Mental Retardation, Autosomal Recessive 49

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-49 (MRT49) is caused by homozygous mutation in the GPT2 gene (138210) on chromosome 16q11.

Clinical Features

Celis et al. (2015) reported a distantly consanguineous Mizrahi Jewish family with 3 affected sibs (2 boys and 1 girl) who had developmental encephalopathy characterized by rapid onset of failure to thrive and microcephaly as well as profoundly delayed development. All 3 children were nonverbal. The oldest child, a 15-year-old boy, developed generalized tonic-clonic seizures at 10 years of age. His 14-year-old affected sister developed seizures at the age of 14. Both older sibs were hypotonic. The youngest affected sib, a 4-year-old boy, was hypertonic and exhibited fisting. The 2 male sibs had bitemporal narrowing. All 3 sibs had normal cerebrospinal fluid quantitative amino acid levels. Plasma quantitative amino acid levels were normal except for alanine. Exhaustive metabolic workups were unrevealing.

Ouyang et al. (2016) reported 14 patients from 2 unrelated consanguineous families with MRT49. The patients had postnatal microcephaly (up to -6.8 SD) and delayed psychomotor development with intellectual disability. Most were hypotonic during infancy but later developed progressive spasticity mainly affecting the lower limbs and resulting in walking difficulties. All had delayed speech and oral-motor dysfunction with dysarthria and drooling. Five had seizures. Brain MRI was normal in all except 1, who had reduced white matter volume and thin corpus callosum.

Inheritance

The transmission pattern of MRT49 in the families reported by Ouyang et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

Using whole-exome sequencing, Celis et al. (2015) detected a homozygous missense mutation in the GPT2 gene (S153R; 138210.0001) in 3 sibs with mental retardation-49 (MRT49). Functional in vitro analyses demonstrated loss of function.

In affected members of 2 unrelated large consanguineous families with MRT49, Ouyang et al. (2016) identified 2 different homozygous mutations in the GPT2 gene (R404X, 138210.0002 and P272L, 138210.0003). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. HeLa cells transfected with the mutations showed almost undetectable enzyme activity, consistent with a loss-of-function effect.

Animal Model

Ouyang et al. (2016) found that Gpt2-null mice had reduced brain growth, decreased number of synapses, and decreased total brain Gpt activity compared to wildtype. At around postnatal day 18, mutant mice showed reduced motor activity and subsequently grew sickly and died between P18 and P26. Mutant brains also showed abnormal metabolites, including decreased alanine, decreases in several TCA cycle intermediates, decreased glutamine-dependent anaplerosis, and misregulation of pathways implicated in neuroprotective mechanisms involving glutathione, folate, and cystathionine. Heterozygous mice showed Gpt2 immunostaining in the prefrontal cortex, striatum, hippocampus, and granular cell layer of the cerebellum.