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Brain : a Journal of Neurology Aug 2023In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later...
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Topics: Male; Humans; Cross-Sectional Studies; Mutation; Phenotype; Dystonia; Dystonic Disorders; Nervous System Malformations; Molecular Chaperones
PubMed: 36757831
DOI: 10.1093/brain/awad039 -
Brain and Behavior Jun 2023Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically... (Review)
Review
BACKGROUND
Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear.
OBJECTIVES
This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques.
METHODS
A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211).
RESULTS
All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers.
CONCLUSIONS
Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.
Topics: Humans; Dystonia; Dystonic Disorders; Molecular Chaperones; Neuroimaging
PubMed: 37165749
DOI: 10.1002/brb3.3023 -
Frontiers in Systems Neuroscience 2023The normal hemispheric balance can be altered by the asymmetric sensorimotor signal elicited by Cervical Dystonia (CD), leading to motor and cognitive deficits.
INTRODUCTION
The normal hemispheric balance can be altered by the asymmetric sensorimotor signal elicited by Cervical Dystonia (CD), leading to motor and cognitive deficits.
METHODS
Directional errors, peak velocities, movement and reaction times of pointing towards out-of-reach targets in the horizontal plane were analysed in 18 CD patients and in 11 aged-matched healthy controls.
RESULTS
CD patients displayed a larger scatter of individual trials around the average pointing direction (variable error) than normal subjects, whatever the arm used, and the target pointed. When pointing in the left hemispace, all subjects showed a left deviation (constant error) with respect to the target position, which was significantly larger in CD patients than controls, whatever the direction of the abnormal neck torsion could be. Reaction times were larger and peak velocities lower in CD patients than controls.
DISCUSSION
Deficits in the pointing precision of CD patients may arise from a disruption of motor commands related to the sensorimotor imbalance, from a subtle increase in shoulder rigidity or from a reduced agonists activation. Their larger left bias in pointing to left targets could be due to an increased right parietal dominance, independently upon the direction of head roll/jaw rotation which expands the left space representation and/or increases left spatial attention. These deficits may potentially extend to tracking and gazing objects in the left hemispace, leading to reduced skills in spatial-dependent motor and cognitive performance.
PubMed: 38090048
DOI: 10.3389/fnsys.2023.1306387 -
Molecular Therapy : the Journal of the... Jul 2023X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a retrotransposon insertion in intron 32 of the TAF1 gene. This insertion causes...
X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a retrotransposon insertion in intron 32 of the TAF1 gene. This insertion causes mis-splicing of intron 32 (TAF1-32i) and reduced TAF1 levels. TAF1-32i transcript is unique to XDP patient cells and can be detected in their extracellular vesicles (EVs). We engrafted patient and control iPSC-derived neural progenitor cells (hNPCs) into the striatum of mice. To track TAF1-32i transcript spread by EVs, we transduced the brain-implanted hNPCs with a lentiviral construct called ENoMi, which consists of a re-engineered tetraspanin scaffold tagged with bioluminescent and fluorescent reporter proteins under an EF-1α promoter. Alongside this improved detection in ENoMi-hNPCs-derived EVs, their surface allows specific immunocapture purification, thereby facilitating TAF1-32i analysis. Using this ENoMi-labeling method, TAF1-32i was demonstrated in EVs released from XDP hNPCs implanted in mouse brains. Post-implantation of ENoMi-XDP hNPCs, TAF1-32i transcript was retrieved in EVs isolated from mouse brain and blood, and levels increased over time in plasma. We compared and combined our EV isolation technique to analyze XDP-derived TAF1-32i with other techniques, including size exclusion chromatography and Exodisc. Overall, our study demonstrates the successful engraftment of XDP patient-derived hNPCs in mice as a tool for monitoring disease markers with EVs.
Topics: Humans; Mice; Animals; Neurodegenerative Diseases; Transcription Factor TFIID; Biomarkers; Brain; Extracellular Vesicles
PubMed: 37198883
DOI: 10.1016/j.ymthe.2023.05.011 -
Neurobiology of Disease Jan 2024X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP is an insertion of a SINE-VNTR-Alu...
X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP is an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within intron 32 of TATA-binding protein associated factor 1 (TAF1) that causes an alteration of TAF1 splicing, partial intron retention, and decreased transcription. Although TAF1 is expressed in all organs, medium spiny neurons (MSNs) within the striatum are one of the cell types most affected in XDP. To define how mutations in the TAF1 gene lead to MSN vulnerability, we carried out a proteomic analysis of human XDP patient-derived neural stem cells (NSCs) and MSNs derived from induced pluripotent stem cells. NSCs and MSNs were grown in parallel and subjected to quantitative proteomic analysis in data-independent acquisition mode on the Orbitrap Eclipse Tribrid mass spectrometer. Subsequent functional enrichment analysis demonstrated that neurodegenerative disease-related pathways, such as Huntington's disease, spinocerebellar ataxia, cellular senescence, mitochondrial function and RNA binding metabolism, were highly represented. We used weighted coexpression network analysis (WGCNA) of the NSC and MSN proteomic data set to uncover disease-driving network modules. Three of the modules significantly correlated with XDP genotype when compared to the non-affected control and were enriched for DNA helicase and nuclear chromatin assembly, mitochondrial disassembly, RNA location and mRNA processing. Consistent with aberrant mRNA processing, we found splicing and intron retention of TAF1 intron 32 in XDP MSN. We also identified TAF1 as one of the top enriched transcription factors, along with YY1, ATF2, USF1 and MYC. Notably, YY1 has been implicated in genetic forms of dystonia. Overall, our proteomic data set constitutes a valuable resource to understand mechanisms relevant to TAF1 dysregulation and to identify new therapeutic targets for XDP.
