E/ii/qi\iu. zyxwvutsrqponmlk 40(8): zyxwvutsrqponmlkji 1091--1099, zyxwvutsrqponm 1999 Lippincot1 Williams & Wilkins, Inc., Philadelphia zyxwvutsrqp 0 International League Against Epilepsy Clinical Research Epilepsy and EEG Findings in Males with Fragile X Syndrome z S. A. Musumeci, *R. J. Hagerman, R. Ferri, P. Bosco, TB. Dalla Bernardina, SC. A. Tassinari, zy SG. B. De Sarro, and M. Elia Ousi Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy; “Department of Pediatrics, University of Colorudo Health Sciences Center, Child Development Unit, The Children Hospital, Denver, Colorado, U.S.A.; f Child Neuropsychiatry, Universiv of Verona, Verona; $Department of Neurology, University zyxwv of Bologna, Bellaria Hospital, Bologna; and $Department of Experimental and Clinical Medicine, School of Medicine, University of Reggio Calabria, Reggio Calabria, Italy Summary: Purpose and Methods: One hundred and ninety- two fragile X male patients were investigated for seizures and EEG findings, 168 in a retrospective and 24 in another pro- spective study, to characterize the natural history of seizures, epilepsy, and EEG abnormalities in males with this syndrome. Results: Seizures were documented in 35 (18.2%) of 192 patients; they never started before the age of 2 years or after the age of 9 years. Seizures were frequently of the complex partial type and less frequently of the partial motor and generalized type. Seizures involving frontal and temporal lobes were com- monly seen and were usually well controlled by anticonvul- sants. In the majority of young fragile X patients studied, an age-related paroxysmal EEG pattern was found, which showed neurophysiologic characteristics very similar to those of the centrotemporal spikes. Conclusions: These findings confirm that fragile X syndrome can be considered a genetic model of epilepcy. Key Words: Epilepsy-Fragile X syndrome-EEG-Centrotemporal spikes-FMR- 1 gene. The fragile X [fra(X)] syndrome is the most common familial form of mental retardation (MR). Lubs (1) first detected the marker X, and subsequently Sutherland (2) reported that the demonstration of the fragile site at the Xq21.3 region was dependent on the use of folate- deficient tissue-culture media. Subsequently many stud- ies have identified the phenotype of the fra(X) syndiome including MR, macroorchidism, large and prominent ears, narrow face, and other signs related to a connective tissue dysplasia (3,4). Recently molecular genetic studies demonstrated that fra(X) syndrome results from a mutation in a (CCG)n repeat found in the coding sequence of the FMR- 1 (Frag- ile X Mental Retardation) gene (5). Analysis of length variation in this region in normal individuals shows a range of allele sizes varying from a low of six to a high of 54 repeats. When 3200 repeats are present, this phe- nomenon is associated with transcriptional silencing of the gene and is commonly referred to as the FMR-1 full Accepted January 22, 1999. Address correspondence and reprint requests to Dr. S. A. Musumeci at Oasi Institute for Research on Mental Retardation and Brain Aging, Via C. Ruggero, 73, 1-94018 Troina (EN), Italy. mutation. The intermediate range of repeats (50-200) is referred to as the premutation. The risk of expansion during oogenesis to the full mutation with MR increases with the number of repeats (5). The FMR-1 gene codes for the FMR-1 protein, and its lack of expression in .a functional form results in fra(X) syndrome (6). Attention has been focused on the central nervous sys- tem (CNS) dysfunction in fra(X) syndrome, particularly epilepsy and abnormal EEG findings (4). We previously reported a characteristic EEG pattern in fra(X) syndrome and suggested that it can be considered as a “marker” for this condition, because of its specificity and sensitivity in comparison with control groups of etio- logically different patients with MR or epilepsy (7). Re- viewing an overall sample of 285 patients reported by different authors (1 ,8-19), the prevalence of epilepsy is 22.8% (65 of 285). There is, however, a significantly different degree of involvement reported in the different studies, ranging from 13 or 14% (12,13) to 41 or 44% (14,18), depending on the referral bias of the different clinics. Other important questions still need an answer including the age at onset of seizures, their frequency and semiology, and the response to anticonvulsants (AEDs). 1092