Cia_1794_hagerman.indd

Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems Abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological
disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a signifi cant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the effi cacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.
Keywords: fragile X syndrome, dementia, ataxia, neurodegeneration, parkinsonism, tremor
Introduction
Fragile X-associated tremor/ataxia syndrome (FXTAS) is seen in a subgroup of older adults who are carriers of premutation alleles (55–200 cytosine, guanine and guanine [CGG] repeats) of the fragile X mental retardation 1 (FMR1) gene (Hagerman et al 2001; Berry-Kravis et al 2007; Jacquemont et al 2007; Leehey et al 2007). The patho- genesis of FXTAS results from the direct neural cell toxicity of elevated levels of the Pediatrics, 4Department of Psychiatry & Behavioral Sciences, 5Department of expanded-CGG-repeat FMR1 mRNA (RNA toxic gain-of-function), which leads in turn to dysregulation of a number of proteins including lamin A/C and alpha B crystal- 10Department of Pathology and Laboratory Medicine, 14Department of Biochemistry lin (Arocena et al 2005). Characteristic neuropathological fi ndings of FXTAS include formation of inclusions in neurons and astrocytes throughout the brain; spongioform California, Davis, School of Medicine, Sacramento, CA, USA; 3Department of white matter changes in subcortical, periventricular and brainstem regions, including Neurology, University of Colorado, Denver, the middle cerebellar peduncles (MCP sign); and global brain atrophy (Greco et al CO, USA; 7Department of Pediatrics, Neurology, and Biochemistry, 8Department 2002; Jacquemont et al 2003; Cohen et al 2006; Greco et al 2006). The natural history of FXTAS begins with the onset (average age, 60 yr) of a movement disorder involv- of Biochemistry, Rush University Medical Center, Chicago, IL, USA; 11Physical Edge, ing intention tremor and/or gait ataxia with tremor often preceding the ataxia by one Inc., Davis, CA, USA; 12Seaside Therapeutics, to several years (Leehey et al 2007). Decline in mobility generally progresses through Cambridge, MA, USA; 13Department of Physical Medicine and Rehabilitation, the use of a cane, walker, and wheelchair, with eventual inability to ambulate (Leehey et al 2007). FXTAS also includes neuropathy in the majority of patients, often involv- ing pain, particularly in the lower extremities (Jacquemont et al 2004; Berry-Kravis Correspondence: Randi J HagermanUC Davis M I N D Institute, 2825 50th Additional features include autonomic dysfunction involving impotence, hyperten- sion, orthostatic hypotension, urinary frequency, and urinary and bowel incontinence (in the later stages). Psychiatric problems commonly seen in patients with FXTAS include anxiety, agitation, apathy, and depression (Bacalman et al 2006). However, Clinical Interventions in Aging 0000:0(0) 1–12 0000 Hagerman et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
a subgroup of premutation carriers may have psychiatric severity of brain atrophy, and white matter disease (Loesch problems even in childhood or adolescence, with features that et al 2005; Cohen et al 2006), the density of inclusions and can include ADHD, obsessive/compulsive thinking, anxiety the age of death (Greco, Berman et al 2006), all correlate disorders, or social diffi culties (Cornish et al 2005; Farzin et al 2006; Hessl et al 2006). Cognitive changes in patients The diagnosis of FXTAS is made clinically utilizing with FXTAS include executive function defi cits and memory criteria set forth in Jacquemont and colleagues (2003) problems, which may be present at the time the individual which can be seen in Table 1. Defi nite FXTAS requires is diagnosed with tremor and/or ataxia (Grigsby et al 2006, the presence of the major radiological sign, white matter 2007). The cognitive changes progress at a variable rate disease in the MCP, in addition to tremor and/or ataxia in a and dementia develops in at least 50% of cases (Bourgeois premutation carrier. On autopsy, the presence of eosinophilic (ubiquitin-positive; tau-, synuclein-negative) inclusions in Premutation alleles of the FMR1 gene are relatively the nuclei of neurons and astrocytes is also characteristic of common in the general population, carried by ~1 in 130–250 defi nite FXTAS, and has been added to the diagnostic criteria females and ~1 in 500–800 males (Rousseau et al 1995; Pesso (Hagerman and Hagerman 2004). However, the MCP sign is et al 2000; Dombrowski et al 2002; Beckett et al submitted). only seen in 60% of males with FXTAS (Cohen et al 2006), FXTAS occurs in older carriers (Ͼ50 years), is more common and in approximately 13% of females with FXTAS (Adams in males, and has age-dependent penetrance: 17% in their et al 2007). Individuals with the premutation with tremor 50s, 38% in their 60s, 47% in their 70s, and 75% in their 80s and ataxia but without the MCP sign (including those who (Jacquemont et al 2004). These numbers lead to an estimated have not had an MRI or cannot have an MRI) are described prevalence of FXTAS as approximately 1 in 8,000 males as probable FXTAS. Those with fewer symptoms, such as over 50 years in the general population (Jacquemont et al tremor or ataxia only, are described as possible FXTAS 2004, 2007). A recent study in female carriers suggests that 4% overall and 8% over 50 years of age develop FXTAS, but it has a milder course than in males, perhaps related to a protective effect of the second (normal) X chromosome in Table 1 Clinical diagnostic criteria for FXTAS (Adapted from
females (Jacquemont et al 2004; Coffey et al in press).
