Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.

Department of Neurology, Beth Israel Medical Center, New York, NY, USA.
Neurology (Impact Factor: 8.3). 02/2012; 78(9):649-57. DOI: 10.1212/WNL.0b013e3182494d51
Source: PubMed

ABSTRACT To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research.
Movement 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.
Genetic 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.
Ataxia 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.

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    ABSTRACT: Dopa-responsive dystonia (DRD) has a classic presentation of childhood or adolescent-onset dystonia, mild parkinsonism, marked diurnal fluctuations, improvement with sleep or rest, and a dramatic and sustained response to low doses of L-dopa without motor fluctuations or dyskinesias. However, there have been many papers on patients with a wide range of features, which report them as DRD mainly because they had dystonic syndromes with L-dopa responsiveness. Many mutations in the dopaminergic system have been found as molecular genetic defects. Therefore, the clinical and genetic spectra of DRD are unclear, which lead to difficulties in diagnostic work-ups and planning treatments. We propose the concept of DRD and DRD-plus to clarify the confusion in this area and to help understand the pathophysiology and clinical features, which will help in guiding diagnostic investigations and planning treatments. We critically reviewed the literature on atypical cases and discussed the limitations of the gene study.
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    ABSTRACT: Background Pediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychological changes. Such studies may contribute to the further understanding of AT and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. Methods Twenty-two patients with the classic phenotype of AT were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared to healthy controls and standard norms. Results AT-I patients scored low average compared to standard norms on all tests, and were impaired compared to healthy controls for Verbal IQ (p < .001), Vocabulary and Comprehension (p = .007), processing speed (p = .005), visuospatial processing (p = .020) and working memory (p = .046). AT-II patients scored below average compared to standard norms on all tests, and impaired compared to controls for attention (p < .001), working memory (p < .001) and abstract reasoning (p < .001). Comprehension scores were lower in AT-II than in AT-I patients (p = .002) while vocabulary scores showed no difference between groups (p = .480). Conclusion Cognitive impairments in AT present early coinciding with cerebellar pathology, and are characteristic of the cerebellar cognitive affective syndrome (CCAS). Widespread and deeper cognitive deficits manifest in later stages of AT when additional non-cerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar / subcortical contributions to the range of cognitive domains affected in AT, and need to be confirmed in future studies.
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May 19, 2014