The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia

Méneret, Aurélie; Ahmar-Beaugendre, Yara; Rieunier, Guillaume; Mahlaoui, Nizar; Gaymard, Bertrand; Apartis, Emmanuelle; Tranchant, Christine; Rivaud-Péchoux, Sophie; Degos, Bertrand; Benyahia, B.; Suarez, Félipe; Maisonobe, Thierry; Kœnig, M.; Dürr, Alexandra; Stern, Marc‐Henri; d’Enghien, Catherine Dubois; Fischer, Alain; Vidailhet, Marie; Stoppa‐Lyonnet, Dominique; Grabli, David; Anheim, Mathieu

doi:10.1212/wnl.0000000000000794

Cited by 66 publications

(92 citation statements)

References 37 publications

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“…An obvious example is Wilson’s disease, which may first present as isolated dystonia in adults, but DBS is not the most appropriate initial therapy (Hedera 2014; Machado et al 2006; Svetel et al 2001; Walshe and Yealland 1992). Another example is ataxia telangiectasia, which may first present in adults with isolated dystonia rather than ataxia (Meneret et al 2014; Charlesworth et al 2013; Saunders-Pullman et al 2012; Verhagen et al 2009). Similarly, dystonia may be the dominating clinical feature of several spinocerebellar ataxias (Neychev et al 2011; Rossi et al 2014).…”

Section: Can Genetic Testing Improve Dbs Outcomes?mentioning

confidence: 99%

Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

et al. 2017

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The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal movements and postures. There are many different clinical manifestations and underlying causes. Deep brain stimulation (DBS) provides an effect treatment, but outcomes can vary considerably among the different subtypes of dystonia. Several variables are thought to contribute to this variation including age of onset and duration of dystonia, specific characteristics of the dystonic movements, location of stimulation and stimulator settings, and others. The potential contributions of genetic factors have received little attention. In this review, we summarize evidence that some of the variation in DBS outcomes for dystonia is due to genetic factors. The evidence suggests that more methodical genetic testing may provide useful information in the assessment of potential surgical candidates, and in advancing our understanding of the biological mechanisms that influence DBS outcomes.

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Section: Can Genetic Testing Improve Dbs Outcomes?mentioning

confidence: 99%

Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

et al. 2017

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“…Another ATM-targeted pig has recently been reported using similar strategy , however that model is still in early stages, and only the generation of heterozygote females was described without any neurological or behavioral characterization (66). The initial characterizations have shown several neuropathologic and motor features of AT patients (15,16,52,53) suggesting the suitability of the new model to study AT.…”

Section: Discussionmentioning

confidence: 99%

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

et al. 2015

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Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. † These authors contributed equally.

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“…Along with the extensive use of WES for the genetic diagnostic came a broadening of the phenotypes linked to several genes, either through an enlargement of the clinical picture previously observed or a novel implication in a different disease. ATM mutations, responsible for ataxia-telangectasia, have been described in several families with atypical presentation, such as later age at onset, normal levels of alpha-foeto-protein, and a large range of movement disorders, including dystonia and tremor [38]. More dramatically, a TGM6 mutation previously implicated in SCA35 has been shown to segregate with acute myeloid leukaemia [39].…”

Section: A Bumper Harvest Of Novel Genesmentioning

confidence: 99%

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

2015

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Hereditary cerebellar ataxias (HCAs) are clinically and genetically heterogeneous neurodegenerative disorders, characterised by a cerebellar syndrome and other neurological or non-neurological signs. So far, more than 20 genes have been described in autosomal dominant HCA; in autosomal recessive HCA, even more genes are involved, in often more complex phenotypes. Because of that complexity, the genetic diagnosis of these diseases is often based on the next-generation sequencing techniques. In this review paper, we discuss the major contributions that they have made to the genetic landscape of HCAs. Numerous novel genes have been identified; still more have recently been implicated in HCAs in addition to being responsible for other diseases. The phenotypic spectrum associated with a single gene constantly gains in complexity. Novel types of mutations or transmissions in known genes are regularly being identified. All these factors make genotype-phenotype correlations particularly difficult. Some but not all of this variability can be explained by different pathophysiological consequences (loss of function, gain of function, variable levels of haploinsufficiency). This also raises the question of modifier genes. Finally, we highlight some functional pathways that increasingly appear important in HCAs.

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The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia

Cited by 66 publications

References 37 publications

Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

Deep brain stimulation for dystonia: a novel perspective on the value of genetic testing

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

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