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Revista de Neurologia Oct 2006Dystonia is after spasticity and tics the most common movement disorder in childhood. The etiology, diagnostic methods and treatment of childhood dystonia is reviewed. (Review)
Review
AIMS
Dystonia is after spasticity and tics the most common movement disorder in childhood. The etiology, diagnostic methods and treatment of childhood dystonia is reviewed.
DEVELOPMENT
Children have generalized dystonia more often than adults. The most frequent secondary dystonia are due to cerebral palsy, and often it is associated with other movement disorders like spasticity. The study of dystonia must consider the diverse heredo-degenerative causes because the genetic counseling, natural evolution and treatment may be specific. Among the primary dystonias, torsion dystonia DYT1 and dopa responsive dystonias (DRD) are the more frequent. DRD can be produced by mutation of GCH1 (DYT5) or other enzymatic defects of the neurotransmitter formation pathway. The clinical features of DYT1, DYT5, DYT11, DYT12 and other primary dystonias presenting in childhood are described. The treatment of dystonias depends on the anatomic distribution. Focal dystonias are best treated with botulinum toxin type A. Most of generalized dystonias are improved by oral drugs (trihexiphenidil, baclofen, clonazepam, tizanidine, tetrabenazine, neuroleptics) in monotherapy or in associations. Intratecal baclofen and deep brain stimulation are the most useful treatments of severe childhood dystonias.
CONCLUSION
The study of dystonias in children is complex, there are many disorders to consider as possible causes. Pharmacological and surgical treatments can be time-consuming and expensive but give a significant improvement of symptoms and quality of life to the patients.
Topics: Child; Dystonia; Humans
PubMed: 17061184
DOI: No ID Found -
British Medical Journal Jan 1963
Topics: Child; Conversion Disorder; Dystonia Musculorum Deformans; Dystonic Disorders; Genetic Diseases, X-Linked; Humans; Hysteria; Trihexyphenidyl
PubMed: 14017147
DOI: 10.1136/bmj.1.5325.260 -
Association of Pallidal Neurostimulation and Outcome Predictors With X-linked Dystonia Parkinsonism.JAMA Neurology Feb 2019Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia... (Observational Study)
Observational Study
IMPORTANCE
Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy.
OBJECTIVE
To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected.
EXPOSURES
All patients underwent bilateral GPi-DBS in Lübeck, Germany.
MAIN OUTCOMES AND MEASURES
Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes.
RESULTS
The study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004).
CONCLUSIONS AND RELEVANCE
Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.
Topics: Adult; Caudate Nucleus; Deep Brain Stimulation; Dystonic Disorders; Follow-Up Studies; Genetic Diseases, X-Linked; Germany; Globus Pallidus; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Philippines
PubMed: 30508028
DOI: 10.1001/jamaneurol.2018.3777 -
Proceedings of the National Academy of... Jun 2004
Review
Topics: Adenosine Triphosphate; Animals; Carrier Proteins; Cytoskeleton; Dystonia Musculorum Deformans; Humans; Membrane Transport Proteins; Models, Molecular; Molecular Chaperones; Mutation; Nuclear Envelope
PubMed: 15187229
DOI: 10.1073/pnas.0402441101 -
International Journal of Molecular... Feb 2022X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA)...
X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the intron retention transcript can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.
Topics: Adolescent; Adult; DNA Methylation; Dystonic Disorders; Female; Genetic Diseases, X-Linked; Histone Acetyltransferases; Humans; Introns; Male; Middle Aged; Parkinsonian Disorders; Promoter Regions, Genetic; Retroelements; Short Interspersed Nucleotide Elements; TATA-Binding Protein Associated Factors; Transcription Factor TFIID; Transcription, Genetic; Young Adult
PubMed: 35216353
DOI: 10.3390/ijms23042231 -
NeuroImage. Clinical 2018Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP) suggests tissue loss may occur first and/or most severely in the striatal striosome...
