MRD13 is an autosomal dominant form of mental retardation associated with variable neuronal migration defects resulting in cortical malformations. More variable features include early-onset seizures and mild dysmorphic features. Some patients may also show signs of peripheral neuropathy, ... MRD13 is an autosomal dominant form of mental retardation associated with variable neuronal migration defects resulting in cortical malformations. More variable features include early-onset seizures and mild dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait, hyporeflexia, and foot deformities (summary by Willemsen et al., 2012 and Poirier et al., 2013).
Vissers et al. (2010) reported a 4-year-old boy with de novo occurrence of moderately severe mental retardation. He showed hypotonia at age 6 months, followed by delayed psychomotor development. Mild dysmorphic features included prominent forehead, plagiocephaly, hypotonic face ... Vissers et al. (2010) reported a 4-year-old boy with de novo occurrence of moderately severe mental retardation. He showed hypotonia at age 6 months, followed by delayed psychomotor development. Mild dysmorphic features included prominent forehead, plagiocephaly, hypotonic face with downslanting palpebral fissures, and short, broad hands and feet. Brain MRI was reported as normal. His parents were unaffected. Follow-up of the patient at age 6 years by Willemsen et al. (2012) noted that he had hypotonia, hyporeflexia, and broad-based waddling gait with toe-walking. Reevaluation of brain MRI showed signs of bilateral cortical malformation with deficient gyration of the frontal lobes and an area suggestive of focal cortical dysplasia. Willemsen et al. (2012) also reported a 51-year-old woman with severe mental retardation and an inability to walk or speak. She had short stature, microcephaly, clubfeet, and small hands and feet with short toes. Craniofacial features included brachycephaly, prominent forehead, hypertelorism, deep-set eyes, wide mouth with everted lower lip, and downturned corners of the mouth. She developed generalized seizures at age 3 years. Other features included kyphoscoliosis, spastic tetraplegia, and swallowing difficulties. Cerebral CT scan at the age 46 years showed enlarged ventricles and clear signs of cortical malformation with wide opercular regions and an abnormal flat cortex with only a few simple and shallow sulci; MRI scan was not possible. Poirier et al. (2013) reported 8 unrelated patients with mental retardation associated with cortical brain malformations on MRI. All but 1 had seizures, most of early onset. Three had microcephaly, 3 were bedridden with spastic tetraplegia, 2 were described as having 'awkwardness' on neurologic examination, and 3 patients had foot deformities consistent with axonal neuropathy. Brain MRI showed predominantly posterior pachygyria, and some patients also had frontal polymicrogyria or nodular heterotopia. Several patients also had other brain abnormalities, including dysmorphic basal ganglia and hypoplasia of the corpus callosum, brainstem, and/or cerebellum.
By family-based exome sequencing of 10 case-parent trios of de novo mental retardation, Vissers et al. (2010) identified a de novo heterozygous mutation in the DYNC1H1 gene (H3822P; 600112.0002) in 1 patient. Willemsen et al. (2012) identified a ... By family-based exome sequencing of 10 case-parent trios of de novo mental retardation, Vissers et al. (2010) identified a de novo heterozygous mutation in the DYNC1H1 gene (H3822P; 600112.0002) in 1 patient. Willemsen et al. (2012) identified a second de novo heterozygous mutation in the DYNC1H1 gene (E1518K; 600112.0003) in a 51-year-old woman with severe mental retardation since infancy and an inability to walk or speak. Willemsen et al. (2012) noted that DYNC1H1 interacts with LIS1 (601545), haploinsufficiency of which results in the severe neuronal migration disorder lissencephaly-1 (607432), and that Dync1h1 mutant mice show neuronal migration defects (Ori-McKenney and Vallee, 2011), providing evidence of the pathogenicity of the mutations. Willemsen et al. (2012) also noted that their 2 patients showed variable signs consistent with peripheral neuropathy and that some patients with CMT2O (614228) (Weedon et al., 2011) carrying a DYNC1H1 mutation showed learning difficulties, indicating that DYNC1H1 mutations may result in a broad neurologic phenotypic spectrum. Poirier et al. (2013) identified 8 different de novo heterozygous mutations in the DYNC1H1 gene (see, e.g., 600112.0007-600112.0009) in 8 unrelated patients ascertained for evaluation due to malformations of cortical development. Mutations in the first several patients were found by whole-exome sequencing, whereas subsequent patients were identified by direct sequencing of this gene in a larger cohort of affected individuals. In vitro functional expression studies of 2 of the variants showed that the mutant proteins had decreased microtubule binding affinity compared to wildtype. In addition, there was 1 family in which a mother and her 2 children carried a missense variant (K3241T): 1 of the children had mild intellectual disability, but the mother and the other child had normal cognition. All 3 were normocephalic, showed posterior pachygyria, and had focal seizures. No functional studies were performed on the K3241T variant, which occurred at a nonconserved residue.