Case of the Week
Section Editors: Matylda Machnowska1 and Anvita Pauranik2
1University of Toronto, Toronto, Ontario, Canada
2BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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September 29, 2022
Fragile X–Associated Tremor/Ataxia Syndrome (FXTAS)
- Background:
- FXTAS is a rare, adult-onset neurodegenerative disorder affecting premutation carriers of the fragile X mental retardation (FMR1) gene.
- Fragile X syndrome occurs in patients with “full mutations” of the FMR1 gene, defined as having >200 CGG repeats in the 5’ untranslated region, and presents with cognitive impairment and autistic features in children.
- Premutation carriers, having 55–200 CGG repeats, do not have symptomatic disease in childhood, but have increasing rates of penetrance later in adulthood, particularly in male patients.
- Clinical Presentation:
- Patients with more CGG repeats tend to present at a younger age and with more rapidly progressive symptoms.
- A usual presentation is a male patient in his fifties or sixties with unexplained tremor and gait disturbance, which can be mistaken for Parkinson disease, essential tremor, or multiple system atrophy.
- Additional features include cognitive decline, psychiatric impairment, and autonomic dysregulation, which are more common in advanced disease.
- When affected, female patients usually have less severe disease.
- Key Diagnostic Features:
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Typical MRI findings include symmetric, T2-hyperintense lesions in the middle cerebellar peduncles (MCPs)—the so-called “MCP sign”—and in the splenium of the corpus callosum.
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Less specific imaging findings include generalized cerebral and cerebellar volume loss and T2/FLAIR-hyperintense cerebral white matter lesions.
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- Differential Diagnoses:
- Multiple system atrophy type C (MSA-C): T2/FLAIR signal hyperintensity may be seen in the MCPs, though disproportionate volume loss involving the pons, MCPs, and cerebellum is usually the more striking finding. The “hot cross bun” sign may be seen in the pons.
- Spinocerebellar ataxia (SCA): Imaging findings may be identical to those of MSA-C, particularly in SCA2 and SCA6.
- Adrenoleukodystrophy (ALD): T2/FLAIR signal hyperintensity may be seen in the MCPs and is typically also seen in the pyramidal tracts and in the cerebellar and posterior cerebral white matter.
- Wilson disease: Characteristic findings include symmetric T2/FLAIR signal hyperintensity in the putamina, thalami, midbrain, and pons, though involvement of the superior and middle cerebellar peduncles can be seen.
- Bilateral anterior inferior cerebellar artery (AICA) territory ischemic infarctions: AICA territory infarcts may involve the MCPs but would be expected to have an acute rather than gradual clinical presentation.
- Posterior reversible encephalopathy syndrome (PRES): Although PRES more typically involves the posterior cerebral white matter, involvement of the brainstem, MCPs, and cerebellum may be seen.
- Intoxication: In particular, toluene abuse and heroin inhalation may result in symmetric white matter lesions with involvement of the MCPs.
- Treatment:
- There is no cure for FXTAS, though symptom-targeted treatments may improve quality of life.
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