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

Saunders‐Pullman, Rachel; Raymond, Deborah; Stoessl, A. Jon; Hobson, Douglas E.; Nakamura, Tomoya; Pullman, Seth L.; Lefton, D; Okun, Michael S.; Uitti, Ryan J.; Sachdev, Rivka; Stanley, Kaili; Luciano, Marta San; Hagenah, Johann; Gatti, Richard A.; Ozelius, Laurie J.; Bressman, Susan

doi:10.1212/wnl.0b013e3182494d51

Cited by 88 publications

(96 citation statements)

References 38 publications

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“…Mild Forms of A-TClassic FormMild FormNeurologicalManifestationsNeurological deficits are typically observed during the toddler years resulting in wheelchair dependency around the age of 10.Individuals have more mild neurological deficits in childhood with slower age-related neurodegeneration. The predominant neurological symptoms or symptoms to present first may be myoclonus, dystonia, choreoathetosis or tremor with ataxia appearing later [175–177]. Oculomotor apraxia may also appear later or not at all [95].…”

Section: Introductionmentioning

confidence: 99%

Ataxia telangiectasia: a review

Rothblum-Oviatt

Wright²,

Lefton‐Greif

et al. 2016

Orphanet J Rare Dis

439

488

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Definition of the diseaseAtaxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.EpidemiologyThe world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.Clinical descriptionA-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.EtiologyA-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.DiagnosisThe diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.Differential diagnosisThere are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.Antenatal diagnosisAntenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.Genetic counselingGenetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.Management and prognosisTreatment of the neurologic problems associated wit...

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Section: Introductionmentioning

confidence: 99%

Ataxia telangiectasia: a review

Rothblum-Oviatt

Wright²,

Lefton‐Greif

et al. 2016

Orphanet J Rare Dis

439

488

View full text Add to dashboard Cite

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“…However, these features were not included in our algorithm because many clinicians will have limited experience with these rare disorders and specific clinical patterns will easily remain unrecognised. In addition, recent insights from more widely applied NGS testing demonstrate that the clinical heterogeneity of many disorders is much larger than expected,23 31 so clinical pattern recognition of milder, intermediate and unusual phenotypes remains problematic.…”

Section: Discussionmentioning

confidence: 99%

“…However, it should be noted that a positive response on a levodopa trial is not specific for the classic DRDs, but can also be seen in other disorders such as ataxia telangiectasia and GLUT-1 deficiency 31 32…”

Section: Dystonia In Children and Adolescents: State Of The Artmentioning

confidence: 99%

Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm

Egmond

Kuiper

Eggink

et al. 2014

J Neurol Neurosurg Psychiatry

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“…All patients also manifested dystonia from an early age (Yanofsky et al 2009; Saunders-Pullman et al 2012). The onset of ataxia was later than that of this dystonia, especially in the c.6200C>A homozygotes.…”

Section: Discussionmentioning

confidence: 99%

A‐T_W_innipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early‐onset dystonia, cancer, and life‐threatening radiotoxicity

Nakamura

Fike

Haghayegh

et al. 2014

Molec Gen & Gen Med

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We studied 10 Mennonite patients who carry the c.6200C>A missense mutation (p.A2067D) in the ATM gene, all of whom exhibited a phenotypic variant of ataxia-telangiectasia (A-T) that is characterized by early-onset dystonia and late-onset mild ataxia, as previously described. This report provides the pathogenetic evidence for this mutation on cellular functions. Several patients have developed cancer and subsequently experienced life-threatening adverse reactions to radiation (radiotoxicity) and/or chemotherapy. As the c.6200C>A mutation is, thus far, unique to the Mennonite population and is always associated with the same haplotype or haplovariant, it was important to rule out any possible confounding DNA variant on the same haplotype. Lymphoblastoid cells derived from Mennonite patients expressed small amounts of ATM protein, which had no autophosphorylation activity at ATM Ser1981, and trace-to-absent transphosphorylation of downstream ATM targets. A-T lymphoblastoid cells stably transfected with ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein. The same stable cell line with mutated ATM cDNA also showed a trace-to-absent transphosphorylation of downstream ATM targets SMC1pSer966 and KAP1pSer824. From these results, we conclude that c.6200A is the disease-causing ATM mutation on this haplotype. The presence of at least trace amounts of ATM kinase activity on some immunoblots may account for the late-onset, mild ataxia of these patients. The cause of the dystonia remains unclear. Because this dystonia-ataxia phenotype is often encountered in the Mennonite population in association with cancer and adverse reactions to chemotherapy, an early diagnosis is important.

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

Abstract: 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.

Cited by 88 publications

References 38 publications

Ataxia telangiectasia: a review

Ataxia telangiectasia: a review

Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm

A‐T_W_innipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early‐onset dystonia, cancer, and life‐threatening radiotoxicity

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

Abstract: 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.

Cited by 88 publications

References 38 publications

Ataxia telangiectasia: a review

Ataxia telangiectasia: a review

Dystonia in children and adolescents: a systematic review and a new diagnostic algorithm

A‐TWinnipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early‐onset dystonia, cancer, and life‐threatening radiotoxicity

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A‐T_W_innipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early‐onset dystonia, cancer, and life‐threatening radiotoxicity