forms of focal or segmental dystonia as well as in 2,233 ethnically matched controls. 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. The allele frequency of rs11655081 varies substantially between different populations. The population stratification in our sample was modest (λ = 1.07), but the effect size may be overestimated. Using a small but homogenous patient sample, we provide data for a possible association of ARSG with MD. The variant may also contribute to the risk of WD, a form of dystonia that is often found in relatives of MD patients.

THE D216H VARIANT IN THE DYT1 GENE: A SUSCEPTIBILITY FACTOR FOR DYSTONIA IN FAMILIAL CASES?

Primary focal dystonia is a clinically and genetically heterogeneous disorder. In contrast, early-onset generalized torsion dystonia is often caused by a heterozygous deletion of three nucleotides (GAG) in the DYT1 gene leading to the loss of a glutamic acid residue (deltaE) of the gene product TorsinA.1 Interestingly, the only nonsynonymous coding sequence variation in DYT1 , rs1801968 (D216H), was demonstrated to reduce penetrance of the GAG deletion when present in trans to this mutation.2 While one study suggested a protective effect of H216 in a small number of tested Indian patients with primary dystonia, other reports failed to show any association.3–5 The aim of the present study was to evaluate the role of D216H in German patients with familial primary dystonia and, in case of association, to establish the frequency of this variant in patients with dystonia regardless of their family history. ### Subjects. Study subjects were recruited from four movement disorders centers in Northern Germany. After obtaining informed consent and approval of the study by the local ethical standards committee, all participants underwent a standardized neurologic examination by a movement disorders specialist, and blood samples were drawn. We included 111 unrelated familial cases with primary focal or segmental dystonia, along with 241 unrelated control subjects. Family history was regarded as positive when at least one …

Depression and Quality of Life in Monogenic Compared to Idiopathic, Early-Onset Parkinson's Disease

Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early‐onset PD cases, 21% of late‐onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson‐associated depression reported fewer feelings of guilt or self‐doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early‐onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized.

Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations.

A three‐nucleotide (GAG) deletion (ΔE) in TorsinA (TOR1A) has been identified as the most common cause of dominantly inherited early‐onset torsion dystonia (DYT1). TOR1A encodes a chaperone‐like AAA+‐protein localized in the endoplasmic reticulum. Currently, only three additional, likely mutations have been reported in single dystonia patients. Here, we report two new, putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wild‐type (WT) protein and two known mutations (ΔE and p.R288Q). While inclusion formation is a characteristic feature for ΔE TOR1A, elevated levels of aggregates for other mutations were not observed when compared with WT TOR1A. WT and mutant TOR1A showed preferred degradation through the autophagy‐lysosome pathway, which is most pronounced for p.A14_P15del, p.R288Q, and ΔE TOR1A. Notably, blocking of the autophagy pathway with bafilomycin resulted in a significant increase in inclusion formation in p.E121K TOR1A. In addition, all variants had an influence on protein stability. Although the p.A14_P15del mutation affects the proposed oligomerization domain of TOR1A, this mutation did not disturb the ability to dimerize. Our findings demonstrate functional changes for all four mutations on different levels. Thus, both diagnostic and research genetic screening of dystonia patients should not be limited to testing for the ∆E mutation.