FXTAS Should be Considered in the Diagnosis of Patients With Essential Tremor Who Show Certain Signs, Study Says

Fragile X-associated tremor/ataxia syndrome (FXTAS) should be considered in the diagnosis of patients with essential tremor who show signs of cerebellar involvement and/or drug-induced movement disorders (extrapyramidal signs), according to a study.

The study, “Prevalence of fragile X‐associated tremor/ataxia syndrome: A survey of essential tremor patients with cerebellar signs or extrapyramidal signs,” was published recently in Brain and Behavior.

Like fragile X syndrome (FXS), FXTAS is a genetic disorder caused by the expansion of CGG repeats in the fragile X mental retardation 1 (FMR1) gene, which provides instructions for making a protein called fragile X mental retardation protein (FMRP).

Patients with fragile X normally have more than 200 CGG repeats within the FMR1 gene sequence (full mutation), while those with FXTAS normally have between 55 and 200 CGG repeats (premutation). FXTAS affects mostly older male patients and is often associated with motor and cognitive impairments.

Essential tremor (ET) is a neurological disorder that causes involuntary shaking. In some cases, patients also may experience cognitive impairments and extrapyramidal signs (EPS). EPS is commonly referred to as a drug-induced movement disorder, and is the most common side effect of dopamine-receptor blocking medicines in which patients become unable to control their body movements, resembling FXTAS.

“[P]atients with FXTAS have been assigned erroneous initial diagnoses of [essential tremor], before genetic analysis detected an FMR1 premutation. These examples suggest that FXTAS is sometimes so similar to [essential tremor] that it is difficult to distinguish the two entities on a clinical basis,” the investigators wrote.

Researchers at the Sungkyunkwan University School of Medicine, South Korea, examined the prevalence of FMR1 mutations among Asian patients with essential tremor who showed signs of cerebellar involvement, such as intention tremor or gait disorder, EPS, and additional characteristics of FXTAS.

Study participants were recruited from three tertiary care centers from 2014 to 2018. Demographic and clinical data, including the presence of cerebellar symptoms and EPS, were gathered from all participants.

Tremor, cerebellar signs, and EPS were all assessed by neurological examination and appropriate clinical rating scales. For essential tremor patients showing signs of cerebellar involvement or EPS, genetic screening and magnetic resonance imaging (MRI) were performed to look for premutations in FMR1 and to assess brain alterations, respectively.

The prospective study enrolled a total of 603 essential tremor patients. From the 603 study participants, 168 (27.9%) showed signs of cerebellar involvement or EPS. Genetic screening and neurological examination were performed in 74 patients from the sub-group of 168 individuals who showed signs of cerebellar involvement or EPS.

Neurological examination revealed that 52 patients showed signs of only cerebellar involvement, while three only had EPS and 19 had both neurological alterations. Genetic analyses performed in the same sub-group revealed that two (2.7%) individuals carried a FMR1 premutation, fulfilling both clinical and neurological criteria of FXTAS.

“In summary, the result of our study implies that FXTAS might comprise a significant portion of patients with [essential tremor] and additional cerebellar signs or EPS. One should suspect FXTAS and consider performing FMR1 mutation analysis for an [essential tremor] patient who also have cerebellar signs or EPS. This would help find new cases of FXTAS, especially in East Asia,” the researchers concluded.