Epilepsy and mental retardation limited to females: an under-recognized disorder

• DOI: 10.1093/brain/awm338
• Publication Date: 2008-01-31T01:24:26Z
• Authors: Ingrid E. Scheffer; Samantha J. Turner; Leanne M. Dibbens; Marta A. Bayly; Kathryn Friend; Bree Hodgson; Linda Burrows; Marie Shaw; Chen Wei; Reinhard Ullmann; Hans-Hilger Ropers; Pierre Szepetowski; Eric Haan; Aziz Mazarib; Zaid Afawi; Miriam Y. Neufeld; P. Ian Andrews; Geoffrey Wallace; Sara Kivity; Dorit Lev; Tally Lerman-Sagie; Christopher P. Derry; Amos D. Korczyn; Jozef Gecz; John C. Mulley; Samuel F. Berkovic
• Keywords: Adult; Male; 0301 basic medicine; Heterozygote; Adolescent; Genetic Linkage; Developmental Disabilities; 590; 03 medical and health sciences; X-linked inheritance; Intellectual Disability; Humans; Child; Aged; Chromosomes, Human, X; Epilepsy; Mental Disorders; Electroencephalography; Genetic Diseases, X-Linked; females; Middle Aged; Pedigree; 3. Good health; Phenotype; intellectual disability; autistic features; Child, Preschool; epilepsy; intellectual disability; females; X-linked inheritance; autistic features; Public Health and Health Services; epilepsy; Female

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder. We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6-36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis.