Mental Retardation, Autosomal Recessive 34, With Variant Lissencephaly

A number sign (#) is used with this entry because autosomal recessive mental retardation-34 with variant lissencephaly (MRT34) is caused by homozygous or compound heterozygous mutation in the CRADD gene (603454) on chromosome 12q22.

Description

MRT34 is an autosomal recessive neurologic disorder characterized by mild to moderate intellectual disability and megalencephaly or enlarged head circumference. Brain imaging shows a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex. Some patients may have seizures (summary by Di Donato et al., 2016).

Clinical Features

Puffenberger et al. (2012) reported 5 Mennonite patients with nonsyndromic mental retardation. Affected individuals had mildly delayed development and significantly impaired cognitive function, precluding independent living and self-care. Speech was rudimentary, but articulate; autism was not present. Di Donato et al. (2016) found that 3 of the patients reported by Puffenberger et al. (2012) had brain imaging findings consistent with 'thin' lissencephaly; the cerebellum was normal.

Di Donato et al. (2016) reported 6 patients from 4 unrelated families with MRT34 ascertained by the finding of 'thin' lissencephaly on brain imaging. The patients ranged in age from 13 to 51 years. Brain imaging showed frontal predominant symmetric pachygyria with reduced numbers of gyri, shallow sulci, and mildly thickened cortex (5-7 mm). Brainstem and cerebellum were normal. One patient had a mild Chiari malformation. Di Donato et al. (2016) stated that the family previously reported by Puffenberger et al. (2012) (LR15-293) had 7 affected individuals. Of the 13 patients total, all had mild to moderate intellectual disability with poor speech and language, 12 had enlarged head circumference, and 3 had seizures. Most of the patients attended special education classes but were unable to live independently.

Inheritance

The transmission pattern of mental retardation in the family reported by Puffenberger et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By homozygosity mapping followed by exome sequencing of 5 Mennonite patients with nonsyndromic mental retardation, Puffenberger et al. (2012) identified a homozygous mutation in the CRADD gene (G128R; 603454.0001). Seven heterozygous carriers of this mutation were found among 203 Mennonite control samples, yielding a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.)

In 2 sibs (family LR04-101) with MRT34 from the same Pennsylvania Mennonite population studied by Puffenberger et al. (2012), Di Donato et al. (2016) identified homozygosity for the same G128R mutation in the CRADD gene. The mutation was found by whole-exome sequencing. Sanger sequencing of the CRADD gene in 18 individuals with the 'thin' variant of lissencephaly identified 3 additional patients from 2 unrelated families who had homozygous missense mutations (603454.0002-603454.0003), and 1 patient who was compound heterozygous for a missense mutation (603454.0004) and a deletion of 12q22 that included the CRADD gene. In vitro functional expression studies showed that only 1 of the missense mutations (G128R) resulted in an unstable protein and decreased PIDD (605247) binding; the remaining mutations did not disrupt PIDD or CASP2 (600639) binding and did not lead to decreased amounts of the mutant protein. However, the mutant proteins were unable to induce apoptosis when expressed in neuronal cells due to an inability to activate CASP2, despite normal binding to CASP2. Wildtype CRADD induced cell death in neuronal cells. The findings indicated that the mutations caused a loss of function, and suggested that the observed cortical malformations result from reduced apoptosis rather than from a neuronal migration disorder. Di Donato et al. (2016) concluded that CRADD/CASP2 plays a role in synaptic plasticity and cortical architecture during mammalian brain development. Targeted panel sequencing in another 148 individuals with lissencephaly in whom molecular testing had excluded mutations in known lissencephaly-associated genes did not identify additional CRADD mutations.

Animal Model

Di Donato et al. (2016) found that Cradd-null mice had enlarged brain and head sizes, but normal layering of the cerebral cortex. About 26% of mice developed seizures.