Preliminary evidence from postmortem studies of X-linked dystonia-parkinsonism (XDP) suggests tissue loss may occur first and/or most severely in the striatal striosome compartment, followed later by cell loss in the matrix compartment. However, little is known about how this relates to pathogenesis and pathophysiology. While MRI cannot visualize these striatal compartments directly in humans, differences in relative gradients of afferent cortical connectivity across compartments (weighted toward paralimbic versus sensorimotor cortex, respectively) can be used to infer potential selective loss in vivo. In the current study we evaluated relative connectivity of paralimbic versus sensorimotor cortex with the caudate and putamen in 17 individuals with XDP and 17 matched controls. Although caudate and putamen volumes were reduced in XDP, there were no significant reductions in either "matrix-weighted", or "striosome-weighted" connectivity. In fact, paralimbic connectivity with the putamen was elevated, rather than reduced, in XDP. This was driven most strongly by elevated putamen connectivity with the anterior insula. There was no relationship of these findings to disease duration or striatal volume, suggesting insula and/or paralimbic connectivity in XDP may develop abnormally and/or increase in the years before symptom onset.
Topics: Adult; Brain Mapping; Case-Control Studies; Cerebral Cortex; Cohort Studies; Dystonic Disorders; Female; Functional Laterality; Genetic Diseases, X-Linked; Humans; Image Processing, Computer-Assisted; Linear Models; Magnetic Resonance Imaging; Male; Middle Aged; Neural Pathways; Putamen; Severity of Illness Index
PubMed: 29527488
DOI: 10.1016/j.nicl.2017.10.025 -
Cureus Jan 2022This study aims to describe the demographic profile in terms of age, marital status, annual family income, and educational attainment; to describe the physical,...
OBJECTIVE
This study aims to describe the demographic profile in terms of age, marital status, annual family income, and educational attainment; to describe the physical, psychological, and social manifestations; to determine and describe coping mechanisms; to determine the goals, aspirations, and needs; and to determine the interaction and impact of the lived experiences on the quality of life of X-linked dystonia-parkinsonism (XDP) patients.
METHODS
This qualitative-phenomenological study was conducted in the island of Panay. Purposive sampling was utilized. The researchers utilized in-depth interviews, observation, and triangulation as part of the data collection methods. The data were transcribed verbatim, kept for content analysis, and coded in their appropriate cell categories after themes were identified.
RESULTS
Ten male patients who were residents of Panay and aged 30-65 years old participated in this study. Disease manifestations included limb dystonia, blepharospasm, truncal torsion, oromandibular symptoms, torticollis, and dysphonia, contributing to limitations in performing activities of daily living. Denial was the most common initial reaction after being diagnosed with XDP. Social manifestations were greatly affected by family and community. Money and medications were the primary needs identified by the patients with hopes of a better future for their families. There was an overall deterioration in the quality of life of the patients.
CONCLUSIONS
XDP greatly affected the physical, psychological, and social aspects of the patients. Coping with the disease and its effects has been thought to play an important role in the perception of one's quality of life.
PubMed: 35242471
DOI: 10.7759/cureus.21699 -
Frontiers in Molecular Biosciences 2020TorsinA is a AAA+ ATPase involved in the severe neurological disease Early Onset Torsion Dystonia. Despite the impressive progress in the field in the recent years, the...
TorsinA is a AAA+ ATPase involved in the severe neurological disease Early Onset Torsion Dystonia. Despite the impressive progress in the field in the recent years, the structural organization and function of this intriguing molecule is still not clear. One outstanding difference between torsinA and other AAA+ ATPases is that torsinA is a glycoprotein. TorsinA -linked glycans impact torsinA biogenesis and subcellular localization. Here, we propose that torsinA glycans also modulate torsinA oligomerization properties. We used structural modeling to test this idea, and show that -linked glycans appear to restrict torsinA's ability to form closed homohexameric ring assemblies, and instead promote an open hexameric conformation that allows torsinA interaction with key cofactors required for ATP hydrolysis. This mechanism would make torsinA a prime example of Nature's sophisticated molecular glycoengineering.
PubMed: 33134321
DOI: 10.3389/fmolb.2020.585643 -
Scientific Reports Jan 2022TUBB4A-associated disorder is a rare condition affecting the central nervous system. It displays a wide phenotypic spectrum, ranging from isolated late-onset torsion...
