Article

Ataxia with oculomotor apraxia type 2 - A clinical, pathologic, and genetic study

Department of Neurological Sciences, Federico II University, Naples, Italy.
Neurology (Impact Factor: 8.29). 05/2006; 66(8):1207-10. DOI: 10.1212/01.wnl.0000208402.10512.4a
Source: PubMed

ABSTRACT

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients.
To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families.
The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations.
All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation).
The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.

Download full-text

Full-text

Available from: Maria Piane, Nov 05, 2014
  • Source
    • "SETX encodes a 302.8-kD widely expressed protein containing an N-terminal putative protein–protein interaction domain and a C-terminal DEAD-box helicase domain followed by a nuclear localization signal (NLS) (Chen et al. 2004). Most senataxin mutations found in AOA2/ALS4 families either cause premature translational termination or interfere with the function of the helicase or N-terminal protein interaction domains (Chen et al. 2004;Moreira et al. 2004;Duquette et al. 2005;Criscuolo et al. 2006;Fogel and Perlman 2006). However, the precise mechanism of toxicity caused by these mutations and manifested in AOA2/ALS4 patients remains to be elucidated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: R loops are three-stranded nucleic acid structures that comprise nascent RNA hybridized with the DNA template, leaving the nontemplate DNA single-stranded. R loops form naturally during transcription even though their persistent formation can be a risky outcome with deleterious effects on genome integrity. On the other hand, over the last few years, an increasingly strong case has been built for R loops as potential regulators of gene expression. Therefore, understanding their function and regulation under these opposite situations is essential to fully characterize the mechanisms that control genome integrity and gene expression. Here we review recent findings about these interesting structures that highlight their opposite roles in cellular fitness.
    Preview · Article · Jul 2014 · Genes & Development
  • Source
    • "Table 1). Exonic or multiexonic deletions and duplications have also been reported [3] [5]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia associated with mutations in SETX, which encodes the senataxin protein, a DNA/RNA helicase. We describe the clinical phenotype and molecular characterization of a Colombian AOA2 patient who is compound heterozygous for a c.994 C>T (p.R332W) missense mutation in exon 7 and a c.6848_6851delCAGA (p.T2283KfsX32) frameshift deletion in SETX exon 21. Immunocytochemistry of patient-derived fibroblasts revealed a normal cellular distribution of the senataxin protein, suggesting that these mutations do not lead to loss or mis-localization of the protein, but rather that aberrant function of senataxin underlies the disease pathogenesis. Furthermore, we used the alkaline comet assay to demonstrate that patient-derived fibroblast cells exhibit an increased susceptibility to oxidative DNA damage. This assay provides a novel and additional means to establish pathogenicity of SETX mutations.
    Full-text · Article · May 2014 · Journal of Clinical Neuroscience
  • Source
    • "Dysarthria has been seen in all published cases of AOA2, including in participants with the previously reported p.Lys992Arg variant [92]. Both exonic/multiexonic deletions and duplications that disrupt SETX leading to AOA2 have been reported [93-95]. AOA2 is inherited in an autosomal-recessive manner [93,94]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS. As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development. Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent. Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.
    Full-text · Article · Oct 2013 · Journal of Neurodevelopmental Disorders
Show more