Ataxia-Oculomotor Apraxia 3

Alternative Names

  • AOA3
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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

615217

Mode of Inheritance

Autosomal recessive

Gene Map Locus

17p13.1

Description

AOA3 is a rare type of autosomal recessive cerebellar ataxia.  Other disorders in this group include Spinocerebellar Ataxia, Autosomal Recessive 1, Ataxia with Oculomotor Apraxia Type 1, Ataxia-Telangiectasia and Ataxia-Telangiectasia-Like-Disorder.  The disease is characterized by ataxia, dysmetria, peripheral neuropathy, areflexia, cerebellar atrophy, oculomotor apraxia and raised alpha-fetoprotein levels.  Symptoms usually surface in the second decade of life and follow a highly rapid progression.  Patients may hence become wheelchair-bound by the third or fourth decade of life.  AOA3 has so far been diagnosed in only a single Saudi Arab family.

Diagnosis of the disorder is made based on a clinical investigation, the presence of cerebellar atrophy, and levels of alpha-fetoprotein.  While the disorder cannot presently be cured, symptoms can be managed by physical therapy, speech therapy, mobility aids and special education. 

Molecular Genetics

AOA3 follows an autosomal recessive pattern of inheritance and is caused by mutations in the PIK3R5 gene.  This gene encodes a regulatory subunit of the PI3K gamma complex, a family of lipid kinases involved in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking.  Expression of the gene is found to be high in both the fetal and adult human brain.  A missense mutation (P629S) in this gene, predicted to affect the structure of PIK3R5, has been linked to AOA3.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Al Tassan et al. (2012) described a Saudi family with four individuals affected by Ataxia with Oculomotor Apraxia.  The index patient, a 33-year-old male, complained of frequent falls and unsteady legs from the age of 14-years.  Subsequently, he suffered from arms dysmetria, truncal ataxia and cerebellar dysarthric speech.  He was wheelchair bound by the age of 23-years.  Other features included impaired ocular movement, severe limb and axial dysmetria, areflexia, mild distal atrophy and global weakness of the legs.  An MRI revealed bilateral atrophy of the cerebella folia with marked vermal atrophy.  Three other affected siblings had a similar disease pattern.  All four patients showed elevated alpha-fetoprotein levels as well as moderately severe axonal sensory polyneuropathy with absent sensory nerve action potentials in the lower limbs.  When no mutations were uncovered in the SETX gene, linkage analysis and homozygosity analysis were employed to map the disease to chromosome 17.  Sequencing unveiled a homozygous missense change in the PIK3R5 gene.  All affected siblings were homozygous for the mutation while the parents and unaffected siblings were found to be heterozygous.  

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