Aprataxin Gene Mutations in Tunisian Families

Institut National de Neurologie, Département de Biologie Moléculaire et de Neuropathologie,CNRS/INSERM Université Louis Pasteur, Illkirch, CHU de Strasbourg, France.
Neurology (Impact Factor: 8.3). 10/2004; 63(5):928-9. DOI: 10.1212/01.WNL.0000137044.06573.46
Source: PubMed

ABSTRACT The authors report clinical and genetic study of 13 patients from three unrelated Tunisian families with an early onset cerebellar ataxia associated with oculomotor apraxia. Cerebellar ataxia with oculomotor apraxia 1 (AOA1) represents a clinically heterogeneous disease caused by mutations in the aprataxin gene. Two novel mutations were identified, the complete deletion of the gene, which seems to not correlate with an increased severity of the disease, and a splice mutation on the acceptor splice site of exon 7.

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    • "The proband showed shortrapid movements in her fingers, but was able to control them, challenging their choreic origin. Third, mental retardation or cognitive impairment are common in Japanese and French patients [2] [3] manifesting a dysexecutive syndrome related to dysfunction of the front-cerebellar pathways [3]; the proband did not disclosed mental retardation or cognitive impairment similarly to Portuguese and Tunisian patients [12] [13]. Fourth, some authors consider the presence of Babinski sign a distinctive trait of FRDA as to AOA [3]. "
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    ABSTRACT: Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.
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