Fragile X syndrome is a classic neurologic disease with unique manifestations on the clinical and molecular level. It is the most common genetic cause of cognitive impairment in males and can render symptoms of speech and developmental delay. Further, it represents one of the many important inherited diseases that are caused by expansions or amplification of short DNA repeats on specific genes. This article will help elucidate the significance of the fragile X syndrome as well as fragile X tremor-ataxia syndrome (FXTAS) for both younger and older patients and will provide insight on the potential benefits of a diagnostic workup and particular situations where a screening may be beneficial. It will also point to current research that has led to possible future treatments for symptoms of fragile X syndrome.
Historical note and terminology
Fragile X syndrome is the most common inherited cause of cognitive impairment in males. It is named for the folate sensitive fragile site Xq27.3 and is caused by an expansion or amplification of a CGG trinucleotide repeat in the first exon of the fragile X mental retardation gene (FMR1), located on the long arm of the X chromosome. It affects males more severely and more frequently than females. It is a paradigm of a neurologic disease with a well-recognized phenotype and a clearly defined genetic and molecular basis that explains a complex mode of inheritance and the associated phenomenon of anticipation.
Martin and Bell first described this syndrome in 1943 (58). In 1969, Lubs was the first to demonstrate a fragile site on the X chromosome (57). In 1977, Sutherland showed this to be a reliable finding in cells cultured in a folate deficient medium (82). In 1980, Turner and colleagues recognized the combination of macroorchidism and cognitive impairment in males in conjunction with a fragile site to be a distinct clinical entity (90). Verkerk and colleagues discovered the molecular basis of the condition in 1991 (93).
In 2001, Hagerman and colleagues first recognized Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset progressive neurologic disorder. FXTAS develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, parkinsonism, peripheral neuropathy, autonomic disorders, cognitive impairment (38), and essential tremor (32). The elevated mRNA in fragile X premutation carriers are vulnerable to neurotoxin, leading to early cell death and brain disease, consistent with FXTAS exhibiting neuropsychiatric and neurologic symptoms (66).