Ataxia telangiectasia with long survival

Opeskin, Kenneth; Waterston, John; Nirenberg, Alex; Hare, W. S. C.

doi:10.1016/s0967-5868(98)90295-8

Cited by 8 publications

(17 citation statements)

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“…There have been considerable differences in the reported consequences of BMI1 knockdown on the recruitment of DDR proteins to IRIFs (14,16,18,19,24,25). The recruitment of phosphorylated ATM to IRIFs, for example, differed between laboratories.…”

Section: Prt4165 Abrogates the Retention Of Several Ddr Proteins In Imentioning

confidence: 99%

A Small Molecule Inhibitor of Polycomb Repressive Complex 1 Inhibits Ubiquitin Signaling at DNA Double-strand Breaks

Ismail

McDonald

Strickfaden

et al. 2013

Journal of Biological Chemistry

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Background: DNA damage-induced ubiquitylation is important in regulating the DNA damage response. Results: PRT4165 inhibits histone H2A ubiquitylation and the accumulation of ubiquitin at the DNA double-strand break (DSB) sites. Conclusion: PRT4165 is a novel drug for studying DSB response. Significance: PRT4165 may constitute a novel approach for studying DSB response and for development of new cancer therapy.

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Section: Prt4165 Abrogates the Retention Of Several Ddr Proteins In Imentioning

confidence: 99%

A Small Molecule Inhibitor of Polycomb Repressive Complex 1 Inhibits Ubiquitin Signaling at DNA Double-strand Breaks

Ismail

McDonald

Strickfaden

et al. 2013

Journal of Biological Chemistry

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“…One pattern consists of multiple T1 and T2 hypointense foci suggestive of hemosiderin, thought to be related to thrombosis and vascular leaks from multiple capillary telangiectasias. 12 The other pattern, described in a single child and in a few adult patients, 11,13–15 is T2/FLAIR hyperintensity on long TR sequences that simulates leukodystrophy. The purpose of this study was to analyze the MR imaging features of the supratentorial brain in a small series of young adults with A-T, all otherwise healthy and neurologically stable for years, though they were manifesting substantial persistent neurologic deficits.…”

mentioning

confidence: 99%

Cerebral Abnormalities in Adults with Ataxia-Telangiectasia

Lin¹,

Barker²,

Lederman³

et al. 2013

AJNR Am J Neuroradiol

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SUMMARY: Ataxia-telangiectasia, an autosomal recessive disorder caused by defect of the ataxia-telangiectasia mutated gene, is characterized by progressive neurologic impairment with cerebellar atrophy, ocular and cutaneous telangiectasia, immunodeficiency, heightened sensitivity to ionizing radiation and susceptibility to developing lymphoreticular malignancy. Supratentorial brain abnormalities have been reported only rarely. In this study, brain MRI was performed in 10 adults with ataxia-telangiectasia having stable neurologic impairment. Intracerebral telangiectasia with multiple punctate hemosiderin deposits were identified in 60% of subjects. These lesions were apparently asymptomatic. They are similar in appearance to radiation-induced telangiectasia and to cryptogenic vascular malformations. Also noted, in the 2 oldest subjects, was extensive white matter T2 hyperintensity, and in 1 of these a space-occupying fluid collection consistent with transudative capillary leak and edema as evidenced by reduced levels of metabolites on MR spectroscopic imaging. Asymptomatic supratentorial vascular abnormalities appear to be common in adults with ataxia-telangiectasia.

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“…Very few studies have focused on reporting radiological findings in A-T. 133,[143][144][145][146][147][148][150][151][152][153][154][155][156][157] Of these, studies using standard T1-and T2-weighted MRI sequences have consistently shown diffuse cerebellar atrophy, predominantly within the vermis and cerebellar hemispheres. This reflects the loss of Purkinje cells on a histological level, which is a well-established neuropathological hallmark of A-T. Foci of T2-weighted WM hypo-and hyper-intensity have also been observed and attributed to capillary telangiectasia and focal extracerebellar demyelination.…”

Section: Discussionmentioning

confidence: 99%

“…Opeskin and colleagues (147) T1/T2 34 1/0 Findings: gross cerebellar atrophy, lesions consistent with vascular malformations in cerebral WM with surrounding abnormal tissue consistent with gliosis found. MRI scans 6 months apart from the age of 32 years showed progression of lesions.…”

Section: Summary Of Radiological Findings In A-tmentioning

confidence: 99%

“…The specificity of this finding has yet to be established. MRI scans in older patients in their second and third decade also show varied findings in the cerebellar and cerebral lesion progression, such as corpora amylacea, 147 diffuse symmetrical high signal in the central WM of cerebral hemispheres on T2-weighted images, 145 scattered calcified deposits in the cerebrum WM and space occupying lesions in the right frontal lobe WM and left paraventricular WM. 148,154 Both of these lesions were displayed with low intensity on T1-weighted images and high intensity on T2-weighted images.…”

Section: Summary Of Radiological Findings In A-tmentioning

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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Ataxia telangiectasia with long survival

Cited by 8 publications

References 4 publications

A Small Molecule Inhibitor of Polycomb Repressive Complex 1 Inhibits Ubiquitin Signaling at DNA Double-strand Breaks

A Small Molecule Inhibitor of Polycomb Repressive Complex 1 Inhibits Ubiquitin Signaling at DNA Double-strand Breaks

Cerebral Abnormalities in Adults with Ataxia-Telangiectasia

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

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