Cerebellar Ataxia, Mental Retardation, And Dysequilibrium Syndrome 4

A number sign (#) is used with this entry because of evidence that this form of congenital cerebellar ataxia with mental retardation (CAMRQ4) is caused by homozygous mutation in the ATP8A2 gene (605870) on chromosome 13q12. One such family has been reported.

Description

Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011).

For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).

Clinical Features

Onat et al. (2013) reported a consanguineous Turkish family in which 4 individuals had a severe neurologic disorder characterized by mental retardation, dysarthria, and truncal ataxia with or without quadrupedal gait. Brain MRI showed mild atrophy of the cerebral cortex, corpus callosum, and inferior cerebellum. The family had previously been reported as 'family C' by Ozcelik et al. (2008).

Etiology of Quadrupedal Locomotion

Ozcelik et al. (2008) maintained that quadrupedal locomotion in the affected individuals results from abnormal function of brain structures that are critical for gait. Humphrey et al. (2008) concluded that the tendency toward quadrupedal locomotion in affected individuals is an adaptive and effective compensation for problems with balance caused by congenital cerebellar hypoplasia. Thus, the unusual gait could be attributed to the local cultural environment. Herz et al. (2008) also concluded that quadrupedal locomotion is more likely an adaptation to severe truncal ataxia, resulting from a combination of uneven, rough surfaces in rural areas, imitation of affected sibs, and lack of supportive therapy. Ozcelik et al. (2008) responded and defended their position.

Inheritance

The transmission pattern of CAMRQ4 in the family reported by Onat et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 affected members of a consanguineous Turkish family with cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ4), Onat et al. (2013) identified a homozygous mutation in the ATP8A2 gene (I376M; 605870.0001). The mutation, which was found by homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in several large control databases, in 1,210 control chromosomes, or in 750 patients with unknown neurologic disorders. The mutation occurred at a highly conserved residue and was predicted to alter the secondary structure of the protein, but no functional studies were performed.