Abstract (250 words)
Introduction
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare, X-linked adult-onset neurodegenerative disorder affecting carriers of the fragile X mental retardation 1 (FMR1) gene premutation, a 55–200 cytosine, guanine and guanine [CGG] repeat expansion in the 5ʹ untranslated region of the gene. FXTAS differs from the fragile X syndrome as the second is associated with more than 200 CGG repeats of the same gene. FXTAS was initially described in men, typically over the age of 55, and was also recognized in women with premature ovarian failure. Diagnostic criteria for FXTAS were proposed in 2003. While intention tremor and ataxia are deemed to be the core features of the syndrome, executive dysfunction, short-term memory deficiency, peripheral neuropathy and autonomic symptoms are also included in the diagnostic clinical criteria. Parkinsonism has been described in FXTAS, but the characteristic resting tremor, cogwheel rigidity, and postural instability seen in idiopathic Parkinson disease (PD) are generally absent. The major radiological diagnostic criterion of FXTAS is symmetrical T2 FLAIR hyperintensity in the middle cerebellar peduncles (MCP sign). MRI findings also involve cerebral and cerebellar cortical volume loss and periventricular, subcortical global white matter disease in the brainstem and cerebellum. Hyperintensities in the splenium of the corpus callosum have recently been proposed as an additional radiographic diagnostic criterion for FXTAS. The pathophysiological mechanism by which premutation leads to disease remains uncertain but it has been suggested that raised FMR1 mRNA levels may exert a neurotoxic “gain of function” effect, a common mechanism taking place in other repeat expansion diseases like spinocerebellar ataxia (SCA) -8, -10 and -12. Concerning the neuropathological findings in FXTAS, white matter changes, enlarged inclusion-bearing astrocytes in the white matter and intranuclear inclusions in neurons and astrocytes throughout the central nervous system are typically present in affected individuals. Furthermore, there is strong evidence indicating that the number of CGG repeats is a predictor of disease severity in this entity.
Case report
A 68-year-old man, initially diagnosed with Parkinson’s disease, was referred to evaluation for deep brain stimulation surgery. The patient described a 10-year history of progressive resting and action tremor on his hands, cephalic tremor and postural instability accounting for occasional falls. Levodopa was initiated with reasonable symptomatic improvement. Treatment for a depressive syndrome was reported in his medical history. Family history was negative for neurological disorders or mental retardation. Examination revealed asymmetric rigidity and bradykinesia with right-side predominance, postural instability, difficulty on arising from chair, gait impairment without freezing, diminished arm swing on right side and a variable resting tremor on his left upper extremity. Gait ataxia was not noted. Neuropsychological examination revealed attention, processing speed, memory and mild executive dysfunction. MRI scan requested in 2006 revealed symmetrical T2 hyperintensity in the middle cerebellar peduncles along with supratentorial gliotic foci (figure 1), raising the suspicion of a probable diagnosis of FXTAS. Genetic analysis confirmed FMR1 premutation with 90 CGG expansion and the diagnosis of FXTAS was established.
Discussion
FXTAS is a late-onset neurological disorder firstly discovered in 2001, which remains underdiagnosed, possibly mistaken for SCAs, essential tremor and atypical forms of parkinsonism. Significant geographical variation exists in relation to the prevalence of the premutation in FMR1 gene, with estimates of up to 1 in 251 males and 1 in 100 males. Despite a diagnosis of FXTAS will not lead to any specific treatment in the present, it may prevent further unnecessary investigations and treatments, as would occur in our patient if he was offered deep brain stimulation surgery. Furthermore, genetic counselling of the family is necessary. As stated above, the premutation in FMR1 gene is not classically associated with a pure PD phenotype nonetheless some carriers manifest features characteristic of idiopathic PD including improvement with dopaminergic medications and dyskinesias. Additionally, CGG triplet repeat number was found to be correlated to UPDRS-III scores and presynaptic and postsynaptic denervation based on 123I-Ioflupane SPECT imaging was reported in FXTAS patients. Hence, although data does not support screening PD patients for FMR1 expansions, genetic testing in individuals with PD and a family history of developmental delay, autism, premature ovarian failure, FXTAS, fragile X syndrome or other FMR1 related disease is warranted. All daughters of premutation carriers males will be carriers themselves and thus are at high risk to have children with fragile X syndrome. Furthermore, 44% of FXTAS patients had no family history of FXS in one series and therefore FXTAS should be considered even in the absence of a family history of mental retardation. In 2002, Brunberg and colleagues firstly documented hyperintensity of the MCP detected by T2 FLAIR MRI as a distinctive feature in those with FXTAS and thus it was nominated as a major criterion for diagnosis of definite FXTAS. MCP sign is present in approximately 60% of men patients with FXTAS and it is a highly specific sign (albeit not unique) that should raise suspicion for this diagnosis. Additionally, those patients with FXTAS and the MCP sign were subsequently found to have more severe cognitive deficits and a longer history of symptoms.
Patients with FXTAS present with disabling symptoms which lessen patient’s quality of life, however targeted treatments for FXTAS have not been established and symptomatic control with medication has only limited effects. A few case reports documented the improvement of tremor after deep brain stimulation (DBS) but worsening of ataxia after surgery was reported in earlier studies. Due to these equivocal results, DBS of selected targets may represent an effective therapeutic strategy for uncommon tremor disorders, although the level of evidence is incipient and further studies are required to clarify the extent of benefit achievable with DBS in FXTAS patients.
We present the case of a man in his sixties with a history of tremor and parkinsonism. Clinicians who usually see these patients need to be aware of FXTAS as an alternative diagnosis. White matter abnormalities in the MCP on MRI should trigger genetic testing and future genetic counselling when appropriate.