Mental Retardation, Autosomal Recessive 48

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-48 (MRT48) is caused by homozygous mutation in the SLC6A17 gene (610299) on chromosome 1p13.

Clinical Features

Iqbal et al. (2015) reported 3 adult sisters, all in their sixties, with severe mental retardation and very poor speech limited to 3-word sentences. All had delayed psychomotor development from birth, but there were no available records of the timing of childhood milestones. Their behavior was characterized by mood instability, aggression, and self-mutilation. Between 40 and 50 years, all developed a progressive essential hand tremor that was not present in their healthy sibs, and all had a waddling gait. Cerebral imaging performed in 1 patient was normal. Mild dysmorphic features included large ears, prominent chin, narrow palpebral fissures, long philtrum, and high, narrow palate. Two sibs from a consanguineous Iranian family had a similar disorder: they had severe mental retardation with no speech development, and onset of progressive hand tremor in the teenage years. They were unable to walk or care for themselves, and showed aggression and poor impulse control. Facial features included large ears, prominent chin, thick eyebrows, and slightly narrow palpebral fissures.

Inheritance

The transmission pattern in the Iranian family with MRT48 reported by Iqbal et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 affected individuals from 2 unrelated families with MRT48, Iqbal et al. (2015) identified 2 different homozygous missense mutations in the SLC6A17 gene (G162R, 610299.0001 and P633R, 610299.0002). The mutations were found by a combination of homozygosity mapping and exome sequencing. In vitro functional expression studies in mouse embryonic primary hippocampal cells showed that both mutant proteins altered the localization of the protein and/or morphology of the cell compared to wildtype.