Mental Retardation, X-Linked, Syndromic, Houge Type

A number sign (#) is used with this entry because of evidence that Houge-type X-linked syndromic mental retardation (MRXSHG) is caused by hemizygous or heterozygous mutation in the CNKSR2 gene (300724) on chromosome Xp22.

Description

The Houge type of X-linked syndromic mental retardation is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (summary by Damiano et al., 2017).

Clinical Features

Vaags et al. (2014) reported 3 adult French brothers with delayed psychomotor development, seizures limited to childhood, and absent or severely limited speech. All 3 brothers had attention problems and reportedly were hyperactive in childhood, but were calm as adults. They were severely disabled and institutionalized. All were seizure-free without medication after age 10 years. EEG studies were not reported. One of the men had mild cortical atrophy on brain imaging. A maternal uncle was reportedly similarly affected.

Damiano et al. (2017) reported a family of Ashkenazi Jewish descent with variable manifestations of MRXSHG. The 18-year-old male proband, who was the most severely affected, had developmental and language delay in early childhood and onset of seizures at age 3.5 years. EEG showed continuous bilateral centrotemporal or frontal spike and wave activity even during sleep. At age 4, he showed deterioration of behavior, cognition, and language, and became aphasic. He also had attention deficits, hyperactivity, and neuropsychiatric deterioration, and he was institutionalized at age 12. His brother also had seizure onset at age 3.5 years following developmental and language delay. EEG and behavioral abnormalities were similar to those of his brother, although he was less severely affected and was able to attend school. He required ongoing antiepileptic medication. Their sister had mild motor and language delay and seizure onset at age 6 years; EEG showed centrotemporal spikes. At age 16 years, she was seizure-free without medication and had mild learning difficulties. The patients' mother had a history of febrile seizures without language or intellectual impairment. Their mother's brother reportedly had onset of refractory seizures at age 3.5 years, as well as language and motor delay, intellectual disability, and autism. His seizure disorder lessened with time, and he became seizure-free without medication by age 10 years.

Cytogenetics

In a 5-year-old boy of Norwegian descent with delayed psychomotor development with poor language skills, borderline microcephaly, well-controlled absence seizures, and attention deficit-hyperactivity disorder, Houge et al. (2012) identified a hemizygous 234-kb deletion of chromosome Xp22.12 that was detected by copy number analysis. The maternally inherited deletion removed the initial 15 of 21 exons of the CNKSR2 gene, suggesting a loss of function. The deletion in the mother occurred de novo. Vaags et al. (2014) noted that the patient reported by Houge et al. (2012) demonstrated continuous spike-and-slow-waves (CSWS) on EEG during sleep at age 7 years. He had significant intellectual disability, inattention, and impulsivity.

Vaags et al. (2014) reported 2 sets of brothers, of Canadian and French descent, respectively, with mental retardation and seizures associated with 2 hemizygous deletions (1.17 Mb and 0.51 Mb) affecting the CNKSR2 gene. These 4 children had delayed psychomotor development from infancy, acquired walking between 20 and 27 months of age, and had restricted expressive language and attention deficit-hyperactivity disorder. The 2 Canadian brothers had onset of seizures at age 2 years with EEG showing continuous spike-wave discharges during slow-wave sleep (CSWS); both patients had deterioration of speech after seizure onset. One of the 2 French brothers had infantile seizures without CSWS; his brother did not have seizures. The deletions were maternally inherited in both families; one of the mothers had mild learning difficulties in childhood but had normal intellectual function as an adult. Vaags et al. (2014) noted that CNKSR2 functions at the postsynaptic density in neurons of the central nervous system.

By chromosomal microarray analysis, Aypar et al. (2015) identified a hemizygous 342-kb deletion of chromosome Xp22.12 involving the CNKSR2 gene in a 7-year-old boy with nonsyndromic X-linked mental retardation. The deletion was inherited from his unaffected mother. The patient had delayed psychomotor development, severely impaired speech, balance difficulties, and intractable focal seizures with severely abnormal EEG. Brain MRI was normal.

Inheritance

The transmission pattern of MRXSHG in the French family reported by Vaags et al. (2014) was consistent with X-linked recessive inheritance.

The transmission pattern of MRXSHG in the family reported by Damiano et al. (2017) was consistent with X-linked inheritance, with carrier females showing milder deficits compared to affected males.

Molecular Genetics

In 3 adult French brothers with MRXSHG, Vaags et al. (2014) identified a hemizygous frameshift mutation in the CNKSR2 gene (300724.0001). The mutation was found by exome sequencing of the X chromosome. Functional studies of the variant were not performed. The unaffected mother also carried the mutation, and a maternal uncle was reportedly affected, but DNA was not available. The same family (P180) was described by Hu et al. (2016) in a large study of 405 probands with X-linked intellectual disability who underwent X-chromosome exome sequencing.

In 2 brothers and a sister of Ashkenazi Jewish descent with MRXSHG, Damiano et al. (2017) identified hemizygous or heterozygous truncating mutations in the CNKSR2 gene (R712X; 300724.0002). The mutation was found by direct sequencing of the CNKSR2 gene. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patients' mother, who also carried the mutation, had a history of febrile seizures.

Animal Model

Hu et al. (2016) found that depletion of the Cnksr2 gene in mouse primary hippocampal neurons resulted in a severe reduction in the number of dendrite branches, loss of dendrite complexity due to loss of terminal dendrite branches, and decreased total length of neurites per neuron compared to controls. These defects could be rescued by expression of the wildtype protein.