Ataxia-Oculomotor Apraxia 4

A number sign (#) is used with this entry because of evidence that ataxia-oculomotor apraxia-4 (AOA4) is caused by homozygous or compound heterozygous mutation in the PNKP gene (605610) on chromosome 19q13.

Description

Ataxia-oculomotor apraxia-4 is an autosomal recessive neurologic disorder characterized by onset of dystonia and ataxia in the first decade. Additional features include oculomotor apraxia and peripheral neuropathy. Some patients may show cognitive impairment. The disorder is progressive, and most patients become wheelchair-bound in the second or third decade (summary by Bras et al., 2015).

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

Clinical Features

Bras et al. (2015) reported 11 patients from 8 unrelated families of Portuguese descent with ataxia-oculomotor apraxia. The age at onset ranged from 1 to 9 years, and most patients presented with prominent dystonia that attenuated with time. Additional features included ataxia, oculomotor apraxia, and peripheral neuropathy with decreased vibration sense and areflexia. The disorder was rapidly progressive, and most patients became wheelchair-bound in the second or third decade due to severe muscle weakness and atrophy. Seven patients showed cognitive impairment, including 2 with dementia. Brain imaging showed cerebellar atrophy in all patients. Laboratory studies showed increased alpha-fetoprotein (104150) and cholesterol in only some patients.

Inheritance

The transmission pattern of AOA4 in the families reported by Bras et al. (2015) was consistent with autosomal recessive inheritance.

Population Genetics

Bras et al. (2015) concluded that AOA4 is the most common form of AOA among the Portuguese.

Molecular Genetics

In 11 patients from 8 unrelated Portuguese families with autosomal recessive ataxia-oculomotor apraxia-4, Bras et al. (2015) identified homozygous or compound heterozygous mutations in the PNKP gene (see, e.g., 605610.0002 and 605610.0005-605610.0008). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in all families with available samples. Functional studies of the variants were not performed.