1 ARTICLE IN PRESS Turkish Journal of Psychiatry 2012 ARTICLE IN PRESS Fragile X Premutation in Adult Psychiatry: Four Cases and Overview of Clinical Presentation 2 E. Cem ATBAŞOĞLU 1 , Direnç SAKARYA 2 , Güvem GÜMÜŞ AKAY 3 , Ayşegül SAKARYA 4 , Ajlan TÜKÜN 5 Received: 03.12.2011 - Accepted: 06.04.2012 1 M.D., Prof., Ankara University Brain Research Center, Ankara; 2 M.D., Specialist, Denizli Military Hospital Psychiatry Section, Denizli, 3 Ph.D., Assoc Prof., Ankara University Brain Research Center, 4 M.D., Resident, Ankara Unversity Faculty of Medicine, Department of Psychiatry, 5 M.D., Prof., Ankara Unversity Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey. E-mail: e.cem.atbasoglu@medicine.ankara.edu.tr SUMMARY Fragile X carrier status, also named as Fragile X premutation (FraX-PM), is defined by trinucleotide repeat expansions of shorter length compared to those that cause the full syndrome. Its clinical significance has been limited to the risk of further expansion to a full mutation in the offspring of carriers, until it was recently recognized as a clinical syndrome on its own, manifested by unique symptom constellations, as well as a combination of neuropsychiatric signs and symptoms that may be indistinguishable from several commonly seen disorders. The complex heterogeneity of its neu- ropsychiatric manifestations may render the diagnosis challenging, unless the clinician is familiar with the clinical picture and transmission pattern. We present four cases of FraX-PM, diagnosed in an adult psychiatry setting and confirmed by genetic testing. The aim of this report is to increase familiarity among psychiatric practitioners, since this common condition is seldom included in the current diagnostic practice, which is based on atheoretical definitions. Key words: carrier state, diagnosis, genetic testing, Fragile X syndrome, premutation INTRODUCTION Fragile X syndrome (FraX) is the most common inherited ca- use of mental retardation and also the most common single gene cause of autisic disorder. First cases reported by Martin and Bell (1943) were children with mental retardation. At present, autistic disorder and dysmorphic findings (especial- ly long face, prominent jaw, and large ears) are the two ot- her commonly known components. The name was coined upon Lubs’ (1969) description, in cytogenetic analysis, of the distal region in the long arm of X chromosome as ‘fragile.’ Krawczun et. al. (1985) determined the exact locus (Xq27.3). The responsible gene, identified by Verkerk et. al. (1991), was named as the Fragile X mental retardation 1 (FMR1) gene. Findings of the syndrome are indirect results of an expansion of the CGC nucleotide repeats in the 5’-untranslated regi- on (5’-UTR) region of FMR1 (Reiss and Dant 2003). The CGG repeat number in this region is polymorphic in the general population, with common (normal) alleles including 5-54 repeats. Numbers above 200 result in methylation of the promotor region, thereby inhibiting the expression of FMR1 and the synthesis of its product, which is called the Fragile X Related Mental Retardation Protein (FMRP). Patients with this condition (a full mutation) exhibit the characteristic signs and symptoms of the syndrome (Tassone et. al. 1999). Individuals with 55-200 repeats are carriers. Carrier status is also termed as a premutation (PM), since repeat numbers show a tenden- cy to increase during meiosis, being transformed into full mu- tations in the offspring (Fu et al. 1991, Nolin et. al. 2003). Classical FraX is rare (1/2500 - 1/4000), however diagnostic prevalence may not be an accurate reflection of the prevalence of the mutation allele (Hagerman 2008). Fragile X premu- tation (FraX-PM) is not uncommon, and may be relatively higher in some geographic locations (e.g., 1/100 - 1/150 in Israel) (Pesso et. al. 2000, Toledano-Alhadef et. al. 2001). Recently it has been recognized that FraX-PM is also associated with a variety of clinical manifestations (Farzin et al. 2006), among which two are systematically defined phenotypes seen