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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October 24, 2024
FXTAS ( Fragile X Tremor Ataxia Syndrome)
- Background:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive degenerative movement disorder resulting from a fragile X “premutation,” defined as 55-200 CGG repeats in the 5’-untranslated region of the FMR1 gene 1. The premutation can expand in subsequent generations (during oogenesis) to a full mutation causing fragile X syndrome.
- Clinical Presentation:
- The classic presentation is a kinetic tremor and cerebellar ataxia occurring after age 50. Other clinical manifestations include cognitive decline, dementia, psychiatric disorders, peripheral neuropathy, and autonomic dysfunction. Affected women typically experience less severe disease.
- Key Diagnostic Features:
- The revised FXTAS diagnostic criteria include 2 major radiologic features:
- The best-recognized feature of FXTAS is the MCP sign (T2 hyperintensity in the middle cerebellar peduncles) in 60% of affected men and 13% of affected women.
- The second major radiologic feature is T2 hyperintensity in the splenium of the corpus callosum, which is found as frequently as the MCP sign and also occurs more commonly in men. FLAIR hyperintensities are seen within paravermal regions of the cerebellum.
- Other imaging features: T2 hyperintensities in the pons, insula, and periventricular white matter, diffuse cerebral and cerebellar atrophy, along with marked reduction of fractional anisotropy in the middle and superior cerebellar peduncles, cerebral peduncles, fornix, and stria terminalis.
- The revised FXTAS diagnostic criteria include 2 major radiologic features:
- Differential Diagnosis:
- Neuronal intranuclear hyaline inclusion disease (NIID) – closely mimics FXTAS clinically and radiologically. Skin biopsy (both FXTAS and NIID) can show eosinophilic intranuclear inclusions. A genetic test is needed to differentiate these two (as in our case).
- Delayed post-hypoxic leukoencephalopathy – mimics by involvement of diffuse confluent diffusion restriction of the subcortical white matter, sparing the U-fibers, cortex, and deep brain structures. Clinical history of prolonged cerebral hypo-oxygenation or CO helps to diagnose.
- ALERD/ASED – mimics by involvement characteristic “bright tree appearance,” which represents high-signal intensity on DWI in the widespread subcortical white matter, and has the appearance of tree branches. Typical clinical history of prolonged seizures and febrile illness will help in diagnosis.
- Heroin-induced leukoencephalopathy – typical clinical presentation is symmetric involvement of the posterior limb of the internal capsules, corticospinal tracts, perirolandic subcortical white matter, cerebellar white matter, and middle cerebellar peduncles (one of the causes of the so-called MCP sign). There is sparing of adjacent gray matter structures and subcortical U-fibers.
- Other conditions with MCP signs – MSA-C (clinical history and hot cross bun sign), CARASIL (clinical and pontine arc sign), and JC virus granule cell neuronopathy (absence of typical supratentorial imaging findings).
- Treatment and Prognosis:
- The rate of progression of FXTAS is variable and life expectancy ranges from 5 to 25 years following the onset of symptoms. The presence of the MCP sign in patients with FXTAS is correlated with more severe cognitive deficits and a long history of symptoms. Currently, there are no disease-modifying treatments for FXTAS. Drugs under trial include: memantine (NMDA blocker), allopregnanolone (allosteric modulator on GABAA receptor), citicoline, and new therapeutic approaches of curcumin and piperine drugs.
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