Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease found in carriers of the premutation (55–200 CGG repeats) at the 5′-end of the fragile X mental retardation 1 (FMR1) gene. It has been estimated that one-third of male pre-mutation carriers over 50 years [Jacquemont et al., 2004a] and approximately 8–16% of female carriers develop FXTAS [Coffey et al., 2008; Rodriguez-Revenga et al., 2009].

Diagnostic criteria describing FXTAS have been reported [Jacquemont et al., 2003; Hagerman and Hagerman, 2004]. The major clinical phenotype of FXTAS is intention tremor and gait ataxia, but parkinsonism, moderate-to-severe short-term memory deficiency, and executive function deficits are also commonly seen [Loesch et al., 2005a; Grigsby et al., 2006; Berry-Kravis et al., 2007]. There are also psychiatric aspects of FXTAS, including depression, anxiety, irritability, and apathy [Bacalman et al., 2006; Bourgeois et al., 2009, 2011]. MRI features of FXTAS include white matter lesions involving the subcortical and periventricular regions and the middle cerebellar peduncles (MCP) [Brunberg et al., 2002]. The presence of this MCP sign is observed in approximately 60% of affected males and 13% of affected females [Adams et al., 2007]. However, this sign is not specific for FXTAS, and not all patients with FXTAS develop the MCP sign. Cerebral, brainstem, and cerebellar volume loss compared to age-matched controls is observed [Loesch et al., 2005b; Cohen et al., 2006; Adams et al., 2007].

Neuropathological findings of FXTAS include intranuclear inclusions in neurons and astrocytes throughout the brain [Greco et al., 2006] and in the peripheral nervous system [Gokden et al., 2009]. The inclusions are likely caused by an RNA gain-of-function effect from elevated FMR1-mRNA in the premutation [Hagerman and Hagerman, 2004]. The excess mRNA appears to sequester additional proteins, including an RNA-binding protein involved in splicing regulation, Sam 68. Dysfunction of Sam 68 leads to mis-splicing of mRNAs, including that of the SMN gene that is mutated in spinal muscular atrophy [Sellier et al., 2010].

Autonomic dysfunction has been widely noted in patients with FXTAS. Erectile dysfunction typically begins before the onset of tremor and ataxia while other autonomic dysfunction, such as bladder and bowel incontinence, occur late in the course of FXTAS [Greco et al., 2007]. Hypertension has been reported in over 60% of females with FXTAS, a significant increase compared to age-matched controls [Coffey et al., 2008]. Preliminary data suggest that this problem is not uncommon in males with FXTAS [Hagerman and Hagerman, 2004; Jacquemont et al., 2004b]. Here, we explore hypertension in males with the premutation, with and without FXTAS, compared with age-matched controls.

Clinical data including hypertension, blood pressure, and age of onset of hypertension was gathered during a medical appointment or interview. For most patients, a self-reported diagnosis of hypertension by another physician was sufficient to consider them having hypertension. Alternatively, at the MIND Institute, any patient with a blood pressure measurement over 140/90 taken during the appointment was also considered hypertensive. Lastly, any patient on blood pressure medication was categorized to have hypertension diagnosed by the prescribing physician, even if a normal blood pressure measurement was reported during the examination.

All blood pressure values for this study are those directly measured during examinations rather than being self-reported by the patient. For patients with multiple visits to the MIND and thus with multiple blood pressure measurements, the latest observation was used in order to have a single data entry for each patient.

Age of onset of hypertension was also recorded or self-reported during the medical examination and was typically the age when the patient began to take antihypertensive medication.

Hypertension and related autonomic dysfunction have been discussed as symptoms of FXTAS in previous publications [Jacquemont et al., 2003, 2004b; Coffey et al., 2008]; however, extensive controlled studies in males have not been performed. Coffey et al. [2008] reported hypertension as significantly more common in female carriers with FXTAS compared to controls, but not so in premutation carriers without FXTAS. Based on the data collected in this study, a similar result was found in males. There is a significantly higher age-adjusted risk (odds) of hypertension associated with FXTAS compared to controls among male subjects over age 40 years. However, the odds of hypertension in premutation carriers without FXTAS were not different from controls. It should be noted that in this study and in Coffey et al. [2008], medical data were collected via self-report, along with documentation of medication to treat hypertension. Potential bias resulting from this data collection method is limited by the similarity of the collection methods used for patients and age-matched controls.

The cause of hypertension is likely related to the autonomic dysfunction seen in FXTAS [Jacquemont et al., 2003; Leehey, 2009]. These problems may be related to the inclusion involvement of the peripheral nervous system, including both sympathetic and parasympathetic ganglia and pericardial ganglia [Gokden et al., 2009]. However, centers in the brain coordinating autonomic responses, including the insula, thalamus, and hypothalamus, are also affected by white matter disease [Greco et al., 2006, 2008; Hashimoto et al., 2011].

In addition, individuals with the premutation with and without FXTAS often have depression, anxiety, and other psychiatric problems [Hessl et al., 2005; Bourgeois et al., 2009, 2011; Leehey, 2009], which may also be related to elevated blood pressure. Although the precise correlation between hypertension and depression has yet to be established, they often occur together [Scalco et al., 2005]. Depressive symptoms, anxiety, and stress are associated with elevated corticosteroid levels. Premutation mice have an elevated corticosteroid response to stress when they age, and it is likely that this also occurs in humans with the premutation [Brouwer et al., 2008].

Untreated hypertension can result in cardiovascular complications, dementia, and an increased risk of stroke [Perry et al., 2000; Chobanian et al., 2003; Nagai et al., 2010]. More controversially, chronic hypertension may result in an increased incidence of white matter disease [Sierra and Coca, 2006; Gottesman et al., 2010]. Treatment of hypertension and subsequent reduction of blood pressure can slow the progression of white matter disease, and thus in turn reduce the risk of stroke and increasing dementia [Godin et al., 2011]. These benefits may also be seen in those with FXTAS who are treated for their hypertension and thus deserves further study.

There are a number of interventions that can treat hypertension in FXTAS carriers. Attention to the psychiatric problems and daily stresses should be discussed. Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which can also stimulate neurogenesis, can be utilized to treat depression or anxiety in addition to psychotherapy [Hagerman et al., 2008; Bourgeois et al., 2009]. Behavioral treatment of hypertension includes weight loss, salt restriction, exercise, and a healthy diet with reduced cholesterol and fat intake. When lifestyle adjustments are not enough to lower blood pressure, medical and pharmacological treatments are used [Chobanian et al., 2003].

There is currently no cure for FXTAS. However, treatment options for cognitive decline, tremor, gait ataxia, and other FXTAS symptoms have been reported [Hagerman et al., 2008; Berry-Kravis et al., 2010]. Elevated hypertension risk has been established in female premutation carriers with FXTAS [Coffey et al., 2008]. This study supports the same outcome for males. Therefore, all pre-mutation carriers with FXTAS should be screened for hypertension and treated as needed.