Mental Retardation, Autosomal Dominant 54

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-54 (MRD54) is caused by heterozygous mutation in the CAMK2B gene (607707) on chromosome 7p13.

Clinical Features

Kury et al. (2017) reported 10 unrelated patients of northern European descent or from the United States with delayed psychomotor development and mild to severe intellectual disability (ID). The patients ranged in age from 14 months to 14 years; 7 patients were classified as having severe ID. Common features included hypotonia, delayed walking, delayed speech, and behavioral abnormalities, including autistic features. Six patients were unable to walk, and 6 were nonverbal. About half of the patients had poor overall growth and 1 had mild postnatal microcephaly, but only 1 had frank microcephaly (-3.4 SD). Four patients had seizures and 4 had EEG abnormalities. Brain imaging was normal in most patients, although 4 had mild nonspecific abnormalities, such as thin corpus callosum. Seven patients had visual anomalies, including strabismus and visual impairment, and 8 had significant gastrointestinal difficulties, mainly poor feeding, gastroesophageal reflux, and constipation. Six patients were noted to have variable dysmorphic facial features. Additional variable features, seen in 1 or 2 patients, included ectodermal dysplasia, food allergies, and breathing anomalies.

Akita et al. (2018) reported 2 unrelated Japanese boys with MRD54. One was a 7-year-old boy who walked at age 20 months, developed seizures at age 23 months that could be controlled with medication, and had mild intellectual disability and hypotonia at age 6. He was able to speak a few words; brain imaging was normal. The other patient was an 8-year-old boy who presented in infancy with abnormal eye movements, including oculogyric crises. He had severely delayed development and was unable to speak or hold his head at age 8 years. He also developed myoclonic movements; brain imaging showed progressive cerebellar atrophy beginning at 2 years of age.

Molecular Genetics

In 10 unrelated patients with MRD54, Kury et al. (2017) identified 7 different de novo heterozygous mutations in the CAMK2B gene (see, e.g., 607707.0001-607707.0005). The mutations were found by exome sequencing and confirmed by Sanger sequencing in most patients. There were 4 missense variants, including 1 recurrent variant (P139L; 607707.0003) that was found in 4 patients, 2 splicing variants, and 1 nonsense variant. Functional expression studies of some of the missense variants showed variable abnormalities: E110K (607707.0002) and P139L resulted in decreased levels of the mutant protein, whereas other missense variants did not. CAMK2B autophosphorylation at Thr287 is critical for autonomous (calcium-independent) function. E110K, P139L, and E237K (607707.0004) caused a significant increase in autophosphorylation at Thr287, consistent with a gain of function, whereas K301E (607706.0005) showed a significant reduction of Thr287 phosphorylation, consistent with a loss of function. Transfection of human CAMK2B variants into mouse embryonic neurons in the subventricular zone using in utero electroporation showed that variants with increased Thr287 phosphorylation (E110K, P139L, and E237K) disrupted neuronal migration even more than wildtype. K301E, with decreased CAMK2 activity, resulted in a less severe migration defect. In addition, overexpression or knockdown of wildtype CAMK2B resulted in clear neuronal migration defects. The variants appeared to act in a dominant-negative manner. The findings highlighted the importance of tightly controlled autophosphorylation of CAMK2B for normal neuronal function, and suggested that disruption of this event can impair synaptic plasticity and learning, resulting in neurodevelopmental defects.

In 2 unrelated Japanese patients with MRD54, Akita et al. (2018) identified de novo heterozygous missense mutations in the CAMK2B gene (607707.0006 and 607707.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the ExAC or gnomAD databases. Molecular modeling predicted that the mutations, which affected the autoregulatory domain, would result in a loss of autoinhibition. In vitro functional expression studies of 1 of the mutations showed that it resulted in increased basal autophosphorylation compared to wildtype, suggesting that it would cause increased calcium-independent activity and a gain of function.