Fragile X Syndrome vs Fragile X–Associated Tremor/Ataxia Syndrome

We read with interest the article by Dr Cellini and colleagues.¹ The authors help define the broad spectrum of neurological signs that occur in carriers of premutation alleles of the fragile X mental retardation 1 (FMR1) gene and make a number of important observations. Most notably, the article documents the importance of testing for the FMR1 premutation carrier state in men older than 50 years of age with sporadic ataxia, finding that the gene abnormality was the cause in almost 5% of cases.

Our group published the first case reports in 2001 and has since examined more than 100 affected persons. We want to address an issue of nomenclature. The authors refer to the disorder as fragile X syndrome with associated tremor or ataxia. This is misleading, suggesting that affected persons have fragile X syndrome (FXS). Moreover, the term incorrectly implies there would be some similarity in the clinical or molecular pathology between the disorder being discussed and FXS. To avoid these misperceptions, we suggested the disorder be named the fragile X–associated tremor/ataxia syndrome, or FXTAS, in some of our early articles.^{2 - 3}

The clinical features and molecular pathogenesis of FXS and FXTAS are completely distinct. Fragile X syndrome, the most common heritable cause of mental retardation, is a developmental disorder usually diagnosed in childhood. Fragile X syndrome is caused by a mutation (>200 CGG repeats) of the FMR1 gene, which leads to gene methylation, transcriptional silencing, and consequent loss of the FMR1 protein. By contrast, FXTAS, with predominant features of cerebellar ataxia and intention tremor, is a neurodegenerative disorder that has onset in persons older than 50 years. This disorder affects carriers of premutation expansions (55-200 repeats) and is associated with elevated levels of FMR1 messenger RNA (mRNA). Because persons with FXS do not appear to develop FXTAS as they age, FXTAS is not likely to be due to deficient levels of FMR1 protein. Instead, FXTAS is proposed to result from toxic levels of the FMR1 mRNA itself.⁴

We have seen the inaccurate use of the term FXS in reference to FXTAS in other contexts also. When clinicians misuse these terms, patients and families become confused. Families with FMR1 expansions need to clearly understand the distinctions between the 2 disorders to understand their differing risks.

On a different topic, we agree that in case 1 the presentation with spastic paraparesis without clear cerebellar ataxia was atypical. Prominent spastic paraparesis is unusual among premutation carriers.⁵ The patient did, however, have common signs found in FXTAS—kinetic tremor and sensory loss in the legs.² Also, a mild increase in tone is frequently seen in FXTAS.

Lastly, we would like to comment on the authors' conclusion that all patients with spinocerebellar disorders should undergo magnetic resonance image scanning because the high T2 signal in the middle cerebellar peduncles (the MCP sign) is specific to FXTAS and may be an important indication for precise and cost-effective premutation screening. Although the MCP sign is relatively specific for FXTAS, it has been observed in other neurodegenerative disorders, including multiple system atrophy.⁶ The exact frequency of the MCP sign in FXTAS is unclear and, in our experience, appears to be between 50% and 80%.⁷ Further, while brain imaging is indicated in all persons with spinocerebellar ataxia, the FMR1 gene test is generally much less costly than a magnetic resonance image scan. We believe that FMR1 testing should proceed in all men with onset of unexplained ataxia at age 50 years or older regardless of magnetic resonance image findings.

Correspondence: Dr Leehey, Department of Neurology, University of Colorado at Denver and Health Sciences Center, 4200 E Ninth Ave, Box B183, Denver, CO 80262 (maureen.leehey@uchsc.edu).

Financial Disclosure: None reported.