ADCY5-Related Dyskinesia: A Genetic Cause of Early-Onset Chorea-Report of Two Cases and a Novel Mutation.
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ABSTRACT:
SUBMITTER: Padmanabha H
PROVIDER: S-EPMC8680907 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC).We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue.The c.1252C>T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic). The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5 expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend.Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia.
| S-EPMC4501937 | biostudies-literature
Project description:Investigators from the Institute of Neurology, London, UK, and centers in Italy, Germany, and Greece, studied 18 unrelated cases of benign hereditary chorea BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations.
| S-EPMC4747282 | biostudies-literature
Project description:IntroductionWoakes' syndrome is a rare condition commonly defined as recurrent sinonasal polyposis with consecutive destruction of the nasal pyramid. Till now, only a few cases have been reported in the literature. The purpose of this paper is to present the features of woakes' syndrome through two new clinical cases, adding some valuable insight to the recently reported cases.Case reportWe report a series of two consecutive adults male and female patients, aged 55 and 58 years, with Samter's triad, who presented recurrent nasal polyposis and progressive broadening of the nasal dorsum. Facial CT showed in both patients the same radiologic pattern of nasal and paranasal cavities obliteration with nasal bone deformation. Both patients underwent functional endoscopic sinus surgery and correction of the bony nasal vault deformity without osteotomies. At 3 months follow-up, the nasal air passage remained free and aesthetic outcomes were observed.Discussionhaving been described over 130 years ago, the etiology of woakes' syndrome remains unclear. Treatment includes topical treatment and sinonasal surgery. Surgical treatment of the nasal dorsum deformity is rarely addressed.ConclusionThese observations suggest that the external nose deformity may be successfully corrected by digital compression, in combination with endoscopic sinus surgery.
| S-EPMC8377525 | biostudies-literature
Project description:BACKGROUND:We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS:Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS:We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS:We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC5873427 | biostudies-literature
Project description: Not available
| S-EPMC6417756 | biostudies-literature
Project description:We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated with a novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse whole-exome sequencing data from an affected grandmother-granddaughter pair. Whole-exome sequencing identified 18,000 shared variants, of which 46 were non-synonymous changes not present in a local cohort of control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele frequency in the 1000 Genomes Project and on phylogenetic conservation yielded 13 candidate variants, of which the heterozygous missense mutation c.3086T>G, p. M1029R in ADCY5 most closely matched the observed phenotype. This report illustrates the utility of whole-exome sequencing in cases of undiagnosed movement disorders with clear autosomal dominant inheritance. Moreover, ADCY5 mutations should be considered in cases with apparent myoclonus-dystonia, particularly where SCGE mutations have been excluded. ADCY5-related dyskinesia may manifest variable expressivity within a single family, and affected individuals may be initially diagnosed with differing neurological phenotypes.
| S-EPMC5359383 | biostudies-literature
Project description:ObjectivesThe aim of this study was to report a case of levodopa-induced ocular dyskinesia in an early-onset Parkinson disease patient and to investigate the pathogenic gene.MethodsWe report the case of a 49-year-old male patient with a 13-year history of Parkinson disease. Involuntary eye movements were noticed after treatment with amantadine for limb dyskinesias. Levodopa-induced ocular dyskinesias involving repetitive, transient, and stereotyped rightward deviations of gaze appeared after intake of an antiparkinsonian drug. Limb dyskinesias also occurred simultaneously. We used a next-generation sequencing targeted gene panel and found a heterozygous missense mutation (p.R535H) in GBA. Direct Sanger sequencing verified the missense mutation.ConclusionsWe report the case of an uncommon early-onset PD patient carrying a GBA mutation presenting ocular dyskinesia. Genetic screening may provide a better mechanistic insight into dyskinesias.
| S-EPMC8594500 | biostudies-literature
Project description:Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 (DNAAF4) is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of DNAAF4, and almost no DNAAF4-related articles focused on sperm phenotype. Moreover, the association between DNAAF4 and scoliosis has never been reported, to the best of our knowledge. Materials and Methods: We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin–eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity. Results: Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in DNAAF4 (NM_130810.4), c.988C > T, p.(Arg330Trp), and DNAAF4 (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella. Conclusion: Our study identified a novel variant c.733C > T, which expanded the spectrum of DNAAF4 variants. Furthermore, we linked DNAAF4 to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.
| S-EPMC9315306 | biostudies-literature
Project description:To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship.We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases.We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation.ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.
| S-EPMC4676753 | biostudies-literature
Project description: Not available
| S-EPMC8015916 | biostudies-literature