TUBB4A-associated disorder is a rare condition affecting the central nervous system. It displays a wide phenotypic spectrum, ranging from isolated late-onset torsion dystonia to a severe early-onset disease with developmental delay, neurological deficits, and atrophy of the basal ganglia and cerebellum, therefore complicating variant interpretation and phenotype prediction in patients carrying TUBB4A variants. We applied entropy-based normal mode analysis (NMA) to investigate genotype-phenotype correlations in TUBB4A-releated disease and to develop an in-silico approach to assist in variant interpretation and phenotype prediction in this disorder. Variants included in our analysis were those reported prior to the conclusion of data collection for this study in October 2019. All TUBB4A pathogenic missense variants reported in ClinVar and Pubmed, for which associated clinical information was available, and all benign/likely benign TUBB4A missense variants reported in ClinVar, were included in the analysis. Pathogenic variants were divided into five phenotypic subgroups. In-silico point mutagenesis in the wild-type modeled protein structure was performed for each variant. Wild-type and mutated structures were analyzed by coarse-grained NMA to quantify protein stability as entropy difference value (ΔG) for each variant. Pairwise ΔG differences between all variant pairs in each structural cluster were calculated and clustered into dendrograms. Our search yielded 41 TUBB4A pathogenic variants in 126 patients, divided into 11 partially overlapping structural clusters across the TUBB4A protein. ΔG-based cluster analysis of the NMA results revealed a continuum of genotype-phenotype correlation across each structural cluster, as well as in transition areas of partially overlapping structural clusters. Benign/likely benign variants were integrated into the genotype-phenotype continuum as expected and were clearly separated from pathogenic variants. We conclude that our results support the incorporation of the NMA-based approach used in this study in the interpretation of variant pathogenicity and phenotype prediction in TUBB4A-related disease. Moreover, our results suggest that NMA may be of value in variant interpretation in additional monogenic conditions.
Topics: DNA Mutational Analysis; Databases, Genetic; Genetic Association Studies; Genetic Predisposition to Disease; Hereditary Central Nervous System Demyelinating Diseases; Humans; Leukoencephalopathies; Models, Molecular; Mutation; Phenotype; Predictive Value of Tests; Protein Conformation; Structure-Activity Relationship; Tubulin
PubMed: 34997144
DOI: 10.1038/s41598-021-04337-x -
International Journal of Molecular... Mar 2021We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/- knock-out mice. A2A...
We aimed to investigate A2A receptors in the basal ganglia of a DYT1 mouse model of dystonia. A2A was studied in control Tor1a+/+ and Tor1a+/- knock-out mice. A2A expression was assessed by anti-A2A antibody immunofluorescence and Western blotting. The co-localization of A2A was studied in striatal cholinergic interneurons identified by anti-choline-acetyltransferase (ChAT) antibody. A2A mRNA and cyclic adenosine monophosphate (cAMP) contents were also assessed. In Tor1a+/+, Western blotting detected an A2A 45 kDa band, which was stronger in the striatum and the globus pallidus than in the entopeduncular nucleus. Moreover, in Tor1a+/+, immunofluorescence showed A2A roundish aggregates, 0.3-0.4 μm in diameter, denser in the neuropil of the striatum and the globus pallidus than in the entopeduncular nucleus. In Tor1a+/-, A2A Western blotting expression and immunofluorescence aggregates appeared either increased in the striatum and the globus pallidus, or reduced in the entopeduncular nucleus. Moreover, in Tor1a+/-, A2A aggregates appeared increased in number on ChAT positive interneurons compared to Tor1a+/+. Finally, in Tor1a+/-, an increased content of cAMP signal was detected in the striatum, while significant levels of A2A mRNA were neo-expressed in the globus pallidus. In Tor1a+/-, opposite changes of A2A receptors' expression in the striatal-pallidal complex and the entopeduncular nucleus suggest that the pathophysiology of dystonia is critically dependent on a composite functional imbalance of the indirect over the direct pathway in basal ganglia.
Topics: Animals; Basal Ganglia; Cholinergic Neurons; Corpus Striatum; Cyclic AMP; Disease Models, Animal; Dystonia Musculorum Deformans; Gene Expression Regulation; Male; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; Molecular Chaperones; RNA, Messenger; Receptor, Adenosine A2A; Mice
PubMed: 33799994
DOI: 10.3390/ijms22052691