Epilepsy and mental retardation limited to females: an under-recognized disorder Ingrid E. Scheffer, 1,2 Samantha J. Turner, 1 Leanne M. Dibbens, 3,4 Marta A. Bayly, 3 Kathryn Friend, 3 Bree Hodgson, 3 Linda Burrows, 3 Marie Shaw, 3 Chen Wei, 5 Reinhard Ullmann, 5 Hans-Hilger Ropers, 5 Pierre Szepetowski, 6 Eric Haan, 3 Aziz Mazarib, 7 Zaid Afawi, 7 Miriam Y. Neufeld, 7 P. Ian Andrews, 8 Geoffrey Wallace, 9 Sara Kivity, 10 Dorit Lev, 11 Tally Lerman-Sagie, 11 Christopher P. Derry, 1 Amos D. Korczyn, 7 Jozef Gecz, 3,4,12 John C. Mulley 3,4,12 and Samuel F. Berkovic 1 1 Epilepsy Research Centre and Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, 2 Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, 3 Department of Genetic Medicine, Women’s and Children’s Hospital, North Adelaide, South Australia, 4 School of Paediatrics and Reproductive Health, South Australia, Australia, 5 Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin- Dahlem, Germany, 6 INSERM UMR 491,‘Genetics of Human Epilepsies’ Group, Faculte¤ de Me¤ decine de la Timone, Universite¤ de la Me¤ diterrane¤ e, Marseille, France, 7 Department of Neurology, Tel Aviv Sourasky Medical Centre and Sackler Faculty of Medicine, Tel Aviv University, Israel, 8 Sydney Children’s Hospital, Randwick, New South Wales, 9 Mater Medical Centre, South Brisbane, Queensland, Australia, 10 Department of Neurology, Schneider Children’s Medical Centre, Petaq Tikvah, Israel, 11 Metabolic Neurogenetic Clinic, Wolfson Medical Centre, Holon, Israel and 12 School 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@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 dis- order.We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were trans- mitted 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 h = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with con- vulsions 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, diag- nosis will depend on identification of the molecular basis. Keywords: 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. Advance Access publication January 29, 2008 doi:10.1093/brain/awm338 Brain (2008), 131 , 918 ^927 ß The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org at Ben Gurion University - Aranne Library on April 14, 2012 http://brain.oxfordjournals.org/ Downloaded from