HONOLULU—A new movement disorder syndrome is attributable to an old and familiar gene mutation, according to a growing body of research. The disorder, fragile X–associated tremor/ataxia syndrome (FXTAS), affects primarily older men. The mutation is a shorter version of the triplet repeat responsible for fragile X syndrome, the most common heritable cause of mental retardation. And some cases of yet another neurologic disorder, multiple system atrophy, may also be linked to this mutation. Details of this new research were presented at the 55th Annual Meeting of the American Academy of Neurology.

PREMUTATIONS CAUSE LATE-ONSET DISORDER

Fragile X is due to expansion of the FMR1 gene, located on the X chromosome. The normal allele contains between six and 40 CGG repeats. It was discovered in 1991 that expansion of the allele beyond 200 units led to the mental retardation and characteristic physical features of fragile X syndrome, which affects young boys. In 2001, Randi Hagerman, MD, Paul Hagerman, MD, PhD, and colleagues from the Medical School at the University of California at Davis (UC Davis) reported on a small group of men with progressive intention tremor, ataxia, and dementia. Each was the grandfather of one or more boys with fragile X syndrome and in fact came to the attention of Dr. Randi Hagerman through their daughters. “It became apparent in talking to mothers of boys with fragile X syndrome that their fathers were not doing well. This was somewhat surprising,” said Dr. Hagerman, and prompted her team to bring them into the clinic.

They discovered that these men had FMR1 “premutations,” with repeat lengths in the range of 50 to 200 units, a condition originally thought to be largely asymptomatic, although there were several anecdotal reports of a Parkinson’s disease–like condition in a few such patients. Dr. Hagerman’s team has pioneered the study of this syndrome, and its links with fragile X syndrome, and she indicates that it is much more common than originally thought. “Probably a quarter of the grandfathers of affected boys develop this syndrome,” she said, “though these numbers are pretty soft. It’s imperative to look at larger populations” to develop better estimates of this risk.

“The typical male patient initially presents in one of two ways,” Dr. Hagerman explained, “either with ataxia, or an intention tremor. They usually go on to develop other features as well. The ataxia seems to be most consistent—more than 90% of the patients have ataxia, and a somewhat smaller percent have tremor.” Resting tremor can also be present, and dementia often develops later. “The other general feature is autonomic dysfunction,” Dr. Hagerman said, with incontinence or impotence, as well as peripheral neuropathy. As has been recognized for many years, premutation carriers have no mental retardation. In the patients described so far, dementia usually develops some years after the movement disorder.

Patients also have a characteristic imaging sign, consisting of bilateral symmetric hyperintense signal from the middle cerebellar peduncles, seen with T2-weighted MRI. While this is rare among all neurologic patients, it has been noted in multiple system atrophy patients as well, occurring in 40% of patients in one study. “We’d love to see if most of those are FXTAS,” said the Hagermans. In addition, patients with FXTAS have a moderate to severe reduction in brain volume in the parietal cortex and cerebellum, as well as cortical white matter lesions. All of this follows from a single gene mutation, noted Dr. Paul Hagerman, who is a Professor in the Department of Biological Chemistry at the UC Davis School of Medicine.

MISDIAGNOSIS AND EXPANDING PHENOTYPE

Dr. Paul Hagerman suspects that some proportion of patients diagnosed with essential tremor in fact have FXTAS, though there have not yet been studies large enough to determine the proportion (several patients with FXTAS originally diagnosed with essential tremor have been reported in the literature). He also suspects that slightly expanded FMR1 alleles may be associated with cases of multiple system atrophy.

As yet, there are no specific treatments for FXTAS. Donepezil can be helpful for cognitive impairment, as can some antiparkinsonian medications for those patients with parkinsonian features, noted Dr. Randi Hagerman.

The molecular pathogenesis of FXTAS is unknown, but it is clearly not the same as fragile X syndrome. In fragile X, the expanded FMR1 allele is silenced by methylation, and it makes no messenger RNA. In premutation carriers, however, the messenger RNA levels are elevated fivefold to tenfold, and the protein levels range between normal and 50% of normal.

“This brings up the possibility that the RNA is involved,” remarked Dr. Paul Hagerman. “The precedent for this is myotonic dystrophy, in which RNA containing transcribed but untranslated CTG repeats cause a multisystem disorder. It’s a beautiful model for FXTAS,” he said, “but so far it’s just a model.”

THE MULTIPLE SYSTEM ATROPHY CONNECTION?

The connection between the FMR1 gene and multiple system atrophy is less clear-cut but intriguing. Lin Zhang, MD, PhD, from the Neurology Department at UC Davis, determined the FMR1 repeat lengths in 19 patients with multiple system atrophy. Of these, nine—four males and five females—had repeat lengths above normal, with at least one allele between 41 and 60. These patients were similar to the typical patient with multiple system atrophy seen in the clinic, he said, both in their clinical presentation and response to therapy.

These mildly expanded alleles are called “gray zone” expansions, said Dr. Zhang, and their pathologic significance is unknown. “Forty or more repeats is very rare in the general population—less than 5%—but appears to be very common in the multiple system atrophy population,” he noted. “Historically, multiple system atrophy was a diagnosis by exclusion,” but this finding may allow a subgroup of patients to be identified with a common genetic anomaly.

The patients have the same cerebellar peduncle white matter changes seen in typical patients with FXTAS, “right in the right spot,” Dr. Zhang said. No patients known to have gray-zone alleles have yet been studied pathologically, but this and other studies are under way.

Whatever the final verdict on the link between multiple system atrophy and FXTAS, it is clear that the role of FMR1 in neurologic disease is growing. These findings indicate how much remains to be learned about the spectrum of disorders these expanded repeats can cause.

NR

—Richard Robinson

Suggested Reading
Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127-130.
Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet. 2003; 72:869-878.
Loesch DZ, Huggins RM, Bui QM, et al. Relationship of deficits of FMR1 gene specific protein with physical phenotype of fragile X males and females in pedigrees: a new perspective. Am J Med Genet. 2003;118:127-134.

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