Tremor

INDEX

ORIGIN

X-linked inherited condition associated with the FRM1 gene premutation (55–200 CGG repeat expansion).

CLASSIFICATION

Three categories, termed as “definite,” “probable,” and “possible,” are used in the diagnosis of FXTAS.

CLINICAL FEATURES

Typically in males with onset in the sixth decade and includes additional cognitive deficits (executive and memory dysfunction as well as global cognitive deficits), variable degrees of peripheral neuropathy, and occasionally mild parkinsonism. Cognitive problems are not always present during the development of tremor and can occur later in the disease. 

Intention tremor: There is an irregular low-amplitude tremor at rest, posture, and action. Intention tremor is common and is the presenting feature in as many as 70% of cases. The tremor is usually the first sign, with ataxia following 5–7 years later.  However, up to 20% of patients with FXTAS have no clinically observable tremor.

The tremor is heterogeneous but three tremor subtypes have been described: cerebellar intention tremor (3–5 Hz), ET-like, and Parkinsonian tremor. A pure resting tremor is uncommon.

A large proportion of FXTAS patients have neuropathy, which is a length-dependent axonal sensorimotor polyneuropathy.

AGE OF ONSET

Middle age; about 40% of male carriers over the age of 50 develop FXTAS. The penetrance is age related and up to 100% by the age of 80 years.

Approximately 8% of female carriers develop FXTAS.

DIAGNOSIS

Diagnostic Criteria

From: Zafarullah M, Tassone F. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). In: Ben-Yosef D, Mayshar Y, eds. Methods in Molecular Biology. New York, NY: Humana Press, 2019: 173–89.

Probable clinical diagnosis can be made if the patient has an intention tremor and cerebellar ataxia; there are typical findings on MRI and diagnosis is made by genetic testing.

DIFFERENTIAL DIAGNOSIS

DIAGNOSTIC TESTS

MRI brain:  Increased T2/FLAIR signal hyperintensities are present in both the middle cerebral peduncle (MCP sign) and the splenium of the corpus callosum in 2/3 of patients.

DAT may confirm a nigrostriatal deficit in those patients with a parkinsonian tremor.

Case courtesy of Prof FGaillard, Radiopaedia.org. From the case rID: 44196

TREATMENT

Treatment: Tremor associated with FXTAS has been treated with beta blockers, primidone and topiramate.

Tremor has been reported to improve with unilateral VIM gamma knife thalamotomy, and with Vim DBS.

Ataxia does not appear to respond to surgical intervention.

REFERENCES

1            Zafarullah M, Tassone F. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). In: Ben-Yosef D, Mayshar Y, eds. Methods in Molecular Biology. New York, NY: Humana Press, 2019: 173–89.