Fragile X-associated tremor/ataxia syndrome

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.

Epidemiology

The FMR1 premutation occurs in approximately 1/800 males and 1/250 females ¹. Penetrance of FXTAS is age-dependent, affecting 40-45% of male and 8-16% of female premutation carriers (PMC) over the age of 50 years².

Typically, therefore, the affected individual will be an elderly male. If they have had a daughter, then his grandchild may have a known diagnosis of fragile X, as during oogenesis the mutation will have undergone mutation, allowing for the full phenotype of fragile X to be expressed ⁷. 

Clinical presentation

The classical presentation is a kinetic tremor and cerebellar ataxia occurring over the age of 50 ¹. Other clinical manifestations include cognitive decline, dementia, psychiatric disorders, peripheral neuropathy and autonomic dysfunction ². Affected females typically experience less severe disease.

Pathology

The pathogenesis of FXTAS is not yet fully understood ². Neuronal toxicity in FXTAS is thought to result from the formation of pathognomonic eosinophilic and ubiquitin-positive intranuclear inclusions in neurons and astrocytes in the cerebrum, thalamus, basal ganglia and inferior olivary, dentate and hypoglossal nuclei, as well as in the spinal cord and autonomic ganglia.

Neurodegeneration in the cerebellum is characterized by marked Purkinje cell loss, gliosis and axonal swelling. Furthermore, elevated FMR1 mRNA levels seen in premutation carriers have been implicated by way of a neurotoxic gain of function effect. 

The adrenals, thyroid, Leydig cells, pancreas, gastrointestinal tract, kidneys and heart are also involved. 

FXTAS diagnostic criteria

Diagnostic criteria have been developed that rely on clinical and radiological features ³. The combination allows patients to be grouped into one of three diagnostic certainty categories:

• definite: one major clinical and one major radiological; or one major clinical and intranuclear inclusions  

• probable: two major clinical; or one minor clinical and one major radiological

• possible: one major clinical and one minor radiological

Clinical features

• major

  • intention tremor

  • gait ataxia

• minor

  • parkinsonism

  • moderate to severe short-term memory deficiency

  • executive function deficit

  • neuropathy

Radiological features

• major

  • MRI white matter lesions in middle cerebellar peduncle

  • MRI white matter lesions in splenium of the corpus callosum

• minor

  • MRI white matter lesions in cerebrum

  • moderate to severe generalized atrophy

Radiographic features

MRI

The revised FXTAS diagnostic criteria include two major radiological features ³.

The best-recognized feature of FXTAS is the MCP sign, which refers to T2 hyperintensity in the middle cerebellar peduncles, and is present in 60% of affected males and 13% of affected females ⁴. The second major radiological 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 males ².

Other imaging features:

• white matter T2 hyperintensities in the pons, insula and periventricular region ²

• T2 hyperintensity in the afferent projections of the middle and superior cerebellar peduncles has been reported in asymptomatic premutation carriers and may be the earliest neuroanatomical marker heralding the onset of FXTAS ³

• generalized brain and cerebellar atrophy

  • can also occur in asymptomatic premutation carriers

  • brainstem volume has been found to be significantly smaller in asymptomatic premutation carriers than in healthy controls ⁴

• diffusion tensor imaging (DTI)

  • marked reduction of fractional anisotropy in the middle and superior cerebellar peduncles, cerebral peduncles, fornix and stria terminalis in male premutation carriers with FXTAS

  • axial and radial diffusivity values in the middle cerebellar peduncle and cerebral peduncle have been shown to be increased in asymptomatic premutation carriers, without alteration in fractional anisotropy ⁵

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 ². The presence of the MCP sign in patients with FXTAS is correlated with more severe cognitive deficits and a long history of symptoms ². Currently, there are no disease-modifying treatments for FXTAS.

Differential diagnosis

For the MCP sign consider ⁶:

• multiple system atrophy of cerebellar type (MSA-C)

• recessive ataxia

• acquired hepatocerebral degeneration

For T2 hyperintensity in the splenium of the corpus callosum consider:

• stroke