Rolandic Epilepsy, Mental Retardation, And Speech Dyspraxia, X-Linked

A number sign (#) is used with this entry because of evidence that the phenotype can be caused by mutation in the SRPX2 gene (300642) on chromosome Xq22. One such family has been reported.

Clinical Features

Roll et al. (2006) described a 3-generation French family with oral and speech dyspraxia, rolandic seizures, and mental retardation. The proband, a right-handed girl, lacked language at age 2.5 years when diurnal and nocturnal rolandic seizures started. Neurologic examination at age 10 years showed orofacial dyspraxia and severe speech delay. The proband's younger half-brother also had a history of epileptic seizures with speech impairment. A total of 8 individuals in 3 generations had oral and speech dyspraxia, rolandic seizures, and mental retardation; 3 individuals had mental retardation with oral and speech dyspraxia, without seizures.

Roll et al. (2006) also described a 12-year-old boy who presented with focal seizures beginning with numbness of the fingers of the right hand and leg and a sudden fall. Other attacks began with twitching of the right side of the mouth, drooling, and loss of awareness. He was left-handed. Neurologic examination revealed clonus at both knees and generalized hyperreflexia with an equivocal right plantar response. Neuropsychologic examination at age 15 years showed low average to average intellect with weakness in mathematical ability. His EEG showed left centrotemporal epileptiform activity with a rolandic horizontal dipole. MRI showed bilateral posterior perisylvian polymicrogyria (300388), more severe on the left and extending back to involve the parietooccipital regions. Two of his maternal aunts had mild mental retardation, and his mother and another aunt were of normal intelligence.

Mapping

Roll et al. (2006) performed a whole-genome screen in the French family with RESDX described by them and obtained linkage to chromosome Xq with a lod score of 3.01 at a recombination fraction of 0. The region containing the disease gene spanned approximately 20 cM at Xq21-q22, between markers ss16361056 and DXS1230.

Molecular Genetics

Roll et al. (2006) identified a variation in the SRPX2 gene (N327S; 300642.0001) on Xq22 as being responsible for rolandic seizures associated with oral and speech dyspraxia and mental retardation in a 3-generation French family. SRPX2 is a secreted sushi repeat-containing protein expressed in neurons of the human adult brain, including the rolandic area. The N327S variant resulted in gain of glycosylation of the secreted variant protein. A second mutation (X72S; 300642.0002) was identified within the first sushi domain of SRPX2 in a male with rolandic seizures and bilateral perisylvian polymicrogyria and in his female relatives with mild mental retardation or unaffected carrier status. The authors suggested that SRPX2 may play an important role in the development and/or function of the perisylvian region critical for language and cognitive development.

In the French family reported by Roll et al. (2006), Lesca et al. (2013) identified a heterozygous ala716-to-thr (A716T) substitution at a highly conserved residue in the GRIN2A gene (138253) that is associated with focal epilepsy and speech disorder with or without mental retardation (FESD; 245570). All but 2 affected family members with the SRPX2 mutation also carried the GRIN2A mutation. All patients with the GRIN2A mutation had seizures, whereas the 2 patients with only the SRPX2 mutation and not the GRIN2A mutation did not have seizures. It was unclear whether the 2 mutations acted synergistically or independently to affect the phenotype in this family.

Piton et al. (2013) found the N327S variant in 3 males and 8 females of European descent in the Exome Variant Server database. Based on these findings, as well as a lack of reported SRPX2 mutations since 2006, Piton et al. (2013) classified the involvement of SRPX2 mutations in epilepsy and/or cognitive impairment as questionable.

Reinthaler et al. (2014) found the N327S variant (rs121918363) in 2 (0.81%) of 247 patients with rolandic epilepsy who underwent direct sequencing of the SRPX2 gene and in 12 (0.26%) of 4,703 European controls, including those from the Exome Variant Server database. Sequence variants and structural variation were not found in the SRPX2 gene or in 4 interaction partners. Reinthaler et al. (2014) concluded that variation in the SRPX2 gene does not play a major role, if any, in rolandic epilepsy.