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The fragile X syndrome, the most common form of hereditary cognitive impairment, with a frequency of 1:4000 males and 1:6000 females, is caused by expansion of a trinucleotide repeat (CGG) within the FMR1 gene.1 In the normal population, the length varies from five to 50 repeats.2 Subjects with the fragile X syndrome have more than 200 CGG repeats (full mutation, FM) and, as a consequence, the FMR1 promoter region, including the CGG repeat, is hypermethylated.3,4 As methylation results in a lack of FMR1 gene transcription, no FMR1 protein (FMRP) is produced. The absence of FMRP in the brain (neurones) is responsible for the cognitive impairment in the fragile X syndrome.5,6 In addition, some subjects have intermediate sized alleles of between 50 and 200 CGG repeats (premutations; PM). The PM alleles are unmethylated with normal FMRP biosynthesis, but are unstable during transmission to the next generation.
Male fragile X patients are characterised by mild to severe learning difficulties. Macro-orchidism and facial abnormalities, including a long face with large, prominent ears and behavioural features such as hyperactivity, poor eye contact, and hand flapping, may be part of the fragile X phenotype in males. Generally, there is wide variation in the degree of clinical involvement in female FM carriers. Approximately 60% of females carriers have mild to moderate mental impairment, while the remaining 40% have normal intellectual capacity. The molecular basis for the phenotypic variability in both males and females is believed to be linked to the variable number of neurones in the brain that express FMRP. Mosaic males who are affected show a variable combination of PM and FM alleles, but the usual predominance of FM.7 In female carriers of FM, variation in the X chromosome inactivation ratio may account for the clinical variability in …
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