Brain Advance Access originally published online on January 29, 2008
Brain 2008 131(4):918-927; doi:10.1093/brain/awm338
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Epilepsy and mental retardation limited to females: an under-recognized disorder
1Epilepsy Research Centre and Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, 2Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, 3Department of Genetic Medicine, Women's and Children's Hospital, North Adelaide, South Australia, 4School of Paediatrics and Reproductive Health, South Australia, Australia, 5Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin-Dahlem, Germany, 6INSERM UMR 491, ‘Genetics of Human Epilepsies’ Group, Faculté de Médecine de la Timone, Université de la Méditerranée, Marseille, France, 7Department of Neurology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Israel, 8Sydney Children's Hospital, Randwick, New South Wales, 9Mater Medical Centre, South Brisbane, Queensland, Australia, 10Department of Neurology, Schneider Children's Medical Centre, Petaq Tikvah, Israel, 11Metabolic Neurogenetic Clinic, Wolfson Medical Centre, Holon, Israel and 12School of Molecular and Biomedical Sciences, University of Adelaide, South Australia, Australia
Correspondence to: Professor Ingrid E Scheffer, Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Neurosciences Building, Level 1, Heidelberg Repatriation Hospital, Banksia Street, Heidelberg VIC 3081, Australia E-mail: scheffer{at}unimelb.edu.au
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.
Key Words: epilepsy; intellectual disability; females; X-linked inheritance; autistic features
Abbreviations: BAC, bacterial artificial chromosome; CFNS, craniofrontonasal syndrome; EFMR, epilepsy and mental retardation limited to females; ID, intellectual disability.
Received September 24, 2007. Revised December 6, 2007. Accepted December 18, 2007.
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