Katja Ritz

DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation†

Mutations in THAP1, a gene encoding a nuclear pro‐apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio‐cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult‐onset (≥26 years) dystonia (n = 388) and early‐onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early‐onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult‐onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult‐onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

Myoclonus–dystonia: clinical and genetic evaluation of a large cohort

Background: Myoclonus–dystonia (M-D) is an autosomal dominant inherited movement disorder. Various mutations within the epsilon-sarcoglycan (SGCE) gene have been associated with M-D, but mutations are detected in only about 30% of patients. The lack of stringent clinical inclusion criteria and limitations of mutation screens by direct sequencing might explain this observation. Methods: Eighty-six M-D index patients from the Dutch national referral centre for M-D underwent neurological examination and were classified according to previously published criteria into definite, probable and possible M-D. Sequence analysis of the SGCE gene and screening for copy number variations were performed. In addition, screening was carried out for the 3 bp deletion in exon 5 of the DYT1 gene. Results: Based on clinical examination, 24 definite, 23 probable and 39 possible M-D patients were detected. Thirteen of the 86 M-D index patients carried a SGCE mutation: seven nonsense mutations, two splice site mutations, three missense mutations (two within one patient) and one multiexonic deletion. In the definite M-D group, 50% carried an SGCE mutation and one single patient in the probable group (4%). One possible M-D patient showed a 4 bp deletion in the DYT1 gene (c.934_937delAGAG). Conclusions: Mutation carriers were mainly identified in the definite M-D group. However, in half of definite M-D cases, no mutation could be identified. Copy-number variations did not play a major role in the large cohort.

SGCE isoform characterization and expression in human brain: implications for myoclonus-dystonia pathogenesis?

Myoclonus–dystonia (M–D) is a neurological movement disorder with involuntary jerky and dystonic movements as major symptoms. About 50% of M–D patients have a mutation in ɛ-sarcoglycan (SGCE), a maternally imprinted gene that is widely expressed. As little is known about SGCE function, one can only speculate about the pathomechanisms of the exclusively neurological phenotype in M–D. We characterized different SGCE isoforms in the human brain using ultra-deep sequencing. We show that a major brain-specific isoform is differentially expressed in the human brain with a notably high expression in the cerebellum, namely in the Purkinje cells and neurons of the dentate nucleus. Its expression was low in the globus pallidus and moderate to low in caudate nucleus, putamen and substantia nigra. Our data are compatible with a model in which dysfunction of the cerebellum is involved in the pathogenesis of M–D.

Cause and Mechanisms of Intracranial Atherosclerosis

Intracranial atherosclerosis, one of the leading causes of ischemic stroke, is associated with an increased risk for recurrent stroke and dementia.1,2 Individuals of Asian, Hispanic, and African American ancestry are especially affected. Recent European studies revealed a much higher prevalence of intracranial lesions than commonly presumed, suggesting that intracranial atherosclerotic disease is potentially the most common cause of ischemic stroke worldwide.1,3 Ischemic strokes are clinically categorized into 5 subtypes based on their underlying cause: large-artery atherosclerotic stenosis, small-artery disease (lacunes), cryptogenic, major-risk-source cardiogenic embolism, and unusual (eg, dissections, arteritis). Most nonlacunar ischemic strokes are thought to be thromboembolic, which presumably also accounts for most cryptogenic strokes. Embolic sources include minor-risk or covert cardiac sources, veins via paradoxical embolism, and nonocclusive atherosclerotic plaques in the aortic arch or cervical or cerebral arteries.4 Besides embolic strokes, 2 other mechanisms have been associated with intracranial atherosclerosis-related strokes, namely hypoperfusion through a stenotic artery causing watershed or border-zone stroke and plaque overgrowth of perforator artery ostia, which is associated with penetrating artery disease and lacunar infarcts and has been related to cryptogenic strokes.5–7 Even mild stenosis of intracranial atherosclerotic arteries (<50%) may therefore be clinically relevant, and high-resolution magnetic resonance imaging studies are needed to identify and determine the degree and location of stenosis in this patient group.5,8 The possibly causal role of nonstenotic plaques in ischemic stroke highlights the need for more insight into the mechanisms and occurrence of intracranial atherosclerosis. In the 1960s and 1970s, large, descriptive autopsy studies were conducted, providing classic morphological features of intracranial arteries. Despite the importance of intracranial atherosclerosis to stroke and dementia, there is a lack of more recent mechanistic studies. Therefore, we intend to draw attention to this neglected research field by …

Mouse Models to Study the Effect of Cardiovascular Risk Factors on Brain Structure and Cognition

Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimers disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood–brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during aging.

