Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): A Gender Perspective

Abstract

Although larger trinucleotide expansions give rise to a neurodevelopmental disorder called fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a "premutation" (55-200 CGG repeats) in the FMR1 gene. FXTAS is one of the more common single-gene forms of late-onset ataxia and tremor that may have a more complex development in women, with atypical presentations. After a brief presentation of the atypical case of an Italian woman with FXTAS, who had several paroxysmal episodes suggestive of acute cerebellar and/or brainstem dysfunction, this article will revise the phenotype of FXTAS in women. Especially in females, FXTAS has a broad spectrum of symptoms, ranging from relatively severe diseases in mid-adulthood to mild cases beginning in later life. Female FXTAS and male FXTAS have a different symptomatic spectrum, and studies on the fragile X premutation should be conducted separately on women or men. Hopefully, a better understanding of the molecular processes involved in the polymorphic features of FXTAS will lead to more specific and effective therapies for this complex disorder.

Keywords: FXS; FXTAS; Fragile X; ataxia; episodic ataxias; paroxysmal movement disorders; trinucleotide repeat diseases.

Figure 1

MRI of a 75-year-old woman with FXTAS. This patient was repeatedly hospitalized because of rare spells characterized by vomiting, dysarthria, dizziness, acute quadriparesis with bilateral Babinski sign, and consciousness impairment (once including coma requiring intubation). These attacks began when the patient was 71 years and typically lasted for a few days, fully recovering in about one week. She was having about one episode per year. The patient’s coexisting conditions include hypertension and well-compensated ischemic heart disease. She does not suffer from migraines. One of her grandsons was diagnosed with psychomotor retardation due to FXS. Interictal neurological examination was normal except for mild axial ataxia and postural tremor. The Mini-Mental State Examination revealed mild cognitive impairment (scored 20.7/30). No epileptic spikes were observed on the electroencephalogram (EEG). Laboratory assays were irrelevant. Echocardiography, repeated Holter ECG registrations and cardiac loop recording were normal. Electroneurography was normal. Brain CT angiography and neurosonological examination were repeatedly normal. She met the diagnostic criteria for “definite” FXTAS. Genetic testing (based on polymerase chain reaction techniques) confirmed this diagnosis, showing a normal allele with 22 CGG repeats and a “premutated” allele with 91 trinucleotides in the FMR1 gene. (A–C) Axial fluid-attenuated inversion recovery (FLAIR) images showing increased signal in the middle cerebellar peduncles (“Middle Cerebellar Peduncle Sign”), cerebellar hemispheres, and vermis. Pontine pathology is evident in (C). (D,E) Axial FLAIR images reveal increased signals within the midbrain (D) and hemispheric cerebral white matter (E). (F,G) Coronal FLAIR images confirm periventricular, midbrain (F), and cerebellar (G) white matter disease. (H,I) Normal MRI spectroscopy of the cerebellum and vermis.