Mental Retardation, Autosomal Recessive 51

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-51 (MRT51) is caused by homozygous mutation in the HNMT gene (605238) on chromosome 2q22.

Clinical Features

Heidari et al. (2015) reported 7 individuals from 2 unrelated families of Turkish and Kurdish descent, respectively, with autosomal recessive nonsyndromic mental retardation. The patients ranged in age from 13 to 35 years. All had delayed cognitive development since infancy, but only some had had delayed motor development. All had severe intellectual disability and poor speech. In 1 family, affected individuals showed additional worsening of the neurologic condition around age 5 years, and 2 females were more severely affected than 2 males, suggesting possible gender differences. Additional more variable features included mildly decreased height and small head circumference. None of the patients had dysmorphic features, and brain imaging in 1 patient was normal.

Inheritance

The transmission pattern of MRT51 in the families reported by Heidari et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 2 unrelated consanguineous families with MRT51, Heidari et al. (2015) identified 2 different homozygous missense mutations in the HNMT gene (G60D, 605238.0002 and L208P, 605238.0003). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the families. Patient lymphoblasts showed increased vulnerability to the toxic effects of high levels of histamine compared to controls. In vitro studies showed that the G60D mutation disrupted enzymatic activity, and that the L208PP mutation resulted in reduced protein stability. Thus, both mutations impaired the function of HNMT and decreased the inactivation of histamine, a neurotransmitter important for the developing brain.