Mental Retardation, Autosomal Dominant 5

A number sign (#) is used with this entry because autosomal dominant mental retardation-5 (MRD5) is caused by heterozygous mutation in the SYNGAP1 gene (603384) on chromosome 6p21. Almost all reported cases have occurred de novo.

Description

MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Most patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some have acquired microcephaly (summary by Berryer et al., 2013).

Clinical Features

In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). All patients showed global developmental delay with delayed motor development, hypotonia, moderate to severe mental retardation, and severe language impairment. One patient had strabismus, and 2 had epilepsy. There were no other dysmorphic features.

Hamdan et al. (2011) reported 3 unrelated patients with MRD5. In addition to moderate to severe intellectual disability, the children also showed behavioral abnormalities, such as avoidance of other children and impulsivity, and mood problems, such as sullenness and rigidity. Two had well-controlled epilepsy and acquired microcephaly, and 1 had autism, thus expanding the phenotypic spectrum associated with SYNGAP1 mutations.

Berryer et al. (2013) reported 5 unrelated patients with MRD5. All presented with delayed development in the first years of life and all but 1 showed moderate to severe intellectual disability. Four patients had epilepsy, 3 had autism, and 3 had behavioral abnormalities. There were no notable dysmorphic features or structural brain abnormalities.

Carvill et al. (2013) reported 2 unrelated patients with epileptic encephalopathy, severe mental retardation, and autism spectrum disorder. One patient had onset of atypical absence seizures at age 3 years, followed by atonic seizures, focal dyscognitive seizures, and myoclonic jerks associated with EEG abnormalities. The other had onset of absence seizures at age 10 months, followed by myoclonic jerks. Both had delayed development and showed cognitive regression after seizure onset. Each patient carried a de novo heterozygous truncating mutation in the SYNGAP1 gene (603384.0009 and 603384.0010). Three additional unrelated patients with a similar phenotype, mental retardation associated with onset of multiple seizure types in the first years of life and developmental regression, also carried heterozygous truncating SYNGAP1 mutations, but DNA from one or both parents was not available to confirm that the mutations occurred de novo. Carvill et al. (2013) concluded that epileptic encephalopathy should be part of the phenotypic spectrum associated with SYNGAP1 mutations. These patients were identified from a large cohort of 500 patients with epileptic encephalopathy who underwent targeted sequencing of candidate genes. SYNGAP1 mutations accounted for 1% of cases.

Mignot et al. (2016) reported 17 unrelated affected individuals with loss-of-function mutations in the SYNGAP1 gene. All had delayed psychomotor development, with walking achieved in most by age 3 years. Speech delay was common, and 5 patients did not speak at age 10 years. Except for 1 patient who had a single seizure, all patients had epilepsy, particularly myoclonic epilepsy and absence seizures; about half of patients had pharmacoresistant seizures. Eight (50%) of 16 patients older than 3 had autism spectrum disorder with very poor communication skills. Additional common neurologic features included hypotonia, ataxia, and broad-based or clumsy gait. Brain imaging was either normal or showed nonspecific features. There were no apparent genotype/phenotype correlations.

Inheritance

Almost all reported cases of MRD5 have resulted from de novo mutations. However, Berryer et al. (2013) reported a fully affected patient who inherited the mutation from her mildly affected father; he was found to be mosaic for the mutation.

Molecular Genetics

In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003).

In 3 of 60 patients with nonsyndromic intellectual disability, including 30 with autism spectrum disorder and 9 with epilepsy, Hamdan et al. (2011) identified de novo heterozygous truncating mutations in the SYNGAP1 gene (see, e.g., 603384.0005 and 603384.0006).

Berryer et al. (2013) identified 5 different SYNGAP1 mutations (see, e.g., 603384.0007 and 603384.0008) in 5 unrelated patients with nonsyndromic intellectual disability. There were 3 truncating mutations and 2 missense mutations. These patients were identified by targeted sequencing of the SYNGAP1 gene in several cohorts including a total of 34 patients with nonsyndromic intellectual disability. Four of the mutations occurred de novo; 1 was inherited from a mildly affected parent who was mosaic for the mutation. None of the mutant proteins were detected in neuronal cells transfected with the mutations, suggesting decreased stability, even of the missense mutations. Studies in cortical pyramidal neurons showed that the missense mutations were unable to suppress activity-mediated ERK (176872), consistent with a loss of protein function.

Animal Model

Clement et al. (2012) found that haploinsufficiency for Syngap1 in mice accelerated the maturation of glutamatergic synapses in the hippocampus during the first few weeks of neonatal hippocampal development. Dendritic spines in pyramidal neurons grew larger in the mutant mice compared to wildtype mice during this critical developmental period, and the changes persisted into adulthood. There was a disruption in spine head size, with more mushroom-type spines and fewer stubby spines, the spine motility rates were decreased, and there were spine signaling abnormalities. These changes were accompanied by premature acquisition of functional AMPA receptors in the synapses. Syngap1 haploinsufficiency altered disrupted excitatory/inhibitory balance in the hippocampus, with increased excitation and increased seizure susceptibility. Changes occurred in neural networks that support cognition and behavior, such as the hippocampus, and these effects were linked to life-long intellectual disability and impaired memory. These studies provided a neurophysiologic mechanism linking abnormal glutamatergic synapse maturation during development to enduring abnormalities in behaviors indicative of neurodevelopmental disorders in humans.