ABSTRACT
X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.
Subject(s)
Dystonic Disorders/genetics , Genetic Diseases, X-Linked/genetics , Genome, Human , Transcriptome/genetics , Alternative Splicing/genetics , Alu Elements/genetics , Base Sequence , CRISPR-Cas Systems/genetics , Cohort Studies , Family , Female , Genetic Loci , Haplotypes/genetics , High-Throughput Nucleotide Sequencing , Histone Acetyltransferases/genetics , Histone Acetyltransferases/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Introns/genetics , Male , Minisatellite Repeats/genetics , Models, Genetic , Nerve Degeneration/genetics , Nerve Degeneration/pathology , Neural Stem Cells/metabolism , Neurons/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Short Interspersed Nucleotide Elements , TATA-Binding Protein Associated Factors/genetics , TATA-Binding Protein Associated Factors/metabolism , Transcription Factor TFIID/genetics , Transcription Factor TFIID/metabolismABSTRACT
OBJECTIVES: To systematically characterize and describe voice and swallowing manifestations in patients with X-linked dystonia parkinsonism (XDP) and correlate with quality-of-life (QOL) measures. METHODS: Thirty-four patients with XDP with communication and swallowing difficulties underwent neurological examination, head and neck examination, nasopharyngoscopy, QOL surveys (Swallowing Quality of Life questionnaire [SWAL-QOL] and Voice Handicap Index [VHI]), and functional endoscopic evaluation of swallowing (FEES) to assess the extent of dysfunction. RESULTS: All patients showed high rates of lingual, oromandibular, and laryngeal dysfunction, as well as severe QOL changes in swallowing and communication ability. The most common head and neck manifestations of dystonic symptoms were difficulty coordinating the mouth and tongue (79%), uncontrollable tongue thrusting (53%), and jaw opening (35%). Laryngeal symptoms including vocal strain (adductor voice breaks) or stridor (32%), as well as velopharyngeal insufficiency (20%), were also identified. Of the patients with laryngeal symptoms, 18% had respiratory dystonia. Swallowing assessments showed significant abnormalities in oral bolus control and oropharyngeal dysphagia. FEES examinations showed that 87.5% of the study group had penetration or aspiration. QOL scores showed an average VHI of 94.4 (severe dysfunction), and SWAL-QOL showed an average of 37.7 (severe dysfunction). CONCLUSION: Swallowing and voice impairment in XDP is not well characterized and presents a more distinctive phenomenology than other neurological disorders, with a unique set of challenges for treatment. This is the first study to systematically evaluate laryngeal and pharyngeal dysfunction in XDP patients and correlate with QOL measures. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:171-177, 2020.
Subject(s)
Deglutition Disorders/etiology , Dystonic Disorders/complications , Genetic Diseases, X-Linked/complications , Quality of Life , Voice Disorders/etiology , Correlation of Data , Humans , Male , Middle AgedABSTRACT
OBJECTIVE: To characterize hand stereotypies (HS) in a large cohort of participants with Rett syndrome (RTT). METHODS: Data from 1,123 girls and women enrolled in the RTT Natural History Study were gathered. Standard tests for continuous and categorical variables were used at baseline. For longitudinal data, we used repeated-measures linear and logistic regression models and nonparametric tests. RESULTS: HS were reported in 922 participants with classic RTT (100%), 73 with atypical severe RTT (97.3%), 74 with atypical mild RTT (96.1%), and 17 females with MECP2 mutations without RTT (34.7%). Individuals with RTT who had classic presentation or severe MECP2 mutations had higher frequency and earlier onset of HS. Heterogeneity of HS types was confirmed, but variety decreased over time. At baseline, almost half of the participants with RTT had hand mouthing, which like clapping/tapping, decreased over time. These 2 HS types were more frequently reported than wringing/washing. Increased HS severity (prevalence and frequency) was associated with worsened measures of hand function. Number and type of HS were not related to hand function. Overall clinical severity was worse with decreased hand function but only weakly related to any HS characteristic. While hand function decreased over time, prevalence and frequency of HS remained relatively unchanged and high. CONCLUSIONS: Nearly all individuals with RTT have severe and multiple types of HS, with mouthing and clapping/tapping decreasing over time. Interaction between HS frequency and hand function is complex. Understanding the natural history of HS in RTT could assist in clinical care and evaluation of new interventions.
