Mental Retardation, Autosomal Recessive 63

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-63 (MRT63) is caused by homozygous mutation in the CAMK2A gene (114078) on chromosome 5q32. One such family has been reported.

Clinical Features

Chia et al. (2018) reported 2 sibs, born of consanguineous parents from Jordan, with a neurodevelopmental disorder characterized by global developmental delay, severe intellectual disability, and seizures with EEG abnormalities suggestive of myoclonic seizures. At ages 11 and 14 years, the patients were unable to walk or speak, but had eye contact. They also exhibited axial hypotonia with appendicular spasticity. The patients had poor overall growth, but did not have dysmorphic features. Brain imaging was normal.

Inheritance

The transmission pattern of MRT63 in the family reported by Chia et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous parents from Jordan, with MRT63, Chia et al. (2018) identified a homozygous missense mutation in the CAMK2A gene (H477Y; 114078.0006). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived fibroblasts that were reprogrammed into neurons showed significantly reduced spontaneous spikes and firing rate compared to controls, consistent with a loss of function. Additional in vitro functional expression studies in HEK293 cells showed that the mutant protein was expressed at lower levels compared to wildtype, and impaired oligomerization and assembly of the multimeric holoenzyme. The findings were consistent with a partial loss of function, which could explain why the heterozygous parents were unaffected. Transfection of the mutation into unc43-null C. elegans failed to rescue neuronal and synaptic defects, also consistent a loss of function.