SCIENCE

Fragile X Syndrome

Fragile X mental retardation is an X-linked genetic disease affecting about 1 in 4,000 males and is characterized by developmental delay, cognitive defects, hyperactivity and autistic behavior. There is currently no treatment available for this disease. While Fragile X is the most common form of mental retardation and the most common known cause of autism, it is nevertheless a rare disease and covered under the Orphan Drug Act. The disease is caused by expansion of single nucleotide triplets upstream of the Fmr1 gene, causing transcriptional silencing of the gene.

Histochemical analysis of brain samples from Fragile X patients show an increased number of filopodia-like spines that resemble "immature" spine phenotype, as well as an increased overall number of dendritic spines. Targeted deletion of the murine homolog of Fmr1 in mice leads to phenotypes that strongly resemble the human disease: animals show hyperlocomotion, stereotypy as well as defects in cortical function such as trace fear conditioning. Importantly, the cellular phenotype of Fmr1 knockout mice parallels the spine abnormalities observed in samples from human Fragile X patients. In addition, cortical and hippocampal synapses from Fmr1 knockout animals show defects in synaptic plasticity when recorded ex vivo in slice preparations. Taken together, these features make Fragile X mental retardation an ideal test case for the hypothesis as the disease has a well-defined phenotype of excessive number of immature dendritic spines and behavioral abnormalities are seen in both human patients and the murine model.