Epilepsy, X-Linked, With Variable Learning Disabilities And Behavior Disorders

A number sign (#) is used with this entry because of evidence that X-linked epilepsy with variable learning disabilities and behavior disorders is caused by mutation in the SYN1 gene (313440) on chromosome Xp11.

Clinical Features

Garcia et al. (2004) reported a novel X-linked recessive syndrome in a 4-generation kindred in which some males of normal intelligence had epilepsy and others had various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behavior. One patient had a diagnosis of autism. The natural history of seizures was variable, occurring only during childhood in some, developing at age 27 in 1, and appearing only in association with specific stimuli in others.

Fassio et al. (2011) reported a large French Canadian family in which 7 males had X-linked partial epilepsy with variable learning disabilities and behavioral disorders. Two patients also had autism.

Inheritance

The transmission pattern of partial seizures and learning disabilities in the family reported by Fassio et al. (2011) was consistent with X-linked recessive inheritance.

Mapping

By genetic linkage analysis, Garcia et al. (2004) mapped an X-linked epilepsy disorder in a 4-generation kindred to Xp11.3-q12, between the MAOB gene and marker DXS1275. A maximum 2-point lod score of 4.06 at theta = 0.0 was found with DXS1039.

Molecular Genetics

By direct sequencing of the SYN1 gene, Garcia et al. (2004) identified a trp356-to-ter mutation (W356X; 313440.0001) in all 10 affected males and in obligate carrier females.

In 6 males from a large French Canadian family with X-linked partial epilepsy and learning disabilities, Fassio et al. (2011) identified a truncating mutation in the SYN1 gene (Q555X; 313440.0002). Investigation of this gene in several large cohorts of patients with epilepsy and/or autism identified 3 additional variants in the SYN1 gene (see, e.g., 313440.0003 and 313440.0004) in 1% of patients with autism spectrum disorders and 3.5% of patients with epilepsy. Three of the 4 mutations affected the D-domain, which is important for protein function. When expressed in Syn1-null neurons, these 3 mutant proteins were unable to rescue impairments in the size and trafficking of synaptic vesicle pools. The findings demonstrated that SYN1 is a predisposing gene to epilepsy and autism spectrum disorders and strengthened the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both disorders.