Mental Retardation, Autosomal Recessive 5

A number sign (#) is used with this entry because autosomal recessive mental retardation-5 (MRT5) is caused by homozygous mutation in the NSUN2 gene (610916) on chromosome 5p15.

Clinical Features

Najmabadi et al. (2007) reported a large consanguineous Iranian family in which 3 individuals had nonsyndromic moderate to severe mental retardation. Abbasi-Moheb et al. (2012) reported follow-up of the families reported by Najmabadi et al. (2007) and Kuss et al. (2011) with MRT5, and reported an additional family of Iranian descent. Affected individuals had some mild dysmorphic features, including microcephaly, long and narrow face, bushy eyebrows with synophrys, hypotelorism, large nose with long columella and hypoplastic alae nasi, short philtrum, and full upper lip. Many had short stature, and some had later onset of muscular hypertonia and spasticity. Brain malformations were not observed.

Khan et al. (2012) reported a consanguineous Pakistani family in which 3 sisters had MRT5. All had delayed psychomotor development with limited speech, dysarthria, and poor somatic growth. Dysmorphic features included a long face and nose with protruding nasal tip and short philtrum. All also had signs of a distal myopathy, with variable increased muscle tone in the limbs, brisk reflexes, and equivocal plantar responses. Two showed a broad-based gait with pes cavus and tight Achilles tendons. One girl had strabismus and another had intermittent esotropia. Brain imaging was normal. Laboratory studies showed increased lactate dehydrogenase (LDH) in 2 girls and increased serum creatine kinase in 1.

Martinez et al. (2012) reported 3 sibs, born of consanguineous Lebanese parents, with a developmental disorder characterized by low birth weight, poor postnatal growth, progressive microcephaly, delayed psychomotor development, and speech delay. Facial dysmorphic features included blepharophimosis, hypertelorism, broad nasal bridge, smooth philtrum, downturned upper lip, and dental anomalies. All had axial hypotonia. One patient had eczema, 1 had seizures, and 2 had sparse hair. Behavioral abnormalities included self-stimulation and autistic features. Brain MRI was unremarkable. Martinez et al. (2012) noted phenotypic similarities to Dubowitz syndrome (223370).

Inheritance

The transmission pattern of the phenotype in the families reported by Abbasi-Moheb et al. (2012) and Khan et al. (2012) was consistent with autosomal recessive inheritance, as all families were consanguineous.

Mapping

By linkage analysis in a large consanguineous Iranian family (M192) in which 3 individuals had nonsyndromic moderate to severe mental retardation, Najmabadi et al. (2007) identified a candidate locus on chromosome 5p, termed MRT5, with a maximum lod score of 3.0. Haplotype analysis delineated a 5.6-Mb candidate region between SNPs rs1824938 and rs60701.

By homozygosity mapping of a consanguineous Iranian family (M314) in which 2 patients had moderate nonsyndromic mental retardation, Kuss et al. (2011) found linkage to a 6.8-Mb region on chromosome 5p between SNPs rs2008927 and rs60701 (lod score of 3.9).

Molecular Genetics

By Sanger sequencing of a candidate region in a consanguineous family with autosomal recessive mental retardation-5 mapping to chromosome 5p15, Abbasi-Moheb et al. (2012) identified a homozygous truncating mutation in the NSUN2 gene (Q227X; 610916.0001). Sequence analysis of this gene in 2 additional families with the disorder showing linkage to this region identified 2 different homozygous mutations (610916.0002 and 610916.0003) that segregated with the disorder in each family. Two of the 3 families had previously been reported by Najmabadi et al. (2007) and Kuss et al. (2011), respectively. The findings implicated a role for RNA methylation in higher cognitive function.

By homozygosity mapping followed by candidate gene analysis of a consanguineous Pakistani family with MRT5, Khan et al. (2012) identified a homozygous mutation in the NSUN2 gene (610916.0004).

By exome sequencing of 2 Lebanese sibs, born of consanguineous parents, with developmental delay and dysmorphic features, Martinez et al. (2012) identified a homozygous mutation in the NSUN2 gene (610916.0005), resulting in a lack of protein expression.