Fragile X syndrome

Abstract

Fragile X syndrome, the most common genetic disorder associated with mental retardation is caused by an expansion of the unstable CGG repeat within the FMR1 gene. Although overgrowth is not the main hallmark of this condition, the fragile X syndrome is usually included in the differential diagnosis of children with mental retardation and excess growth. This review highlights the most recent advances in the field of fragile X research.

Genotype-Phenotype Correlates in Fragile X Syndrome

“…It is characterized by intellectual and learning disabilities, behavioral and or psychiatric comorbidities, mildly dysplastic connective tissue, and large testes. It occurs in about one in 4000 males and one in 8000 females [1][2][3]. Martin and Bell [4] reported the first documented pedigree of sex linked mental retardation (intellectual disability).…”

“…In male sufferers, peri-pubertal increase in testicular size is a characteristic feature of the syndrome [1][2][3]17]. Cognitively, the sufferers had different degrees of intellectual disability ranging from mild to profound.…”

“…Other abnormalities include thickening of nasal bridge down to the nasal tip, large ears with softening of its cartilage, the irides may be pale blue with epicanthal folds, dental crowding, and prognathism which usually becomes apparent at puberty [1][2][3]27].…”

“…Cluttered speech is characteristic in highly functioning fragile X sufferers. Psychological phenotype is characterized by hyperactivity, labile emotions, and different autistic features [1][2][3]18]. It is well documented that the earlier the diagnosis and implementation of early intervention and individualized rehabilitation programs, the better the prognosis.…”

Mapping of an origin of DNA replication in the promoter of fragile X gene FMR1

“…Sequence analysis of cosmids and cDNAs mapping to this fragile site revealed a polymorphic (CGG) n repeat in the 5′ untranslated region of the FMR1 gene at Xq27.3, which is known as the FRAXA site (Verkerk et al, 1991). Triplet repeat amplification in excess of 200 copies (full mutation) leads to hypermethylation of the FMR1 promoter region and gene silencing, hence a loss-of-function effect in affected males (Terracciano et al, 2005). In the pre-mutation stage, amplifications ranging from approximately 60 to 200 repeats, are associated with increased transcription of the mutant FMR1 gene (Tassone et al, 2000).…”