Adult-onset dystonia with marfanoid features.
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ABSTRACT:
SUBMITTER: Norris SA
PROVIDER: S-EPMC5566795 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.
| S-EPMC9724767 | biostudies-literature
Project description:Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult onset, primary cervical dystonia.Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult onset cervical dystonia and matching controls for sequence variants in this mutant gene.Exome sequencing led to the identification of an exonic splicing enhancer mutation in exon 7 of CIZ1 (c.790A>G, p.S264G), which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified 2 additional CIZ1 missense mutations (p.P47S and p.R672M).Mutations in CIZ1 may cause adult onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system.
| S-EPMC3334472 | biostudies-literature
Project description:Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis.
| S-EPMC5712317 | biostudies-literature
Project description:BackgroundIsolated focal dystonia (IFD) is a heterogeneous group of potentially invalidating movement disorders. The etiopathogenesis is complex, both genetic and environmental factors playing a role, but remains elusive. The CACNA1B gene codes for the N-type neuronal voltage-gated calcium channels CaV2.2, which may play a role in the development of some IFD.MethodsWe analyzed samples from the GENDYS cohort for mutations in CACNA1B gene, using targeted next-generation sequencing (NGS).ResultsThe GENDYS cohort consists of 120 people with adult-onset IFD (cervical dystonia 47.5%, blepharospasm 47.2%, others 8.3%). Of these, 35% had subsequent topographical extension. Average age at onset was 42 and average disease durations 8 years. Targeted NGS revealed a novel frameshift mutation c.2291AGG?>?A, in exon 19, and a previously reported variant, c.6834T?>?G, in exon 47.ConclusionOur findings suggest that disease-causing mutations in CACNA1B gene may be involved in the development of some adult-onset IFD. To our knowledge, this is the first study that identified a disease-causing CACNA1B gene mutation in association with adult-onset IFD.
| S-EPMC7870633 | biostudies-literature
Project description:Osteogenesis Imperfecta is an inherited disease characterized by easily-broken bones, which manifests as multiple fractures with minimal trauma, joint laxity, sclerosis, blue sclera, and several other manifestations. Protrusio acetabuli is defined as the displacement of the femoral head so that it lies medial to the ischioilial line. In a skeletally mature patient with both Marfan syndrome and PA, an eventual hip arthroplasty is the only method available for correction of the deformity. However, in patients with Osteogenesis Imperfecta and PA, THA remains a controversial treatment. A 14-year-old male patient diagnosed with Osteogenesis Imperfecta Type 1A presented to the orthopedic surgery clinic complaining of groin pain of 1-year duration radiating to the thigh and knee. The patient was found to have radiologic signs of protrusion acetabuli. The patient was started with bisphosphonate and after medical failure, underwent a Total Hip Arthroplasty (THA). In post-operative follow-ups, the patient had relief of pain and was able to walk more comfortably and without a lump. The previously operated hip was examined and showed no signs of infection, dislocation, or fracture. Radiographic studies show no evidence of prosthesis failure or loosening with valgus position of the femoral stem and neutral acetabular angle. Ten years after the primary arthroplasty, the previously operated hip had maintained its stability and had no related complications. Despite the controversy surrounding the treatment of younger patients with hip failure, using total hip arthroplasty, this patient exhibited excellent results, with vast improvement in their symptoms and stability.
| S-EPMC6985030 | biostudies-literature
Project description:Generalized dystonia, both primary and secondary forms, and axial dystonias such as tardive dystonia, and idiopathic cervical dystonia are responsive to globus pallidus interna (GPi) DBS. There is a paucity of investigations probing the impact of DBS on adult-onset axial dystonia. We assessed the efficacy of GPi DBS in four patients with rare adult-onset axial dystonia.Primary outcome measure was improvement in the motor component of the Burke-Fahn-Marsden (BFM) rating scale. Secondary outcome measures were quality of life as determined by the SF-36 questionnaire, time to achieve best possible benefit and DBS parameters that accounted for the best response. In patients with prominent concomitant cervical dystonia we also used the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).GPi DBS improved BFM scores by 87.63 ± 11.46%. Improvement in total severity scale of TWSTRS was 71.5 ± 12.7%. Quality of life also remarkably improved as evidenced by 109.38 ± 82.97 and 7.05 ± 21.48% percent change in psychometrically-based physical component summary (PCS), and a mental component summary (MCS) score respectively.GPi DBS is a very effective treatment for adult-onset axial dystonia. Considering its refractoriness to medical therapy and significant impact on quality of life DBS should be considered for this disorder.
| S-EPMC4879957 | biostudies-literature
Project description:BackgroundDystonia is a group of chronic diseases, causing considerable physical and psychosocial stress to patients and health care expenses. We studied the prevalence of different dystonia types in Finland in the years 2007-2016.MethodsAll patients with an ICD-10 code of dystonia were retrieved from the national care register. Average age-adjusted yearly prevalence was assessed for adult-onset isolated idiopathic or hereditary dystonia types from patient records from the Uusimaa and Pirkanmaa provinces.Results1316 patients were confirmed to have adult-onset isolated idiopathic or hereditary dystonia based on hospital records from two provinces. On average, the age-adjusted prevalence for all adult-onset dystonia was 405 per million and for cervical dystonia 304 per million. For other dystonia types the prevalence ranged from 1-33 per million.ConclusionsAdult onset cervical dystonia was the most common type of dystonia with relatively high prevalence in Finland compared with other countries. The prevalence of other types of dystonia was similar compared with other European studies. The higher prevalence of cervical dystonia may be partially explained by the better coverage of patients in public health care, but genetic and exogenous factors might contribute to it.
| S-EPMC6245745 | biostudies-literature
Project description:Gene expression studies were performed to identify pathways possibly dysregulated by mutant in the gene Gα(olf). These experiments employed RNA derived from lymphoblastoid cell lines established for 4 affected carriers and 4 non-carriers. In comparison to endogenous control and other dystonia-associated genes, GNAL was expressed at relatively low levels in lymphoblastoid cell lines.
2013-01-26 | GSE43771 | GEO
Project description:The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although ~10% of probands have at least one first- or second-degree relative to dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1 and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified three Caucasian pedigrees with GNAL mutations [c.591dupA (p.R198Tfs*13); c.733C>T (p.R245*); and c.3G>A (p.M1?)]. These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole-exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [G?(olf)]. G?(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed upregulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that G?(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.
| S-EPMC3658169 | biostudies-literature
Project description: Not available
| S-EPMC7604663 | biostudies-literature