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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 -
Current Opinion in Neurology Aug 2019Our understanding of X-Linked Dystonia-Parkinsonism (XDP) has advanced considerably in recent years because of a wealth of new data describing its genetic basis,... (Review)
Review
PURPOSE OF REVIEW
Our understanding of X-Linked Dystonia-Parkinsonism (XDP) has advanced considerably in recent years because of a wealth of new data describing its genetic basis, cellular phenotypes, neuroimaging features, and response to deep brain stimulation (DBS). This review provides a concise summary of these studies.
RECENT FINDINGS
XDP is associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion within the TAF1 gene. This element includes a hexameric DNA repeat expansion, (CCCTCT)n, the length of which varies among patients and is inversely correlated to age of disease onset. In cell models, the SVA alters TAF1 splicing and reduces levels of full-length transcript. Neuroimaging data have confirmed previous neuropathology studies that XDP involves a progressive striatal atrophy, while further detecting functional alterations in additional brain regions. In patients exhibiting features of both dystonia and parkinsonism, pallidal DBS has resulted in rapid improvement of hyperkinetic movements, but effects on hypokinetic features have been inconsistent.
SUMMARY
The discovery that XDP is linked to a polymorphic hexameric sequence suggests that it could share mechanisms with other DNA repeat disorders, whereas the transcriptional defect in cell models raises the possibility that strategies to correct TAF1 splicing could provide therapeutic benefit.
Topics: Brain; DNA Repeat Expansion; Deep Brain Stimulation; Dystonic Disorders; Genetic Diseases, X-Linked; Humans
PubMed: 31116117
DOI: 10.1097/WCO.0000000000000708 -
JAMA Neurology Jun 2015Dystonia is a heterogeneous neurologic disorder characterized by abnormal muscle contractions for which standard medical therapy is often inadequate. For such patients,... (Review)
Review
IMPORTANCE
Dystonia is a heterogeneous neurologic disorder characterized by abnormal muscle contractions for which standard medical therapy is often inadequate. For such patients, therapeutic brain stimulation is becoming increasingly used.
OBJECTIVES
To review the evidence and effect sizes for treating different types of dystonia with different types of brain stimulation and to discuss recent advances relevant to patient selection, surgical approach, programming, and mechanism of action.
EVIDENCE REVIEW
PubMed was searched for publications on the clinical effect of brain stimulation in dystonia up through December 31, 2014. Recent meta-analyses, consensus statements, and evidence-based guidelines were incorporated. Emphasis was placed on deep brain stimulation (DBS) and randomized clinical trials; however, other stimulation modalities and trial designs were included. For each intervention the mean change in dystonia severity, number of patients studied, and evidence of efficacy based on American Academy of Neurology criteria were determined.
FINDINGS
Strong (level B) evidence supports the use of DBS for the treatment of primary generalized or segmental dystonia, especially when due to mutation in the DYT1 gene, as well as for patients with cervical dystonia. Large effect sizes have also been reported for DBS treatment of tardive dystonia, writer's cramp, cranial dystonia, myoclonus dystonia, and off-state dystonia associated with Parkinson disease. Lesser benefit is generally seen in dystonia secondary to structural brain damage. Other brain stimulation techniques, including epidural cortical stimulation and noninvasive brain stimulation, have been investigated, but generally report smaller effect sizes in fewer patients.
CONCLUSIONS AND RELEVANCE
Patients with dystonia that is not adequately controlled with standard medical therapy should be referred for consideration of DBS, especially patients with generalized, segmental, or cervical dystonia. Other less-invasive stimulation modalities require further research before being considered a therapeutic alternative.
Topics: Deep Brain Stimulation; Dystonia Musculorum Deformans; Humans
PubMed: 25894231
DOI: 10.1001/jamaneurol.2015.51 -
Critical Reviews in Biochemistry and... 2015Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity... (Review)
Review
Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is early-onset torsion (DYT1) dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that have led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options.
Topics: Amino Acid Sequence; Animals; Carrier Proteins; Disease Models, Animal; Dystonia Musculorum Deformans; HSC70 Heat-Shock Proteins; Humans; Membrane Proteins; Molecular Chaperones; Molecular Sequence Data; Mutation; Protein Transport; Sequence Alignment
PubMed: 26592310
DOI: 10.3109/10409238.2015.1091804 -
Neurobiology of Disease Jan 2021X-linked Dystonia Parkinsonism (XDP) is a recessive, genetically inherited neurodegenerative disorder endemic to Panay Island in the Philippines. Clinical symptoms... (Review)
Review
X-linked Dystonia Parkinsonism (XDP) is a recessive, genetically inherited neurodegenerative disorder endemic to Panay Island in the Philippines. Clinical symptoms include the initial appearance of dystonia, followed by parkinsonian traits after 10-15 years. The basal ganglia, particularly the striatum, is an area of focus in XDP neuropathology research, as the striatum shows marked atrophy that correlates with disease progression. Thus, XDP shares features of Parkinson's disease symptomatology, in addition to the genetic predisposition and presence of striatal atrophy resembling Huntington's disease. However, further research is required to reveal the detailed pathology and indicators of disease in the XDP brain. First, there are limited neuropathological studies that have investigated neuronal changes and neuroinflammation in the XDP brain. However, multiple neuroimaging studies on XDP patients provide clues to other affected brain regions. Furthermore, molecular pathological studies have elucidated that the main genetic cause of XDP is in the TAF-1 gene, but how this mutation relates to XDP neuropathology still remains to be fully investigated. Hence, we aim to provide an extensive overview of the current literature describing neuropathological changes within the XDP brain, and discuss future research avenues, which will provide a better understanding of XDP neuropathogenesis.
Topics: Basal Ganglia; Brain; Diffusion Magnetic Resonance Imaging; Dystonic Disorders; Genetic Diseases, X-Linked; Humans; Magnetic Resonance Imaging; Neostriatum
PubMed: 33227492
DOI: 10.1016/j.nbd.2020.105186 -
Nature Cell Biology Nov 2022DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope...
DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope blebbing resulting from defects in nuclear pore complex biogenesis. Whether blebs actively contribute to disease manifestation is unknown. We report that FG-nucleoporins in the bleb lumen form aberrant condensates and contribute to DYT1 dystonia by provoking two proteotoxic insults. Short-lived ubiquitylated proteins that are normally rapidly degraded partition into the bleb lumen and become stabilized. In addition, blebs selectively sequester a specific HSP40-HSP70 chaperone network that is modulated by the bleb component MLF2. MLF2 suppresses the ectopic accumulation of FG-nucleoporins and modulates the selective properties and size of condensates in vitro. Our study identifies dual mechanisms of proteotoxicity in the context of condensate formation and establishes FG-nucleoporin-directed activities for a nuclear chaperone network.
Topics: Humans; Dystonia; Nuclear Envelope; Nuclear Pore Complex Proteins
PubMed: 36302970
DOI: 10.1038/s41556-022-01001-y -
Science Translational Medicine May 2023Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within...
Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1-, we generated a conditional knockout of the torsin family 1 member A () gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the conditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.
Topics: Humans; Mice; Animals; Dystonia; Dystonia Musculorum Deformans; Mice, Knockout; Brain; Molecular Chaperones
PubMed: 37134150
DOI: 10.1126/scitranslmed.adg3904