Mental Retardation, Autosomal Recessive 61

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-61 (MRT61) is caused by homozygous mutation in the RUSC2 gene (611053) on chromosome 9p13.

Description

MRT61 is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, moderate to severe intellectual disability, and variable dysmorphic facial features. More severely affected patients may develop refractory seizures and have brain abnormalities, including hypoplasia of the corpus callosum (summary by Alwadei et al., 2016).

Clinical Features

Alwadei et al. (2016) reported 3 patients from 2 unrelated consanguineous families with delayed psychomotor development apparent from infancy, moderate to severe intellectual disability, hypotonia, and similar dysmorphic features. Two brothers, born of Syrian parents, were 6 and 17 years old at the time of the report. Both had delayed walking at ages 2 and 8 years, respectively, and walked with an unsteady gait; the older brother often used a wheelchair. Both boys developed refractory seizures at about 5 months of age. EEG in the younger patient showed hypsarrhythmia followed by nonspecific decreased cerebral activity and focal epileptiform discharges; this patient eventually became seizure-free on a multiple medication regimen. Neither was toilet-trained, and both were dependent for all activities of daily living. Additional neurologic features included axial hypotonia, mild limb spasticity with hyperreflexia, and variable behavior problems, such as hyperactivity and aggression. Brain imaging showed mild brain atrophy with hypogenesis of the corpus callosum and absence of the splenium in both boys. Dysmorphic features included low-set ears, long face, high-arched palate, bulbous nose, thick eyebrows, and prognathism, which were overall mild. They also had tapering digits, prominent finger volar pads, and foot eversion; the older brother had significant joint laxity and scoliosis. An unrelated 7-year-old girl, born of consanguineous Saudi Arabian parents, presented with a similar disorder, including global developmental delay with delayed speech and hypotonia, but she did not have seizures. She walked at age 3 years with an unsteady gait and exhibited mild spasticity with hyperreflexia and extensor plantar responses. Dysmorphic features included dolichocephaly, dense hair, thick eyebrows, mild synophrys, hypertelorism, long eyelashes, prominent nose, conical shaped teeth, high-arched palate, posteriorly rotated ears, pes cavus, and talipes equinovarus. She was dependent for all activities of daily living; she had no history of seizures and brain imaging was normal. All 3 patients had normal head circumference at birth, but developed mild postnatal progressive microcephaly.

Inheritance

The transmission pattern of MRT61 in the families reported by Alwadei et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated consanguineous Middle Eastern families with MRT61, Alwadei et al. (2016) identified homozygous truncating mutations in the RUSC2 gene (R866X, 611053.0001 and R1318X, 611053.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the authors noted that the phenotype in the first family with the R866X mutation proximal to the RUN domain was more severe than that in the unrelated patient with the R1318X mutation distal to the RUN domain. The RUN domain is thought to interact with RAB1. Alwadei et al. (2016) speculated that the mutations would impair RUSC2 function and disrupt intracellular trafficking and synaptic vesicular transport, resulting in impaired synaptogenesis, neuronal dysfunction, and intellectual disability.