Mental Retardation, Autosomal Dominant 6, With Or Without Seizures

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-6 (MRD6) with or without seizures is caused by heterozygous mutation in the GRIN2B gene (138252) on chromosome 12p13.

Heterozygous mutation in the GRIN2B gene can also cause early infantile epileptic encephalopathy-27 (EIEE27; 616139), a similar disorder characterized by early-onset overt seizures.

Description

MRD6 is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development and intellectual disability of variable severity. Additional features may include seizures, hypotonia, abnormal movements, such as dystonia, and autistic features. Some patients may have structural malformations of cortical development on brain imaging. The phenotype is highly variable and reflects a spectrum of neurodevelopmental abnormalities that range from mild intellectual disability without seizures to an encephalopathy (summary by Platzer et al., 2017).

Clinical Features

Endele et al. (2010) reported 2 unrelated German boys with mental retardation associated with 2 different de novo chromosome translocations, t(9;12)(p23;p13.1) and t(10;12)(q21.1;p13.1), respectively, with a common breakpoint in 12p13.1 that disrupted the GRIN2B gene. The first boy had mild to moderate mental retardation, behavioral anomalies, and abnormal electroencephalogram (EEG), whereas the second boy had a more complex phenotype including severe mental retardation, behavioral and EEG anomalies, ophthalmologic manifestations, choanal atresia, cryptorchidism, and flat feet. Neither had overt seizures. Endele et al. (2010) also reported 4 unrelated patients of European descent with nonsyndromic mild to moderate mental retardation. One of the patients also had irregular slow dysrhythmia on EEG, but none showed seizures. All had behavioral abnormalities that were not specifically delineated.

Lemke et al. (2014) reported a 10.5-year-old girl conceived by in vitro fertilization who showed delayed psychomotor development in early childhood and mild intellectual disability. At age 9 years, she developed focal dyscognitive seizures with occasional bilateral convulsive seizures and status epilepticus with postictal paresis.

Platzer et al. (2017) identified 48 individuals with de novo GRIN2B variants and reviewed 43 additional patients with de novo GRIN2B variants collected from the literature. These patients were identified through several research settings focusing on neurodevelopmental disorders. Variants in 86 of 91 patients were classified as putatively pathogenic; all 86 patients presented with developmental delay, intellectual disability (ID), and/or autism spectrum disorder (ASD). Detailed clinical data were available for 58 patients. Most (60%) had severe ID, 25% had moderate ID, and 15% had mild ID; 28% of patients had ASD. About half (52%) of patients had seizures with a variable age at onset (birth to 9 years), variable frequency, and variable seizure type. EEG patterns comprised hypsarrhythmia and focal, multifocal, and/or generalised epileptiform activity. Follow-up data on 22 patients showed that about half became seizure-free on conventional antiseizure medication, whereas half were refractory to therapy. Additional features included hypotonia (53%), resulting in tube feeding in 5 patients, spasticity (24%), abnormal dystonic, dyskinetic, or choreiform movements (10%), microcephaly (19%), and cortical visual impairment (7%). Neuroimaging showed malformations of cortical development in 6 (14%) of 44 patients imaged: abnormalities included polymicrogyria, abnormal gyri and sulci, hypoplastic corpus callosum, and hippocampal dysplasia. Four patients had cerebral atrophy.

Molecular Genetics

In 4 of 468 patients with mental retardation, Endele et al. (2010) identified 4 different de novo heterozygous mutations in the GRIN2B gene (138252.0001-138252.0004).

By sequencing 44 candidate genes in 2,446 autism spectrum disorder probands, O'Roak et al. (2012) identified 4 individuals with de novo mutations in the GRIN2B gene. The mutations included a frameshift, a missense, a splice site, and a nonsense mutation (138252.0005-138252.0008).

In a child (patient 3) with global developmental delay who developed seizures at age 9 years and 9 months, Lemke et al. (2014) identified a heterozygous de novo missense mutation (R540H; 138252.0012) in the GRIN2B gene. In vitro functional expression studies showed a gain-of-function effect. Lemke et al. (2014) noted that the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous missense GRIN2B mutation (C461F) in the extracellular glutamate-binding domain in a patient with delayed development, intellectual disability, and childhood-onset epilepsy. The C461F variant was found by exome sequencing of a cohort of 264 probands with epileptic encephalopathy; functional studies of that variant were not performed.

In a large cohort of 86 patients with MRD6 or EIEE27, Platzer et al. (2017) identified de novo heterozygous missense or truncating mutations in the GRIN2B gene; multiple mutations were identified, including several recurrent mutations. In vitro functional expression studies of some of the missense mutations showed that they resulted in altered channel function. Some (e.g., S541R, V558I, and I655F) increased glutamate EC(50) values, indicating that higher concentrations of glutamate were needed to activate the receptors, consistent with a loss of function or haploinsufficiency. Other missense mutations (e.g., S810R, M818T, and A819T) increased glutamate and glycine potency, suggesting a potential gain-of-function effect with possible excitotoxicity. Most, but not all, of the missense mutations clustered within or close to ligand-binding sites or transmembrane domains. There was no correlation between missense versus truncating mutations and occurrence of seizures, although there was an association between truncating mutations and mild or moderate ID versus severe ID. In vitro studies showed that the NMDAR antagonist memantine could reduce membrane hyperactivity of some of the gain-of-function mutations, but treatment of patients with memantine did not reduce seizure frequency. Combining the results of several cohorts of over 10,000 patients with neurodevelopmental disorders and/or epilepsy who underwent genetic analysis by either gene panel sequencing or whole-exome sequencing, Platzer et al. (2017) estimated the frequency of GRIN2B mutations to be 0.2%.

In a 6-year-old girl with severe neurologic and developmental delay, born of nonconsanguineous parents of Ashkenazi Jewish ancestry, Adams et al. (2014) identified heterozygosity for a de novo missense mutation (E413G) in the GRIN2B gene. In addition, the patient and her older sister, who both experienced multiple episodes of hypoglycemia and lactic acidosis associated with illness or fasting (PCKDC; 261680), were found to be homozygous for a missense mutation in the PCK1 gene (I45T; 614168.0001). Heterozygosity for a de novo nonsense mutation (W758X) in the RAI1 gene (607642) was also detected in the older sister, who had signs and symptoms consistent with Smith-Magenis syndrome (182290). Adams et al. (2014) concluded that this family demonstrated that complex medical disorders can represent the cooccurrence of multiple diseases.