Screening for FXTAS in 95 Spanish Patients Negative for Huntington Disease Laia Rodriguez-Revenga, 1,2, * M. Mo` nica Santos, 1, * Aurora Sa´ nchez, 1 Montserrat Pujol, 3 Beatriz Go´ mez-Anson, 4 Celia Badenas, 1 Dolores Jime´ nez, 1 Irene Madrigal, 1,2 and Montserrat Mila` 1 Fragile X syndrome is the most common form of hereditary mental retardation. The molecular basis of this syndrome is mainly a CGG expansion in the 5 0 untranslated region of the FMR1 gene. Expansions with more than 200 CGG repeats abolish gene expression causing the classical fragile X phenotype. Premutation carriers (55–200 CGG) have normal cognitive function with increased risk of developing premature ovarian failure and fragile X-associated tremor–ataxia syndrome (FXTAS). Some clinical features associated with FXTAS, such as tremor, gait ataxia, cognitive decline, and generalized brain atrophy, are also seen in other movement disorders. Ninety-five patients referred for HD, who tested negative for the expansion in the IT15 gene, were screened for FMR1 CGG-repeat expansion. One FMR1 premutation male carrier was detected, giving an FXTAS frequency of 1.6%. Our results highlight that FXTAS is still not well diagnosed; therefore, we recommend FMR1 premutation screenings in all patients with late-onset tremor, ataxia, and cognitive dysfunction. Introduction F ragile x syndrome (FXS) is the most common cause of hereditary mental retardation, with a frequency in the general population of 1=4000 in males and 1=6000 in females (Turner et al., 1996). FXS is caused by a dynamic mutation, an expansion of the CGG trinucleotide repeats in the 5 0 un- translated region of the FMR1 gene that is inherited in an unstable fashion throughout FXS families. FXS-affected indi- viduals carry alleles with more than 200 repeats (full muta- tion). Under these circumstances, the FMR1 gene is silenced, leading to an absence of FMR1 protein (FMRP). Premutation alleles are defined by an expansion ranging from 55 to 200 CGG repeats, and their frequency in the Spanish popu- lation has been estimated to be 1 in 1200 males and 1 in 400 females (Rife et al., 2003). In the last 5 years, fragile X- associated tremor–ataxia syndrome (FXTAS, OMIM 300623), a neurodegenerative disorder, has been described among FMR1 premutation carriers older than 50 years. This disorder is associated with elevated levels of FMR1 mRNA, and is thought to be the result of the toxic effect of the FMR1 mRNA itself (reviewed in Hagerman and Hagerman, 2004). Typical features of FXTAS are tremor and gait ataxia, cognitive de- cline, and generalized brain atrophy ( Jacquemont et al., 2006). Additionally, many patients also show parkinsonism, pe- ripheral neuropathy, lower limb muscle weakness, and au- tonomic dysfunction, clinical symptoms that are also common in other movement disorders like Huntington disease (HD), Parkinson’s disease (PD), multiple system atrophy, or essen- tial tremor (ET). The discovery of FXTAS has led to the in- vestigations of the frequency of FMR1 premutation alleles in several groups of patients with movement disorders, espe- cially in individuals with sporadic late-onset cerebellar atax- ias (reviewed by Jacquemont et al., 2006). However, very few studies have been performed in patients with HD-suggestive phenotypes. Taking into account the high frequency of FXS premutation alleles in the general population and the varia- tion in clinical presentation of FXTAS, we tested FMR1 CGG repeats in 95 unrelated Spanish individuals referred for ge- netic testing of HD. Materials and Methods Subjects Ninety-five unrelated patients (62 males=33 females) older than 50 years with a phenotype suggestive of HD were studied. All patients tested negative for the CAG triplet- repeat expansion in the IT15 gene. All samples were ascer- tained from patients referred to the Molecular Laboratory at 1 Biochemistry and Molecular Genetics Department, Hospital Clı ´nic, and Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 2 Centre for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain. 3 Servei de Neurologia, H. Santa Maria de Lleida, Lleida, Spain. 4 Radiology Department, CDI, Hospital Clı ´nic, and Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. *These authors have contributed equally to this work. GENETIC TESTING Volume 12, Number 1, 2008 ª Mary Ann Liebert, Inc. Pp. 135–138 DOI: 10.1089=gte.2007.0074 135