Abnormal Saccades Differentiate Adolescent Onset Variant Ataxia Telangiectasia from Other Myoclonus Dystonia.
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SUBMITTER: Cherian A
PROVIDER: S-EPMC8513963 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.MethodsMovement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations.ResultGenetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies.ConclusionAtaxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.
| S-EPMC3286230 | biostudies-literature
Project description:https://onlinelibrary.wiley.com/page/journal/23301619/homepage/mdc312564-sup-v001_1.htm.
| S-EPMC6090590 | biostudies-literature
Project description:The ataxia telangiectasia mutant (ATM) protein is a sensor and signal transducer that amplifies and communicates signals of DNA damage further to the mediators of cell cycle arrest, apoptosis, and senescence (p16, p19, p21, BAX etc.) which is modified by the strength of the cellular stress. They are able to act as recognition and signaling proteins because of their kinase activity. Classic ataxia telangiectasia is associated with homozygous mutations of the ATM gene, the complete absence of its kinase activity and/or deleterious ATM gene mutations such as truncation/nonsense mutations, loss of function mutation, non-conservative substitutions, frameshift, and deletions. On the other hand, variant ataxia-telangiectasia (A-T) is associated with the presence of residual kinase activity. We report a six-year-old male patient who presented to us with abnormal neck movements as his initial complaint. ATM gene analysis showed a rare pathogenic variant of the ATM gene. The variant was a homozygous nonsense mutation in exon 2 of the ATM gene that resulted in the formation of a stop codon and premature truncation of the protein at codon 23 in exon 2 (p.Arg23Ter). In conclusion, we report a case of an unusual presentation of classic A-T. We should pursue a long-term follow-up and maintain a low threshold for performing pedigree analysis and genetic testing in pediatric patients with movement disorders. In resource-limited settings where kinase enzyme assays are not universally available to patients, web-based mutation prediction tools may be beneficial to predict the deleterious effects of the mutation.
| S-EPMC9697739 | biostudies-literature
Project description:ObjectiveTo identify the cause of cervical dopa-responsive dystonia (DRD) in a Muslim Indian family inherited in an apparently autosomal recessive fashion, as previously described in this journal.MethodsPrevious testing for mutations in the genes known to cause DRD (GCH1, TH, and SPR) had been negative. Whole exome sequencing was performed on all 3 affected individuals for whom DNA was available to identify potentially pathogenic shared variants. Genotyping data obtained for all 3 affected individuals using the OmniExpress single nucleotide polymorphism chip (Illumina, San Diego, CA) were used to perform linkage analysis, autozygosity mapping, and copy number variation analysis. Sanger sequencing was used to confirm all variants.ResultsAfter filtering of the variants, exome sequencing revealed 2 genes harboring potentially pathogenic compound heterozygous variants (ATM and LRRC16A). Of these, the variants in ATM segregated perfectly with the cervical DRD. Both mutations detected in ATM have been shown to be pathogenic, and α-fetoprotein, a marker of ataxia telangiectasia, was increased in all affected individuals.ConclusionBiallelic mutations in ATM can cause DRD, and mutations in this gene should be considered in the differential diagnosis of unexplained DRD, particularly if the dystonia is cervical and if there is a recessive family history. ATM has previously been reported to cause isolated cervical dystonia, but never, to our knowledge, DRD. Individuals with dystonia related to ataxia telangiectasia may benefit from a trial of levodopa.
| S-EPMC3795596 | biostudies-literature
Project description:Ataxia-telangiectasia (AT) is a complex genetic neurodegenerative disease with autosomal recessive inheritance. The typical initial features of ataxia telangiectasia include ataxia, cutaneous telangiectasia, and immune deficiency with recurrent infections. Usually, movement disorder occurs late in the course of the disease. A diagnosis of variant or atypical ataxia-telangiectasia (variant AT) is considered in case of any deviation from the normal course of illness giving rise to variable presentations of the disease. Only a few cases of variant AT with predominant movement disorder have been reported worldwide. A knowledge of atypical presentations helps in early diagnosis and thus to initiate management and counselling of the family at the earliest. Here, we report a case of genetically confirmed ataxia-telangiectasia with an initial presentation of dopamine responsive dystonia.
| S-EPMC9996480 | biostudies-literature
Project description:Ataxia telangiectasia (A-T) is a common, genetically inherited cause of early childhood-onset ataxia that is classically characterized by progressive cerebellar malfunction, oculocutaneous telangiectasia, genome instability, and immunodeficiency. There is vast phenotype variation in patients with A-T and recently, dystonia, an extrapyramidal movement disorder. Here, we report the case of a 10-year-old girl who had experienced repeated diarrhea and mild gait ataxia since the age of two years. At age seven, ataxia and ocular telangiectasia were evident and immunoglobulin level assessment showed hyper IgM immune phenotype, thus a diagnosis of A-T was made based on clinical and laboratory findings, and she was started on intravenous immunoglobulin therapy. Generalized dystonia appeared when she was 10-years-old. Molecular analysis revealed two heterozygous mutations, c.6259delG and c.6658C>T, in the ATM gene of which one (c.6259delG) is novel. Dystonia can be part of the clinical picture in the A-T disorder and may even mask ataxia. This should be considered as a major feature mainly in variant A-T, which may occur without general ataxia and may be misdiagnosed in adults with primary dystonia.
| S-EPMC7024809 | biostudies-literature
Project description: Not available
| S-EPMC8642371 | biostudies-literature
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| S-EPMC6353315 | biostudies-literature
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| S-EPMC6417756 | biostudies-literature
Project description:Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.
| S-EPMC11004927 | biostudies-literature