CACNA1B mutation is linked to unique myoclonus-dystonia syndrome

Using exome sequencing and linkage analysis in a three-generation family with a unique dominant myoclonus-dystonia-like syndrome with cardiac arrhythmias, we identified a mutation in the CACNA1B gene, coding for neuronal voltage-gated calcium channels CaV2.2. This mutation (c.4166G>A;p.Arg1389His) is a disruptive missense mutation in the outer region of the ion pore. The functional consequences of the identified mutation were studied using whole-cell and single-channel patch recordings. High-resolution analyses at the single-channel level showed that, when open, R1389H CaV2.2 channels carried less current compared with WT channels. Other biophysical channel properties were unaltered in R1389H channels including ion selectivity, voltage-dependent activation or voltage-dependent inactivation. CaV2.2 channels regulate transmitter release at inhibitory and excitatory synapses. Functional changes could be consistent with a gain-of-function causing the observed hyperexcitability characteristic of this unique myoclonus-dystonia-like syndrome associated with cardiac arrhythmias.

RELN rare variants in myoclonus-dystonia

Myoclonus‐dystonia (M‐D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M‐D cases are caused by mutations in the epsilon‐sarcoglycan gene. In remaining M‐D patients, no genetic factor has been established, indicating genetic heterogeneity.

Is TOR1A a risk factor in adult‐onset primary torsion dystonia?

Studies of genetic association between TOR1A and adult‐onset primary torsion dystonia have contradictory results.

Screening for dystonia genes DYT1, 11 and 16 in patients with writer's cramp.

Task‐specific focal upper limb dystonia can be part of the phenotypic spectrum of different types of hereditary dystonia. We investigated whether writers cramp as presenting symptom is associated with mutations in DYT11, DYT16, or with the DYT1 GAG deletion in 43 patients. No DYT11 and DYT16 mutations were identified. One patient carried the GAG deletion in the DYT1 gene. In our cohort, writers cramp as presenting symptom is not associated with mutations in DYT11, DYT16, but it can be the sole manifestation of DYT1 GAG deletion mutation carriers.

Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia

Cervical dystonia (CD) may be accompanied by a bilateral postural tremor of the arms. The mechanisms leading to dystonia and tremor are not clear; aberrant neuroplasticity may, however, play a role. The brainderived neurotrophic factor (BDNF, OMIM #113505) is involved in neuroplasticity modulation. A functional polymorphism Val66Met (rs6265) in BDNF has been described. Two small association studies have investigated the Val66Met polymorphism in CD, with contradicting results. In order to adequately clarify the role of the Val66Met polymorphism in CD, we investigated this variant in a large, clinically well-defined Dutch CD cohort. All CD patients (n 1⁄4 472) were examined by a movement disorders specialist. A subgroup of CD patients exhibited postural arm tremor, previously termed ‘‘tremor associated with dystonia.’’ An ageand sex-matched control group (711 subjects, not available for examination) was recruited from the Dutch National Blood Bank. All details regarding patient inclusion, genotyping, and data analysis can be found in the Supporting Information. The clinical characteristics of the CD cohort are listed in Table 1. The frequency of the 66Met-allele was 0.21 in the CD group and 0.20 in the unaffected group (P 1⁄4 .60, odds ratio [OR], 1.05; Fisher’s exact test). In addition, no genotype association was found (P 1⁄4 .67). To assess the genetic modifier effects of this polymorphism as they relate to CD, we defined phenotypic subgroups based on postural arm tremor and the spread of symptoms (Table 1). We compared the genotype frequencies of Val66Met between subgroups (Table 1) and found that Met66Met was not associated with an increased risk of segmental spread of dystonia (OR for Met66Met, 0.46; 95% confidence interval [CI], 0.13–1.59; P 1⁄4 .22), nor did it influence the age at onset (AaO, P 1⁄4 .98). Interestingly, we did find a significantly higher frequency of bilateral postural arm tremor in CD patients with the BDNF Met66Met polymorphism (53%), compared to 35% in Val66Met and 29% in Val66Val carriers (P 1⁄4 .02; OR, 2.52; 95% CI, 1.10–5.76). This result could not be attributed to AaO, disease duration, age at examination, or sex (adjusted ORs: 2.60, 2.51, 2.85, and 2.77, respectively). The effect is only present in the homozygous Met66Met and not in theVal66Met group (OR, 1.28; 95% CI, 0.84–1.95; P 1⁄4 .23). The literature tells us that subjects carrying the Met-allele lack training-dependent increases in the motor evoked potential (MEP) amplitude, show a reduced motor map reorganization and a differential response to repetitive transcranial magnetic stimulation (rTMS) plasticity induction protocols. Replication of the association between Met66Met and postural arm tremor in CD will require over 400 CD patients with arm tremor to reach 80% power to detect an equal effect as seen in the present study (OR 2.50 or higher). With a prevalence of arm tremor in CD of approximately 32%, a CD cohort of at least 1250 patients is required. Our findings suggest that the BDNF polymorphism is associated with arm tremor in CD. Further research is needed to investigate whether this effect is only present in CD patients or if BDNF is also a risk factor for other tremor syndromes, such as essential tremor.