Subject(s)
Hand , Rett Syndrome/epidemiology , Stereotyped Behavior , Adolescent , Adult , Aged , Child , Child, Preschool , Disease Progression , Female , Follow-Up Studies , Hand/physiopathology , Humans , Infant , Longitudinal Studies , Methyl-CpG-Binding Protein 2/genetics , Middle Aged , Movement , Prevalence , Rett Syndrome/diagnosis , Rett Syndrome/genetics , Rett Syndrome/physiopathology , Severity of Illness Index , Young AdultABSTRACT
INTRODUCTION: Hand stereotypies (HS) are a primary diagnostic criterion for Rett syndrome (RTT) but are difficult to characterize and quantify systematically. METHODS: We collected video on 27 girls (2-12 years of age) with classic RTT who participated in a mecasermin trial. The present study focused exclusively on video analyses, by reviewing two five-minute windows per subject to identify the two most common HS. Three raters with expertise in movement disorders independently rated the five-minute windows using standardized terminology to determine the level of agreement. We iteratively refined the protocol in three stages to improve descriptive accuracy, categorizing HS as "central" or "peripheral," "simple" or "complex," scoring each hand separately. Inter-rater agreement was analyzed using Kappa statistics. RESULTS: In the initial protocol evaluating HS by video, inter-rater agreement was 20.7%. In the final protocol, inter-rater agreement for the two most frequent HS was higher than the initial protocol at 50%. CONCLUSION: Phenotypic variability makes standardized evaluation of HS in RTT a challenge; we achieved only 50% level of agreement and only for the most frequent HS. Therefore, objective measures are needed to evaluate HS.
Subject(s)
Hand/physiopathology , Rett Syndrome/complications , Stereotypic Movement Disorder/diagnosis , Stereotypic Movement Disorder/etiology , Child , Child, Preschool , Female , Growth Substances/therapeutic use , Humans , Insulin-Like Growth Factor I/therapeutic use , Recombinant Proteins/therapeutic use , Rett Syndrome/drug therapy , Stereotypic Movement Disorder/drug therapy , Video RecordingABSTRACT
Mutations in the ATP1A3 gene (the α-3 subunit of the Na+/K+ ATPase) are associated with rapid-onset dystonia-parkinsonism; alternating hemiplegia of childhood; and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). The authors report 3 cases with pleiotropic movement disorders, including a novel mutation in a patient who presented with ataxia and dysphagia. Case 1 had a history of attention deficit hyperactivity disorder and developed dysphagia, chorea, and limb dystonia after a febrile illness at age 12 years. Case 2 presented with limb dystonia at age 26 years and dysarthia and dysphagia after a febrile illness. Case 3 had a history of learning disability and developed progressive ataxia with cerebellar atrophy at age 20 years. In all cases, deleterious mutations were identified in ATP1A3. They illustrate wide phenotypic variability, including chorea and ataxia. New cases are likely to be diagnosed as knowledge about the phenotypic spectrum expands.
ABSTRACT
X-linked dystonia-parkinsonism (XDP) is a hereditary neurodegenerative disorder involving a progressive loss of striatal medium spiny neurons. The mechanisms underlying neurodegeneration are not known, in part because there have been few cellular models available for studying the disease. The XDP haplotype consists of multiple sequence variations in a region of the X chromosome containingTAF1, a large gene with at least 38 exons, and a multiple transcript system (MTS) composed of five unconventional exons. A previous study identified an XDP-specific insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon in intron 32 ofTAF1, as well as a neural-specific TAF1 isoform, N-TAF1, which showed decreased expression in post-mortem XDP brain compared with control tissue. Here, we generated XDP patient and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with this disease. As initial validation of the model, we compared expression ofTAF1and MTS transcripts in XDP versus control fibroblasts and iPSC-derived neural stem cells (NSCs). Compared with control cells, XDP fibroblasts exhibited decreased expression ofTAF1transcript fragments derived from exons 32-36, a region spanning the SVA insertion site. N-TAF1, which incorporates an alternative exon (exon 34'), was not expressed in fibroblasts, but was detectable in iPSC-differentiated NSCs at levels that were â¼threefold lower in XDP cells than in controls. These results support the previous findings that N-TAF1 expression is impaired in XDP, but additionally indicate that this aberrant transcription might occur in neural cells at relatively early stages of development that precede neurodegeneration.
