New autosomal recessive cerebellar ataxias with oculomotor apraxia

Ber, Isabelle Le; Brice, Alexis; Dürr, Alexandra

doi:10.1007/s11910-005-0066-4

Cited by 33 publications

(12 citation statements)

References 49 publications

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“…A distinct form of AOA linked to chromosome 9q34, AOA2 also has an overlapping clinical phenotype with the three disorders described in the previous paragraph (Nemeth et al, 2000; Duquette et al, 2005; Le Ber et al, 2005). This syndrome is characterized by cerebellar atrophy, oculomotor apraxia, peripheral neuropathy, and elevated serum α-fetoprotein in some cases (Le Ber et al, 2005; Criscuolo et al, 2006).…”

Section: Introductionmentioning

confidence: 72%

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Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage

Suraweera

Bécherel

Chen

et al. 2007

The Journal of Cell Biology

182

154

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Adefective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome.

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Section: Introductionmentioning

confidence: 72%

“…This syndrome is characterized by cerebellar atrophy, oculomotor apraxia, peripheral neuropathy, and elevated serum α-fetoprotein in some cases (Le Ber et al, 2005; Criscuolo et al, 2006). The gene defective in AOA2, SETX , was recently identified (Moreira et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage

Suraweera

Bécherel

Chen

et al. 2007

The Journal of Cell Biology

182

154

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“…It has been suggested that A-T is the second most common cause of ataxia [11,53,54]. However, in the three studies that tested for both AOA and A-T genes, AOA was found to be more common in two studies (in Portugal and Alsace), while A-T was more common in Norway.…”

Section: Discussionmentioning

confidence: 97%

The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies

et al. 2014

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Background: Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait impairment, often leading to permanent disability. Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology. Summary: Our objective was to assess the global distribution and prevalence of HCA and HSP by a systematic review and meta-analysis of prevalence studies. The MEDLINE, ISI Web of Science and Scopus databases were searched (1983-2013) for studies performed in well-defined populations and geographical regions. Two independent reviewers assessed the studies and extracted data and predefined methodological parameters. Overall, 22 studies were included, reporting on 14,539 patients from 16 countries. Multisource population-based studies yielded higher prevalence values than studies based primarily on hospitals or genetic centres. The prevalence range of dominant HCA was 0.0-5.6/10⁵, with an average of 2.7/10⁵ (1.5-4.0/10⁵). Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6. The autosomal recessive (AR) HCA (AR-HCA) prevalence range was 0.0-7.2/10⁵, the average being 3.3/10⁵ (1.8-4.9/10⁵). Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia. The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/10⁵ and that of AR-HSP from 0.0 to 5.3/10⁵, with pooled averages of 1.8/10⁵ (95% CI: 1.0-2.7/10⁵) and 1.8/10⁵ (95% CI: 1.0-2.6/10⁵), respectively. The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A, while SPG11 was the most frequent AR-HSP, followed by SPG15. In population-based studies, the number of families without genetic diagnosis after systematic testing ranged from 33 to 92% in the AD-HCA group, and was 40-46% in the AR-HCA, 45-67% in the AD-HSP and 71-82% in the AR-HSP groups. Key Messages: Highly variable prevalence values for HCA and HSP are reported across the world. This variation reflects the different genetic make-up of the populations, but also methodological heterogeneity. Large areas of the world remain without prevalence studies. From the available data, we estimated that around 1:10,000 people are affected by HCA or HSP. In spite of advances in genetic research, most families in population-based series remain without identified genetic mutation after extensive testing.

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“…Senataxin is thought to be involved in double strand break DNA repair and response to oxidative stress but also in transcription regulation via exon splicing (Airoldi et al 2009, Suraweera et al 2007, Suraweera et al 2009). Patients with AOA2 have elevated α-fetoprotein (AFP) levels, a tumor marker (Anheim et al 2009b, Le Ber et al 2005), but without increased occurrence of cancer as observed in ataxiatelangiectesia. Oculomotor apraxia is not a systematic finding and appears to be present in about 50% of patients (Anheim et al 2009b).…”

Section: Introductionmentioning

confidence: 99%

1H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2

Iltis¹,

Hutter²,

Bushara³

et al. 2010

Brain Research

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Background and aim-Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias. However, brain metabolism in these disorders is poorly characterized and biomarkers of the disease progression are lacking. We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases.Corresponding author: Isabelle Iltis Center for Magnetic Resonance Research University of Minnesota 2021 6 th St SE Minneapolis, MN 55455 isabelle@cmrr.umn.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Section. Disease-related NeuroscienceResearch highlights 1 H MR Spectroscopy in Friedreich's Ataxia and Ataxia with Oculomotor Apraxia Type 2 •Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias• Biomarkers of the disease progression are lacking •( 1 H) magnetic resonance spectroscopy (MRS) was used to assess the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases• Distinct neurochemical patterns were observed in the two patient populations• In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p < 0.01)• Studies with larger patient populations will determine if the alterations in metabolite levels observed here may be utilized to monitor disease progression and treatment Methods-Short-echo, single voxel proton ( 1 H) magnetic resonance spectroscopy data were acquired from 8 volunteers with FRDA, 9 volunteers with AOA2, and 38 control volunteers at 4T. Disease severity was assessed by the Friedreich's Ataxia Rating Scale (FARS). NIH Public AccessResults-Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N-acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p < 0.01).Conclusion...

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New autosomal recessive cerebellar ataxias with oculomotor apraxia

Cited by 33 publications

References 49 publications

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage

The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies

1H MR spectroscopy in Friedreich's ataxia and ataxia with oculomotor apraxia type 2

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