Mental Retardation, Autosomal Dominant 55, With Seizures

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-55 with seizures (MRD55) is caused by heterozygous mutation in the NUS1 gene (610463) on chromosome 6q22.

Clinical Features

Hamdan et al. (2017) reported 3 unrelated patients with onset of myoclonic seizures in the first years of life. The most severely affected patient (indvKW) was an 8-year-old boy with global developmental delay, moderate intellectual disability, speech delay, and ataxic gait. He developed myoclonic seizures, which could be controlled with medication, at age 12 months. The second patient (HSJ0623) was a 15-year-old boy who presented at age 10 months with myoclonic seizures and mild motor delay. He later developed frequent atonic seizures that were refractory between ages 2 and 7, but were finally controlled with medication. EEG showed diffuse background slowing and high or small amplitude spikes. He was able to run, climb stairs, and play sports, attended special education school, and could speak, but he was clumsy on fine motor tasks. He had a mild tremor without other cerebellar signs, and was diagnosed with autism spectrum disorder. The third patient (HSJ0627) was a 29-year-old woman who presented at 2.5 years of age with febrile myoclonic status epilepticus. She then developed myoclonic absence seizures and drop attacks that eventually were well-controlled with multiple medications. EEG showed generalized spike-wave and polyspike-wave activity. She had mild motor delay and could jump and run, but was unable to ride a bicycle. She could speak and read at a first grade level and had mild dysarthria and tremor, but no ataxia. Brain imaging in all patients was normal.

Molecular Genetics

In 3 unrelated patients with MRD55 with seizures, Hamdan et al. (2017) identified 3 different de novo heterozygous mutations in the NUS1 gene (610463.0002-610463.0004). Two of the mutations were truncating, and 1 was an intragenic deletion encompassing all of exon 2. Two patients were found by whole-genome sequencing of 197 individuals with developmental epileptic encephalopathy; the third patient was found by clinical exome sequencing from another patient cohort. Functional studies of the variants and studies of patients cells were not performed, but Hamdan et al. (2017) postulated haploinsufficiency as the pathogenic mechanism.