Cerebellar Ataxia, Mental Retardation, And Dysequilibrium Syndrome 3

A number sign (#) is used with this entry because this form of congenital cerebellar ataxia with mental retardation (CAMRQ3) is caused by homozygous mutation in the CA8 gene (114815) on chromosome 8q12.

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

Turkmen et al. (2009) reported a consanguineous Iraqi family in which 4 of 8 sibs had congenital ataxia, mild mental retardation, and dysarthria. All walked with a quadrupedal gait, with straight legs and placing their weight on the palms of their hands. The parents claimed that the affected persons never learned to crawl on their knees as most infants do, but ambulated from infancy on with their legs held straight with a 'bear-like' gait. Attempts to teach the children to walk on 2 legs with crutches or other supports failed. All complained of lack of balance and frequent falls when trying to walk bipedally. There were no other neurologic symptoms. Brain imaging was not performed, but the authors speculated that the ataxia resulted from cerebellar dysfunction based on an animal model.

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) defended their position.

Molecular Genetics

By genomewide linkage analysis followed by candidate gene sequencing of a consanguineous Iraqi family with ataxia and mild mental retardation, Turkmen et al. (2009) identified a homozygous mutation in the CA8 gene (S100P; 114815.0001).

By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified a missense mutation in the CA8 gene (114815.0002) as the cause of CAMRQ3 in a family (M107) in which first-cousin parents had 2 healthy and 4 affected children.

Animal Model

The autosomal recessive 'waddles' (wdl) mouse shows ataxia and appendicular dystonia with frequent tail elevation and an abnormally elevated trunk during ambulation. These changes are readily apparent by 2 weeks of age and persist throughout their life span. The appendicular dystonia produces nearly straight limbs with minimal flexion at the knee and elbow joints, elevation of the pelvis, and a waddling motion during ambulation, particularly at higher velocities. Mutant mice also show increased falling compared to wildtype. These abnormalities occur in the absence of associated pathologic changes in the central or peripheral nervous system. Jiao et al. (2005) determined that the wdl phenotype results from a homozygous 19-bp deletion in exon 8 of the Ca8 gene on mouse chromosome 4, resulting in a loss of function.