Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders

Kashimada, Ayako; Hasegawa, Setsuko; Nomura, Toshihiro; Shiraku, Hiroshi; Moriyama, Kengo; Suzuki, Tomonori; Nakajima, Keisuke; Mizuno, Tomoko; Imai, Kohsuke; Sugawara, Yuji; Morio, Tomohiro; Kumada, Satoko; Takagi, Motoki

doi:10.1016/j.braindev.2018.09.007

Cited by 22 publications

(11 citation statements)

References 31 publications

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“…Our results are consistent with previously published diagnostic rates in patients with genetic ataxias associated with cerebellar atrophy. 1,6,8,13,[31][32][33][34] Channelopathies were more frequent in our cohort compared with previously published studies and likely represent an under-recognized cause of cerebellar atrophy in both adults and children. One large cohort study recently reported the frequency of channelopathies in patients with autosomal dominant cerebellar ataxias, in particular CACNA1Arelated disorder.…”

Section: Discussionsupporting

confidence: 44%

Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy

Gauquelin

Hartley

Tarnopolsky

et al. 2020

Movement Disord Clin Pract

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Background Background: Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging. Objectives Objectives: To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Canadian cohort and the diagnostic yield of exome sequencing for this group of conditions. Methods Methods: A total of 92 participants from 66 families with cerebellar atrophy were recruited for this multicenter prospective cohort study. Exome sequencing was performed for all participants between 2011 and 2017 as part of 1 of 2 national research programs, Finding of Rare Genetic Disease Genes or Enhanced Care for Rare Genetic Diseases in Canada. Results Results: A genetic diagnosis was established in 53% of families (35/66). Pathogenic variants were found in 21 known genes, providing a diagnosis for 31/35 families (89%), and in 4 novel genes, accounting for 4/35 families (11%). Of the families, 31/66 (47%) remained without a genetic diagnosis. The most common diagnoses were channelopathies, which were established in 9/35 families (26%). Additional clinical findings provided useful clues to specific diagnoses. Conclusions Conclusions: We report on the high frequency of channelopathies as a cause of genetic ataxias associated with cerebellar atrophy and the utility of exome sequencing for this group of conditions. Cerebellar atrophy is a nonspecific imaging finding observed in a number of acquired and genetic neurological disorders in both pediatric and adult populations. 1-3 It is characterized by a loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae, in a posterior fossa of normal size. 2,4-6 Genetic ataxias associated with cerebellar atrophy are a clinically and genetically heterogeneous group of conditions, which makes the approach to diagnosis challenging. 1-3 Possible causes include chromosomal abnormalities; repeat expansions; inborn errors of metabolism, in particular mitochondrial disorders; and other single gene disorders. 1,2,7-9 Genetic ataxias were historically classified based on their mode of inheritance, with early-onset autosomal recessive conditions being the most common. 10,11 Additional clinical and neuroimaging findings are essential to selecting appropriate genetic investigations. 1,3,12,13 Specific

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Section: Discussionsupporting

confidence: 44%

Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy

Gauquelin

Hartley

Tarnopolsky

et al. 2020

Movement Disord Clin Pract

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“…Diagnosis rates of 39.1% [15], 46% [16], and more than 60% [17] have been reported in various whole exome sequencing WES studies, from families numbering between 22 and 28. A high diagnostic yield of 58.8% was reported in undiagnosed ataxia-telangiectasia-like disorders in a more recent clinical exome study [8]. Future WES studies on undiagnosed patients may increase the amount of data available.…”

Section: Discussionmentioning

confidence: 89%

“…That study reported successful diagnosis after a maximum duration of 35 years [1]. The reported diagnostic yield of one clinical exome study of undiagnosed ataxia-telangiectasia (AT)-like disorders was 58.8% [8].…”

Section: Introductionmentioning

confidence: 98%

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

Arslan

Öncel

Ceylan

et al. 2020

Brain and Development

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“…Chromosomal instability syndromes have an overlap in clinical features, immunodeficiency and/or malignancy predisposition. 34 Despite similarities in the cellular defects displayed by cells derived from patients with chromosomal instability syndromes, the impact on the development and maintenance of specific tissues and organs can be strikingly different, particularly with respect to the nervous system. 26 The underlying reason for this stark contrast in disease-associated neuropathology and how it is related to specific repair deficiencies is not well understood.…”

Section: Other Chromosomal Instability Syndromesmentioning

confidence: 99%

“…Similar to ATLD, other diseases that are included in the chromosomal instability syndromes are: AT, Fanconi anemia, Nijmegen breakage syndrome and Bloom syndrome. Chromosomal instability syndromes have an overlap in clinical features, immunodeficiency and/or malignancy predisposition 34 …”

Section: Literature Reviewmentioning

confidence: 99%

Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia‐Like Disorders

Raslan

Matos

Ciarlariello

et al. 2020

Movement Disord Clin Pract

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Background Background: Ataxia telangiectasia is one of the most common causes of autosomal recessive cerebellar ataxias. However, absence of telangiectasia, normal levels of alpha-fetoprotein and negative genetic test may direct to alternative diagnosis with similar phenotypes such as ataxia telangiectasia-like disorders (ATLD). Cases Cases: We report two instructive cases of ATLD: the first case with ataxia telangiectasia-like disorder type 1 related to MRE11A gene, and the second case with ataxia telangiectasia-like disorder type 2 related to PCNA gene. Literature Review Literature Review: ATLD is an unusual group of autosomal recessive diseases that share some clinical features and pathophysiological mechanisms with ataxia telangiectasia (AT). ATLD may be associated with mutations in the MRE11A (ATLD type 1) and PCNA (ATLD type 2) genes. ATLD belongs to the group of chromosomal instability syndromes. The reason for the term ATLD is related to the similar pathophysiological mechanisms observed in AT, which is characterized by chromosomal instability and radiosensitivity. Conclusions Conclusions: In this review, the main clinical features, biomarkers, brain imaging and genetics of ATLD are discussed. Mutations in the MRE11A and PCNA genes should be included in the differential diagnosis for early onset cerebellar ataxia with absence of telangiectasia and normal levels of alpha-fetoprotein.

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Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders

Cited by 22 publications

References 31 publications

Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy

Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia‐Like Disorders

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