Clinical presentation of a patient with SLC20A2 and THAP1 deletions: differential diagnosis of oromandibular dystonia.
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ABSTRACT:
SUBMITTER: Fujioka S
PROVIDER: S-EPMC4408548 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
Clinical presentation of a patient with SLC20A2 and THAP1 deletions: differential diagnosis of oromandibular dystonia.
Fujioka Shinsuke S Strongosky Audrey J AJ Hassan Anhar A Rademakers Rosa R Dickson Dennis W DW Wszolek Zbigniew K ZK
Parkinsonism & related disorders 20150108 3
Similar Datasets
Project description:Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.
| S-EPMC3969760 | biostudies-literature
Project description:Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.
| S-EPMC8481678 | biostudies-literature
Project description:Meige syndrome (MS) is cranial dystonia characterized by the combination of upper and lower cranial involvement and including binocular eyelid spasms (blepharospasm; BSP) and involuntary movements of the jaw muscles (oromandibular dystonia; OMD). The etiology and pathogenesis of this disorder of the extrapyramidal system are not well-understood. Neurologic and ophthalmic examinations often reveal no abnormalities, making diagnosis difficult and often resulting in misdiagnosis. A small proportion of patients have a family history of the disease, but to date no causative genes have been identified to date and no cure is available, although botulinum toxin A therapy effectively mitigates the symptoms and deep brain stimulation is gaining increasing attention as a viable alternative treatment option. Here we review the history and progress of research on MS, BSP, and OMD, as well as the etiology, pathology, diagnosis, and treatment.
| S-EPMC8039296 | biostudies-literature
Project description:BackgroundMovement disorder is common in Wilson's disease (WD), but there is no report on oromandibular dystonia (OMD). We report on frequency, severity, and MRI correlation of OMD in Wilson's disease with neurological manifestations (WDNM) and its response to treatment.MethodsConsecutive WDNM patients were included and their clinical, hematological, serum chemistry, and MRI findings were noted. Neurological severity of WD and OMD were assessed. Burke-Fahn-Marsden (BFM) score for dystonia was noted. Patients were treated with penicillamine, zinc, and multiple antidystonic drugs. Clinical improvement at 3 and 6 months was noted.ResultsOverall, 61 of 67 (91%) WDNM patients had OMD, whose median age was 13.5 years. Median severity of OMD was 2.5 (range, 1-4). Thirteen patients were anarthric and 12 unable to eat. Severity of OMD correlated with drooling (r = 0.29; P = 0.02), BFM score (r = 0.63; P < 0.001), pancytopenia (r = -0.26; P = 0.04), and serum ceruloplasmin (r = 0.33; P = 0.01), but not with location and number of MRI lesions. Compared to baseline, severity of OMD improved at 6 months (P < 0.001), but not at 3 months. None became asymptomatic. Improvement in OMD paralleled with improvement in severity grade of WDNM (r = 0.26; P = 0.04) and with BFM score (r = 0.31; P = 0.02).ConclusionOMD was a common manifestation of WDNM occurring in 91% patients, and OMD improved partially over the study period.
| S-EPMC6178763 | biostudies-literature
Project description: Not available
| S-EPMC6547033 | biostudies-literature
Project description:BackgroundTHAP1 encodes a transcription factor (THAP1) that harbors an atypical zinc finger domain and regulates cell proliferation. An exon 2 insertion/deletion frameshift mutation in THAP1 is responsible for DYT6 dystonia in Amish-Mennonites. Subsequent screening efforts in familial, mainly early-onset, primary dystonia identified additional THAP1 sequence variants in non-Amish subjects.ObjectiveTo examine a large cohort of subjects with mainly adult-onset primary dystonia for sequence variants in THAP1.MethodsWith high-resolution melting, all 3 THAP1 exons were screened for sequence variants in 1,114 subjects with mainly adult-onset primary dystonia, 96 with unclassified dystonia, and 600 controls (400 neurologically normal and 200 with Parkinson disease). In addition, all 3 THAP1 exons were sequenced in 200 subjects with dystonia and 200 neurologically normal controls.ResultsNine unique melting curves were found in 19 subjects from 16 families with primary dystonia and 1 control. Age at dystonia onset ranged from 8 to 69 years (mean 48 years). Sequencing identified 6 novel missense mutations in conserved regions of THAP1 (G9C [cervical, masticatory, arm], D17G [cervical], F132S [laryngeal], I149T [cervical and generalized], A166T [laryngeal], and Q187K [cervical]). One subject with blepharospasm and another with laryngeal dystonia harbored a c.-42C>T variant. A c.57C>T silent variant was found in 1 subject with segmental craniocervical dystonia. An intron 1 variant (c.71+9C>A) was present in 7 subjects with dystonia (7/1,210) but only 1 control (1/600).ConclusionsA heterogeneous collection of THAP1 sequence variants is associated with varied anatomical distributions and onset ages of both familial and sporadic primary dystonia.
| S-EPMC2809032 | biostudies-literature
Project description:THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society.
| S-EPMC3664430 | biostudies-literature
Project description:Oromandibular dystonia (OMD) causes involuntary movements of masticatory and lingual muscles impairing eating, speaking, and swallowing. Treatment options are limited. The objective of this study was to determine the safety and efficacy of abobotulinumtoxinA (aboBoNTA) in OMD. A dose-finding study (phase 1) followed by a single session, prospective, single-blind trial (phase 2) was carried out. OMD subjects were evaluated at baseline, 6 and 12 weeks. Muscles injected were tailored to individual symptoms using EMG guidance, but the aboBoNTA dose for each muscle was pre-specified based on phase 1 results. Evaluations were Global Dystonia Rating Scale (GDS), Unified Dystonia Rating Scale (UDRS), Clinical Global Impression (CGI) improvement and severity, and quality of life (OMDQ-25). Adverse events were monitored. The lowest dosage in phase 1 resulted in adverse effects in two of three patients and thus was used in phase 2. In phase 2, adverse effects were observed in 50% of subjects including dysphagia, voice change, and soft palate weakness. Most were mild. Significant improvement was seen in quality of life (OMDQ-25), speech (BFMq21), and change in GDS, UDRS, CGI severity assessed by the unblinded investigator, but not in blinded video ratings. We conclude that aboBoNTA therapy in this study was associated with improved quality of life and was generally well tolerated in OMD, but occurrence of dysphagia dictated the importance of using low genioglossus dosing. Face to face assessment appears to be more sensitive than video assessment for change in OMD severity. Consideration of the disability in OMD places constraints on traditional placebo-control trial design. Development of novel trial designs is warranted.
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Project description:A case of atypical blepharospasm with oromandibular dystonia is presented in a patient found to have cerebral amyloid angiopathy on magnetic resonance imaging and a shared mechanism is discussed.
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