30 January 2004. Elderly men with symptoms of ataxia and intention tremor may actually have a disorder related to fragile X syndrome, a common form of mental retardation in children. These men show signs of Parkinson's disease or dementia and are sometimes misdiagnosed as having PD or AD. Instead, they carry a fragile X mutation that during aging leads to motor and cognitive problems, according to a study reported in the January 28 Journal of the American Medical Association.
Fragile X syndrome arises when the fragile X mental retardation gene (FMR1) is disrupted by an expansion of a nucleotide triplet (CGG), much like that in the huntingtin gene, except the FMR1 expansion resides upstream of its coding region. The FMR1 protein is thought to be involved in synaptic function through a role in mRNA transport and translation. Expansion of the triplet to over 200 repeats usually silences FMR1, causing juvenile mental retardation, but a sizeable portion of the population (one in 259 males; one in 813 females) carry smaller expansions of between 50 to 200 repeats. These “premutations” have been associated generally with emotional problems and with premature ovarian failure in women. But scientists have recently reported that male carriers of these premutations may suffer from late-onset neurological symptoms including ataxia and intention tremor (Leavitt et al., 2003; Oostra and Willemsen, 2003).
Paul Hagerman at the University of California, Davis, together with colleagues there and elsewhere, set out to determine the prevalence of what is now known as fragile X-associated tremor/ataxia syndrome (FXTAS). First author Sebastien Jacquemont and coauthors studied 192 people who have family members in the Northern or Southern California Fragile X Associations. Ninety-nine were carriers (40 male and 59 female), the others controls. All volunteers answered a survey designed to uncover symptoms of neurologic impairment, while 93 volunteers, including male and female carriers and controls, underwent neurological examination.
The researchers' results suggest that the statistical risk for FXTAS in male carriers increases with age. In their fifties, male carriers have about a 17 percent chance of having tremor or gait problems; in the seventies, that risk increases to 47 percent, and to 75 percent in men over 80. Female carriers scored lower than age-matched controls in neurologic tests, but the authors were not able to ascertain if any of them have FXTAS. The sample size in this study was particularly small in some of the subgroups; only four men with premutations were over age 80, for example.
One of the important questions which now needs to be addressed is whether there is a direct relationship between repeat length and the severity of symptoms, the authors write In the meantime, screening for FMR1 premutations may prove a useful diagnostic tool.—Tom Fagan.
Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, Zhang L, Jardini T, Gane LW, Harris SW, Herman K, Grigsby J, Greco CM, Berry-Kravis E, Tassone F, Hagerman PJ. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004 January 28;291:460-469. Abstract