Clinical spectrum of ataxia-telangiectasia in adulthood

Verhagen, Mijke M.M.; Abdo, Wilson F.; Willemsen, M.A.A.P.; Hogervorst, F.B.L.; Smeets, Dominique; Hiel, J.A.P.; Brunt, Ewout; Rijn, Monique A. van; Krakauer, D.; Oldenburg, Rogier A.; Broeks, Annegien; Veer, Laura J. van’t; Tijssen, Marina A. J.; Dubois, A; Kremer, Hannie; Weemaes, C.M.R.; Taylor, Alexander M.; Deuren, Marcel van

doi:10.1212/wnl.0b013e3181af33bd

Cited by 156 publications

(165 citation statements)

References 26 publications

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“…The majority of these mutations are frameshift or nonsense mutations, [10][11][12][13] accounting in our diagnosis series for 73% of cases, 14 suggesting that the classical A-T phenotype is due to total loss of ATM protein. ATM missense mutations could be responsible for typical, 13 or milder phenotypes, 15,16 but the consequences of many missense mutations not previously associated with A-T remain unknown. Bioinformatics tools are helpful in the latter case but generally insufficient to definitely establish the A-T diagnosis, and direct biological analyses are necessary to determine the pathogenic character of such mutations.…”

Section: Introductionmentioning

confidence: 99%

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

et al. 2011

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Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T.

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Section: Introductionmentioning

confidence: 99%

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

et al. 2011

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“…The presence of parkinsonism in a heterozygous family member as well as in 3 siblings of an obligate carrier and prior reports of rest tremor in variant A-T, 8 raise the question of whether parkinsonism may be part of a motor phenotype in heterozygous and homozygous A-T mutation carriers. There is selective loss of dopaminergic nigrostriatal neurons in ATM-deficient mice, 26 and substantia nigra Lewy bodies occurred in a 31-year-old individual with A-T. 27 Although no nigral cell loss was reported in d Impaired vibration and joint position sense as well as lower extremity areflexia.…”

Section: Additional Clinical Featuresmentioning

confidence: 99%

“…Consequently, some hypothesize that the clinical presentation may result from faulty DNA repair. 5,32 The postulated mechanism of variant A-T is that it is due to mutations that result in higher residual levels of ATM protein than those that cause classic A-T. 8,31 Hence, for homozygous mutations with higher ATM activity, the milder phenotype would tend to segregate within families, and the family as a whole may present with movement disorders rather than ataxia as the primary feature. The pA2067D missense mutation identified in these families (personal communication, T. Nakamura, The Gatti Laboratory, UCLA, 2009) was reported in the heterozygote state in a German patient with A-T (Ae003), 10 and in the homozygous state in Canadian Mennonites.…”

Section: Additional Clinical Featuresmentioning

confidence: 99%

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

2012

Neurology

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Objective: To compare the phenotype of primary-appearing dystonia due to variant ataxiatelangiectasia (A-T) with that of other dystonia ascertained for genetics research. Methods: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 CϾA (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.Result: 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 ϭ 12) than in patients with other dystonia (n ϭ 23), (12 years vs 40 years, p Ͻ 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.

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“…34 There is also a clear genotype-phenotype relationship for AT patients as the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype. 35 ATM mutations that cause AT in bi-allelic carriers are breast cancer susceptibility alleles in mono-allelic carriers. 23 Therefore there is good evidence for Atm, p53 and Chek2 acting as tumor suppressor genes in both mouse and human.…”

confidence: 99%

A minimally invasive assay for individual assessment of the ATM/CHEK2/p53 pathway activity

Kabacik¹,

Ortega-Molina

Efeyan

et al. 2011

Cell Cycle

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Clinical spectrum of ataxia-telangiectasia in adulthood

Cited by 156 publications

References 26 publications

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

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

A minimally invasive assay for individual assessment of the ATM/CHEK2/p53 pathway activity

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