Subject(s)
Dystonic Disorders/genetics , Dystonic Disorders/pathology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Histone Acetyltransferases/genetics , Neural Stem Cells/metabolism , TATA-Binding Protein Associated Factors/genetics , Transcription Factor TFIID/genetics , Adult , Aged , Aged, 80 and over , Alternative Splicing/genetics , Amino Acid Sequence , Brain/metabolism , Brain/pathology , Cell Line, Tumor , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Genetic Markers , Genotype , Haplotypes/genetics , Histone Acetyltransferases/chemistry , Histone Acetyltransferases/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Male , Middle Aged , Neural Stem Cells/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , TATA-Binding Protein Associated Factors/chemistry , TATA-Binding Protein Associated Factors/metabolism , Transcription Factor TFIID/chemistry , Transcription Factor TFIID/metabolismABSTRACT
ADCY5 mutations have been reported as a cause of early onset hyperkinetic movements associated with delayed motor milestones, hypotonia, and exacerbation during sleep. The movement disorder may be continuous or episodic, and can vary considerably in severity within families and in individuals. The authors report a case series of 3 patients with ADCY5 mutations treated with deep brain stimulation after unsuccessful medication trials. All had extensive imaging, metabolic, and genetic testing prior to confirmation of their ADCY5 mutation. Two of the patients had the c.1252C>T; p.R418W mutation, while the youngest and most severely affected had a de novo c.2080_2088del; p.K694_M696 mutation. All had variable and incomplete, but positive responses to deep brain stimulation. The authors conclude that deep brain stimulation may provide benefit in ADCY5-related movement disorders. Long-term efficacy remains to be confirmed by longitudinal observation. ADCY5 should be considered in the differential diagnosis of early onset hyperkinetic movement disorders, and may respond to deep brain stimulation.
Subject(s)
Adenylyl Cyclases/genetics , Chorea/therapy , Deep Brain Stimulation , Dystonic Disorders/therapy , Hyperkinesis/therapy , Mutation , Adult , Child , Child, Preschool , Chorea/genetics , Dystonic Disorders/enzymology , Dystonic Disorders/genetics , Female , Humans , Hyperkinesis/enzymology , Hyperkinesis/genetics , Male , PhenotypeSubject(s)
Tourette Syndrome/diagnosis , Tourette Syndrome/therapy , Adolescent , Diagnosis, Differential , Humans , MaleSubject(s)
Ataxia/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Age of Onset , Ataxia/diagnosis , Ataxia/etiology , Child , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/deficiency , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Female , Humans , Neuronal Ceroid-Lipofuscinoses/metabolism , Spinocerebellar Degenerations/diagnosis , Spinocerebellar Degenerations/genetics , Tripeptidyl-Peptidase 1Subject(s)
Coccidioides/isolation & purification , Coccidioidomycosis/complications , Coccidioidomycosis/diagnosis , Pneumothorax/complications , Pneumothorax/diagnosis , Adolescent , Antibodies, Fungal/blood , Antifungal Agents/administration & dosage , Coccidioides/classification , Coccidioides/immunology , Coccidioidomycosis/drug therapy , Coccidioidomycosis/pathology , Female , Fluconazole/administration & dosage , Humans , Immunoglobulin G/blood , Pleural Effusion/microbiology , Pneumothorax/pathology , Radiography, ThoracicABSTRACT
CD93 is a cell-surface glycoprotein that has been shown to influence defence collagen-enhanced Fc-receptor or CR1-mediated phagocytosis of suboptimally opsonized targets in vitro, and CD93-deficient mice are defective in the clearance of apoptotic cells in vivo. To investigate the mechanism of CD93 modulation of phagocytic activity, GST fusion proteins containing the 47 amino acid intracellular domain (GST-Cyto), or various mutants of the intracellular domain of CD93, were constructed and used to identify intracellular CD93-binding molecules. The intracellular protein moesin, well characterized for its role in linking transmembrane proteins to the cytoskeleton and in cytoskeletal remodelling, bound to GST-Cyto when either cell lysates or recombinant moesin were used as a source of interacting molecules. An association of moesin with CD93 within intact cells was confirmed by co-capping moesin with CD93 in human monocytes. The moesin-binding site on CD93 mapped to the first four positively charged amino acids in the juxtamembrane region of the CD93 cytoplasmic tail. Interestingly, deletion of the last 11 amino acids from the C terminus of CD93 (GST-Cyto-C11) dramatically increased moesin binding to the cytoplasmic tail of CD93 in the cell lysate assay, but not when the binding of purified recombinant moesin was assessed. Furthermore, moesin binding to CD93 was enhanced by the addition of phosphatidylinositol 4,5-bisphosphate (PIP(2)). Taken together, these data suggest that the interaction of moesin with the CD93 cytoplasmic domain is modulated by binding of other intracellular molecules to the C11 region and implies that a PIP(2) signalling pathway is involved in CD93 function.