Radiological Imaging in Ataxia Telangiectasia: a Review

Sahama, Ishani; Sinclair, Kate; Pannek, Kerstin; Lavin, Martin F.; Rose, Stephen

doi:10.1007/s12311-014-0557-4

Cited by 56 publications

(55 citation statements)

References 96 publications

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“…The reduced PC number in the cerebellum of AT pigs is interesting, as similar studies cannot be performed in humans. In newborns, retrospective autopsy studies or prospective imaging studies are limited by ethical standards, sufficient patient numbers, adequate controls and the low sensitivity of imaging techniques required for early lesion assessment (56).…”

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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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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“…FA reductions in the cerebral cortex, cerebellar and spinal cord regions suggest involvement of these areas in young A-T patients, and provide an insight into the advanced state of neuropathy, absence of reflexes (ankle, knee and bicep tendons) and proprioception observed in the extremities of these patients. While cerebellar degeneration is a wellestablished finding in A-T, structural changes in the cerebral motor cortex and spinal cord, particularly in histopathological studies, have been confined mainly to older A-T patients (reviewed in Sahama 15 ) and sparingly in young patients. 88,157 Cerebral abnormalities in structural MRI studies have also been observed largely in adult A-T patients, 145,158,193 however exceptional cases in early A-T have been noted.…”

Section: Discussionmentioning

confidence: 99%

“…To this end, the cause of death among most patients is lymphoreticular malignancy or recurrent chronic respiratory infections. 4,5 The hallmark neuropathological condition of A-T is progressive cerebellar atrophy, which can extend to cerebral motor areas and the spinal cord with advanced age (reviewed in Sahama 15 ). Extensive study of these neuropathological features have been conducted in both histopathological and postmortem anatomy study, however non-invasive study of A-T neuropathology using structural imaging modalities in living patients is limited.…”

Section: Introduction Imaging In Ataxia-telangiectasiamentioning

confidence: 99%

“…Extensive study of these neuropathological features have been conducted in both histopathological and postmortem anatomy study, however non-invasive study of A-T neuropathology using structural imaging modalities in living patients is limited. Indeed, conventional T1-and T2-weighted magnetic resonance imaging (MRI) remains the predominant imaging modality used in A-T to date (reviewed in Sahama 15 ). Additional information regarding these studies can be viewed in Table 2.1 (Chapter 2) and Table 2.2 (Appendices) in this thesis.…”

Section: Introduction Imaging In Ataxia-telangiectasiamentioning

confidence: 99%

“…4,5 To date, conventional T1-and T2-weighted MRI imaging studies have highlighted hallmark neuropathological features, namely progressive cerebellar atrophy, in A-T (reviewed in Sahama 15 ).…”

Section: Introductionmentioning

confidence: 99%

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Investigating neural connectivity of corticomotor networks in ataxia telangiectasia: improving our understanding of the clinical phenotype

Sahama¹

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The human genetic disorder ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative condition occurring in 3 per million live births. The disease is characterised by neurodegeneration, immunodeficiency, radiosensitivity, cell cycle checkpoint defects, genomic instability and cancer predisposition among patients. The most debilitating aspect of the disease is progressive cerebellar ataxia, which represents the hallmark neuropathological condition of A-T.At present, long term therapy to cure or prevent progressive symptoms of A-T are not currently available. While short term treatment to alleviate symptoms associated with immunodeficiency and deficient lung function are available to patients, the predisposition to cancer and the progressive neurodegeneration associated with A-T cannot be prevented with such efforts. To gain a more informed understanding of the A-T condition, research has focused on clinical, genetic and immunological aspects of the disorder; however, minimal attention has been directed towards identifying altered brain structure and function using imaging modalities such as magnetic resonance imaging (MRI).Imaging studies in A-T are limited to structural MRI imaging, where various radiological anomalies in patients are reported as clinical case studies. While these studies provide a detailed focus on the morphological and histopathological conditions of A-T, they provide limited insight into the mechanisms of neurodegeneration and loss of neural motor network connectivity among patients. In other ataxic diseases such as Friedrich's ataxia and spinocerebellar ataxia, the use of high-resolution MRI and diffusion-weighted imaging (DWI) has given valuable insight into the microstructural tissue environment, and the loss of white matter integrity of motor networks due to abnormal neurodevelopmental and/or progressive neurodegenerative conditions associated with the disease.Such imaging approaches have not yet been extended to the study of A-T, and could provide important new information regarding the relationship between the ataxia-telangiectasia gene mutation (ATM) and loss of motor pathway integrity in A-T patients. ivThe key objective of this PhD programme was to investigate white matter integrity and grey matter volume changes associated with A-T using a combination of structural MRI and diffusion-weighted imaging, to pinpoint potential neurodegenerative biomarkers that can be targeted for therapeutic use among young A-T patients. Performing diffusion imaging in children with A-T presents a significant challenge, as spontaneous movement at resting positions form part of the A-T condition, and nonsedated imaging procedures will contribute to excessive motion artefact and limited image quality in diffusion-weighted images. To effectively detect and correct for motion artefacts, a series of data preprocessing and correction steps were introduced to the DWI processing pipeline of A-T images in this project. Whole brain imaging analysis, specifically voxel-based morphometry (based...

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Genotype, extrapyramidal features, and severity of variant ataxia‐telangiectasia

Schon

Oscroft

et al. 2019

Annals of Neurology

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Objective Variant ataxia‐telangiectasia is caused by mutations that allow some retained ataxia telangiectasia‐mutated (ATM) kinase activity. Here, we describe the clinical features of the largest established cohort of individuals with variant ataxia‐telangiectasia and explore genotype‐phenotype correlations. Methods Cross‐sectional data were collected retrospectively. Patients were classified as variant ataxia‐telangiectasia based on retained ATM kinase activity. Results The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%). There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands. Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset. Only one third had predominant ataxia, and 18% had a pure extrapyramidal presentation. Individuals with extrapyramidal presentations had milder neurological disease severity. There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy. Missense mutations were associated with milder neurological disease severity, but with a higher risk of malignancy, compared to leaky splice site mutations. Interpretation Individuals with variant ataxia‐telangiectasia require malignancy surveillance and tailored management. However, our data suggest the condition may sometimes be mis‐ or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha‐fetoprotein levels in some individuals. Missense mutations are associated with milder neurological presentations, but a particularly high malignancy risk, and it is important for clinicians to be aware of these phenotypes. ANN NEUROL 2019;85:170–180.

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Radiological Imaging in Ataxia Telangiectasia: a Review

Cited by 56 publications

References 96 publications

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

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

Investigating neural connectivity of corticomotor networks in ataxia telangiectasia: improving our understanding of the clinical phenotype

Genotype, extrapyramidal features, and severity of variant ataxia‐telangiectasia

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