Clinical involvement and protein expression in individuals with the FMR1 premutation

Most individuals with the fragile X premutation are clinically unaffected; however, some show clinical manifestations, including learning difficulties, emotional problems, or even mental retardation. The basis of clinical involvement in these individuals is unknown. Premutation alleles are reportedly associated with normal levels of mRNA and protein (FMRP). To examine this issue in more detail, we studied six individuals with a premutation. We are reporting these cases to demonstrate a spectrum of phenotypic involvement which can be seen clinically. These cases include one individual with the premutation who has no evidence of FMR1 gene dysfunction but has mental retardation from other causes. Other cases presented here show varying degrees of FMR1 gene dysfunction as assessed by FMRP and FMR1 mRNA levels and various clinical features of fragile X. In two cases we observed a significant reduction in FMRP expression and an elevated FMR1 mRNA expression level associated with moderate cognitive deficit. Thus, the utilization of FMRP measures can be helpful in understanding for which premutation patients clinical involvement is caused by dysfunction of the FMR1 gene.