Progressive Peripheral Neuron Degeneration In Ataxia‐Telangiectasia: An Electrophysiological Study In Children

Kwast, O.; Ignatowicz, R

doi:10.1111/j.1469-8749.1990.tb08485.x

Cited by 27 publications

(13 citation statements)

References 15 publications

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“…Other movement disorders progress less rapidly than ataxia, and when assessed separately, both hypokinetic and hyperkinetic features progress for 10 to 15 years. The axonal sensory‐motor neuropathy is progressive with time, manifesting as an ascending loss of deep tendon reflexes, worsening of electromyographic parameters, and accentuated distal weakness and amyotrophy . Although good quality evidence for changes in cognitive deficits is lacking, some data points to progression in severity and cognitive domains involved with a possible plateau in later life .…”

Section: Progression Of Neurological and Systemic Featuresmentioning

confidence: 99%

“…The axonal sensory-motor neuropathy is progressive with time, manifesting as an ascending loss of deep tendon reflexes, worsening of electromyographic parameters, and accentuated distal weakness and amyotrophy. 8,43 Although good quality evidence for changes in cognitive deficits is lacking, some data points to progression in severity and cognitive domains involved with a possible plateau in later life. 36 Cognitive progression does not mirror motor progression and disability.…”

Section: Progression Of Neurological and Systemic Featuresmentioning

confidence: 99%

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Ataxia‐telangiectasia: A review of movement disorders, clinical features, and genotype correlations

Levy

Lang

2018

Movement Disorders

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Ataxia-telangiectasia is an autosomal recessive neurodegenerative disorder that was initially thought to present exclusively in childhood. With the discovery of the ATM gene, the phenotypic spectrum of the condition has expanded. This review elaborates the expanded phenomenology, including oculomotor apraxia and immunodeficiency, and estimates the presence of each movement disorder feature from previously reported literature. Initial manifestations of Ataxia-telangiectasia include cerebellar symptoms (67%), dystonia (18%), choreoathetosis (10%), and tremor (4%), with parkinsonism and myoclonus not reported as initial features. The prevalence of movement disorders during the course of the disease includes cerebellar symptoms (96%), dystonia (89%), parkinsonism (41%), choreoathetosis (89%), myoclonus (92%), and tremor (74%). Phenomenology and age of onset is modulated by presence of residual ATM kinase activity, with genotypes heavily truncating the ATM protein associated with the most severe phenotypes. Ataxia-telangiectasia commonly results in a spectrum of movement disorders beyond ataxia and telangiectasias. © 2018 International Parkinson and Movement Disorder Society.

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Section: Progression Of Neurological and Systemic Featuresmentioning

confidence: 99%

Section: Progression Of Neurological and Systemic Featuresmentioning

confidence: 99%

Ataxia‐telangiectasia: A review of movement disorders, clinical features, and genotype correlations

Levy

Lang

2018

Movement Disorders

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“…Distal to proximal advancing loss of tendon reflexes is also characteristic of A-T [8], reflecting a progressive sensory and motor neuropathy [4, 15]. …”

Section: Introductionmentioning

confidence: 99%

Ataxia telangiectasia: a review

Rothblum-Oviatt

Wright²,

Lefton‐Greif

et al. 2016

Orphanet J Rare Dis

471

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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“…A taxia-telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Symptoms of A-T include altered DNA damage repair, immunodeficiency, increased cancer incidence, sterility, and muscle atrophy (Barlow et al 1998;Boder and Sedgwick 1958;Chun and Gatti 2004;Eisen et al 1965;Gotoff et al 1967;Kwast and Ignatowicz 1990). Although cerebellar atrophy is most prominent, patients exhibit degenerative changes of various severities in various brain regions (Habek et al 2008;Oba et al 2010;Tavani et al 2003;Verhagen et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Mutation of ataxia–telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia

Campbell

Bushman

Munger

et al. 2015

Glia

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Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia–telangiectasia (A–T), a disease caused by mutations in the ataxia–telangiectasia mutated (ATM) gene. A hallmark of A–T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A–T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A–T astroglia. Metabolic labeling of L-cystine, the major precursor for GSH, revealed that a key component of the defect in A–T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A–T mutant astroglia providing a possible future avenue for targeted therapeutic intervention.

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Progressive Peripheral Neuron Degeneration In Ataxia‐Telangiectasia: An Electrophysiological Study In Children

Cited by 27 publications

References 15 publications

Ataxia‐telangiectasia: A review of movement disorders, clinical features, and genotype correlations

Ataxia‐telangiectasia: A review of movement disorders, clinical features, and genotype correlations

Ataxia telangiectasia: a review

Mutation of ataxia–telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia

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