Ataxia-Oculomotor Apraxia 3

A number sign (#) is used with this entry because of evidence that ataxia-oculomotor apraxia-3 (AOA3) is caused by homozygous mutation in the PIK3R5 gene (611317) on chromosome 17p13. One such family has been reported.

Description

AOA3 is an autosomal recessive progressive neurologic disorder with onset in the second decade of life (Al Tassan et al., 2012).

For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (208920).

Clinical Features

Al Tassan et al. (2012) reported 4 sibs, born of consanguineous Saudi Arabian parents, with ataxia-oculomotor apraxia. The proband developed progressive unsteady gait and had frequent falls at age 14 years with later onset of arm dysmetria and dysarthria. He became wheelchair-bound at age 23. Ocular movement was impaired, with slowed saccadic eye movements and head-eye lag resulting in head thrust, but smooth pursuit was normal. He had severe limb and axial dysmetria with mild distal atrophy and weakness affecting the lower limbs more than the upper limbs. He also had distal sensory impairment, more prominent in the lower limbs, areflexia, and axonal sensory polyneuropathy with absent sensory nerve action potentials in the lower limbs. Laboratory studies showed increased level of alpha-fetoprotein, and brain MRI showed atrophy of the cerebellar folia and vermis. His 3 sibs were similarly affected.

Inheritance

The transmission pattern of AOA3 in the family reported by Al Tassan et al. (2012) was consistent with autosomal recessive inheritance.

Mapping

By linkage analysis in a consanguineous Saudi family with AOA, Al Tassan et al. (2012) found linkage to a 5.8-Mb region on chromosome 17p13-p12 (lod score of 3.38).

Molecular Genetics

In affected members of a family with AOA3, Al Tassan et al. (2012) identified a homozygous mutation in the PIK3R5 gene (P629S; 611317.0001). The mutation was found by linkage analysis followed by sequencing of the genes within the region. Mutations were not found in the SETX (608465), APTX (606350), or MRE11A (600814) genes in this family.