Spinocerebellar Ataxia, Autosomal Recessive 1

Alternative Names

  • SCAR1
  • Ataxia-Oculomotor Apraxia 2
  • AOA2
  • Ataxia-Ocular Apraxia 2

Associated Genes

Senataxin
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WHO-ICD-10 version:2010

Diseases of the nervous system

Polyneuropathies and other disorders of the peripheral nervous system

OMIM Number

606002

Mode of Inheritance

Autosomal recessive

Gene Map Locus

9q34.13

Description

AOA2 belongs to a group of autosomal recessive cerebellar ataxias (ARCA) which also includes Ataxia with Oculomotor Apraxia Type 1, Ataxia-Telangiectasia and Ataxia-Telangiectasia-Like-Disorder. It is characterized by gait ataxia, choreoathetosis, myoclonus, peripheral neuropathy, cerebellar atrophy, oculomotor apraxia and raised alpha-fetoprotein levels. Creatine Phosphokinase levels may also be elevated. AOA2 is caused by mutations in the SETX gene. Unlike AOA1, AOA2 does not show reduced levels of albumin and the chorea and myoclonus do not abate with time. It also has a later onset, starting in adolescence. It is a highly progressive disorder and most patients become wheelchair bound by the third or fourth decade of life. AOA2 has been found to occur in 1 in 900,000 individuals.  

Diagnosis is made based on clinical features, levels of alpha-fetoprotein, presence of cerebellar atrophy and via genetic testing of the SETX gene. Treatment options are currently limited to the management of symptoms with physical therapy, speech therapy, mobility aids and special education.

Molecular Genetics

AOA2 is an autosomal recessive disorder caused by mutations in the SETX gene. The SETX gene codes for the senataxin protein, which has been predicted to be a helicase involved in DNA repair, RNA splice site selection and transcription regulation. Mutations in the SETX gene lead to a disrupted helicase domain affecting the process of DNA repair and leading to the accumulation of DNA damage in cells. Around 115 different mutations have been found in the SETX gene in AOA2 affected patients. Most of these mutations are found in exon 8 resulting in the disruption of the C-terminal motifs containing the DNA/RNA helicase domain. 

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Bohlega et al. (2011) reported on the genetic mutations affecting ataxia and oculomotor apraxia patients in the country. Nine patients from 4 consanguineous families of central and western Saudi Arabia were recruited for this study. Two sisters from family A, aged 27 and 23, developed ataxia at ages 14 and 20 respectively. The first sister showed oculomotor apraxia, poor smooth pursuit ocular movements, frequent head thrusts and slow horizontal saccadic eye movement. Investigations also found an absence of tendon reflexes, elevated alpha-fetoprotein levels and reduced sensor nerve action potentials. Genetic testing was carried out with a particular focus on the APTX, MRE11 and SETX genes. The authors uncovered a novel homozygous truncating mutation 6859C>T (R2287X) in exon 20 of the SETX gene in both affected sisters of family A. As most previously reported SETX mutations have been in exon 8 of the gene, disrupting C-terminal motifs, this finding is particularly interesting as it highlights the importance of other domains of SETX.

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