Topics: Humans; Dystonia; Neurodegenerative Diseases; Proteomics; Transcription Factor TFIID; Dystonic Disorders; Neurons; RNA, Messenger; Parkinsonian Disorders
PubMed: 38042508
DOI: 10.1016/j.nbd.2023.106367 -
Journal of Neurology Sep 2023X-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the...
BACKGROUND
X-Linked dystonia-parkinsonism (XDP) is a movement disorder characterized by the presence of both dystonia and parkinsonism with one or the other more prominent in the initial stages and later on manifesting with more parkinsonian features towards the latter part of the disease. XDP patients show oculomotor abnormalities indicating prefrontal and striatal impairment. This study investigated oculomotor behavior in non-manifesting mutation carriers (NMC). We hypothesized that oculomotor disorders occur before the appearance of dystonic or parkinsonian signs. This could help to functionally identify brain regions already affected in the prodromal stage of the disease.
METHODS
Twenty XDP patients, 13 NMC, and 28 healthy controls (HC) performed different oculomotor tasks typically affected in patients with parkinsonian signs.
RESULTS
The error rate for two types of volitional saccades, i.e., anti-saccades and memory-guided saccades, was increased not only in XDP patients but also in NMC compared to HC. However, the increase in error rates of both saccade types were highly correlated in XDP patients only. Hypometria of reflexive saccades was only found in XDP patients. Initial acceleration and maintenance velocity of smooth pursuit eye movements were only impaired in XDP patients.
CONCLUSIONS
Despite being asymptomatic, NMC already showed some oculomotor deficits reflecting fronto-striatal impairments, typically found in XDP patients. However, NMC did not show saccade hypometria and impaired smooth pursuit as seen in advanced Parkinson's disease and XDP, suggesting oculomotor state rather than trait signs in these mutation carriers. Neurodegeneration may commence in the striatum and prefrontal cortex, specifically the dorsolateral prefrontal cortex.
Topics: Humans; Dystonic Disorders; Genetic Diseases, X-Linked; Dystonia; Brain; Ocular Motility Disorders
PubMed: 37191726
DOI: 10.1007/s00415-023-11761-8 -
Experimental Neurology Sep 2023Dystonia is a neurological movement disorder characterized by repetitive, unintentional movements and disabling postures that result from sustained or intermittent...
Dystonia is a neurological movement disorder characterized by repetitive, unintentional movements and disabling postures that result from sustained or intermittent muscle contractions. The basal ganglia and cerebellum have received substantial focus in studying DYT1 dystonia. It remains unclear how cell-specific ∆GAG mutation of torsinA within specific cells of the basal ganglia or cerebellum affects motor performance, somatosensory network connectivity, and microstructure. In order to achieve this goal, we generated two genetically modified mouse models: in model 1 we performed Dyt1 ∆GAG conditional knock-in (KI) in neurons that express dopamine-2 receptors (D2-KI), and in model 2 we performed Dyt1 ∆GAG conditional KI in Purkinje cells of the cerebellum (Pcp2-KI). In both of these models, we used functional magnetic resonance imaging (fMRI) to assess sensory-evoked brain activation and resting-state functional connectivity, and diffusion MRI to assess brain microstructure. We found that D2-KI mutant mice had motor deficits, abnormal sensory-evoked brain activation in the somatosensory cortex, as well as increased functional connectivity of the anterior medulla with cortex. In contrast, we found that Pcp2-KI mice had improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, as well as reduced functional connectivity of the striatum with the anterior medulla. These findings suggest that (1) D2 cell-specific Dyt1 ∆GAG mediated torsinA dysfunction in the basal ganglia results in detrimental effects on the sensorimotor network and motor output, and (2) Purkinje cell-specific Dyt1 ∆GAG mediated torsinA dysfunction in the cerebellum results in compensatory changes in the sensorimotor network that protect against dystonia-like motor deficits.
Topics: Mice; Animals; Dystonia; Dystonia Musculorum Deformans; Cerebellum; Corpus Striatum; Molecular Chaperones
PubMed: 37321386
DOI: 10.1016/j.expneurol.2023.114471 -
BMC Neurology Aug 2023Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) is a noninvasive method for controlling tremor and has recently been used in patients with X-linked...
Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) is a noninvasive method for controlling tremor and has recently been used in patients with X-linked dystonia-parkinsonism (XDP). This study aims to determine the improvement in dystonia and parkinsonism in patients with XDP after MRgFUS pallidothalamic tractotomy. This prospective study will be conducted at the Philippine General Hospital, University of the Philippines Manila. The primary outcome measure is the change in the pre- and post-treatment XDP-Movement Disorder Society of the Philippines Scale scores. In addition, demographic and clinical data will be collected, including the Burke-Fahn-Marsden Dystonia Rating Scale, Part III of the Movement Disorder Society-Unified Parkinson's disease Rating Scale score, XDP clinical and functional stage, the five-level EuroQol five-dimensional questionnaire, Montreal Cognitive Assessment scores, MRgFUS treatment parameters, and adverse events. Patients will be assessed within 24 hours of treatment, then at 2 weeks, 3 months, 6 months, 9 months, and 12 months post-treatment. This protocol was approved by the University of the Philippines Manila Research Ethics Board (UPMREB 2022-0271-01). Data collection began in January 2023. This protocol has been registered with ClinicalTrials.gov: Trial Registration number: NCT05592028.
Topics: Humans; Dystonia; Magnetic Resonance Spectroscopy; Movement Disorders; Philippines; Prospective Studies
PubMed: 37596524
DOI: 10.1186/s12883-023-03344-x