Recent studies have broadened our concept of FXTAS Molecular
CGG repeat 55–200
to include hormonal dysfunction. Inclusions have been Clinical
documented in the anterior and posterior pituitary (Louis et al 2006; Greco et al 2007), and in the Leydig cells in the testicles, which produce testosterone. In one study, testoster- one defi ciency was reported in 5 of 8 carriers that were tested, Moderate to severe short term memory defi ciency with such reductions presumably related to the pituitary and Leydig cell involvement (Greco et al 2007). Additional Radiological
hormonal problems including hypothyroidism are seen in MRI white matter lesions involving middle approximately 50% of women with FXTAS (Coffey et al in press). Fibromyalgia is seen in 40% of women with FXTAS, MRI white matter lesions involving cerebral although the pain associated with that patient description may be diffi cult to distinguish from painful neuropathy (Coffey Moderate to severe generalized brain atrophy Diagnostic categories
It has been known since 1991 that approximately 20% Defi nite
Probable
Possible
of women with the premutation have premature ovarian failure (Cronister et al 1991), with the frequency of this fi nding more recently shown to correlate with the size of the CGG expansion in the premutation range (Sullivan et al 2005). Features of FXTAS, including age of onset of tremor and ataxia (Tassone et al 2007), severity of both tremor Abbreviations: FXTAS, fragile X-associated tremor ataxia syndrome; CGG, cytosine,
and ataxia, overall motor impairment (Leehey et al 2007), guanine and guanine; MRI, magnetic resonance imaging.
Clinical Interventions in Aging 0000:0(0) There is currently no targeted therapeutic intervention that metabolite phenobarbitol (Sasso et al 1991). It is started at can arrest or reverse the pathogenesis of FXTAS; however, low doses (eg, 25 mg/day or less), to minimize side effects there are a number of treatment approaches of potential such as nausea, vomiting, sedation, worsening of motor coor- symptomatic benefi t, and these are reviewed here. Moreover, dination, and confusion. If propanolol and primidone are not there are neuroprotective agents that may slow the course benefi cial, second line treatment includes topiramate, an anti- of FXTAS. We emphasize that no randomized, controlled convulsant with tremor effi cacy in placebo-controlled trials. clinical trials have yet been carried out specifi cally in indi- Sotalol, atenolol (other beta-blockers that may have less side viduals with FXTAS for any therapeutic agent or procedure, effects than propanolol), and alprazolam, a benzodiazepine given its relatively recent discovery. Therefore, the current that is also reported to be effective in some patients, may also review must be considered as a summary of experiential be considered (Gunal et al 2000). Because tremor is exacer- reports by patients with FXTAS and their medical provid- bated by anxiety or stress in most disorders, benzodiazepines ers, or as summaries of the effi cacies of agents/procedures may help to reduce anxiety and reduce tremor secondarily. that have proven to be effective in other disorders that have If these treatments fail, other medications that may be help- signifi cant symptom overlap with FXTAS (Jacquemont et al ful and have shown some effectiveness in open-label trials 2004; Bourgeois et al 2006; Hall et al 2006). Clearly, what is include botulinum toxin, levetiracetam (Bushara et al 2005), necessary at this point is to establish controlled clinical trials clonazepam, clozapine, nadolol, and nimodipine (Zesiewicz for these interventions in patient populations with FXTAS.
et al 2005). In a single open-label study levetiracetam was found to be helpful for cerebellar tremor (Striano et al 2006). Treatment of tremor
The latter is relevant for FXTAS because cerebellar dysfunc- Fifty-six patients with FXTAS completed a questionnaire to tion is a prominent fi nding in many affected persons.
determine if any medications had been effective for neuro- In Hall and colleagues (2006), rest tremor was not evalu- logical symptoms (Hall et al 2006). This was followed by a ated exclusively, but FXTAS patients with parkinsonism record review of treatment of their neurological symptoms. (rest tremor, slowness, or stiffness) improved on carbidopa/ Although 70% of patients with defi nite FXTAS were on levodopa in 4/10 subjects, pramipexole in 3/6 subjects, and medications for their neurological symptoms, only 30% of in one patient on eldepryl (Hall et al 2006). Although par- patients with possible or probable FXTAS were taking medi- kinsonism is considered a minor criteria for FXTAS, some cations for motor signs (tremor, ataxia, or parkinsonism). Of patients are dopamine responsive making them similar to the subjects receiving therapy for action tremor; 3/6 reported patients with idiopathic Parkinson disease. It is unknown mild to moderate improvement on primidone, 3/8 had whether motor fl uctuations, dyskinesia, or other side effects moderate improvement of tremor on beta-blockers, 2/8 had of these medications occur in patients with FXTAS, but moderate improvement on benzodiazepines. One subject dopaminergic therapy should be considered if parkinsonism had improved tremor on memantine, which was prescribed is problematic in a patient with FXTAS.
for cognitive decline. There was no improvement in tremor Botulinum toxin injections
Beta-blockers and primidone are commonly used to treat Botulinum toxin (BTX) is most commonly used in treating essential tremor (ET) and may be the most likely candidates conditions that involve involuntary muscle activities, such for initiating therapy in FXTAS. Because controlled studies as dystonia and spasticity. Its indications, though not all yet have not been carried out in FXTAS, we discuss data from the approved, have expanded during recent years, to include its ET treatment literature. Propranolol, a β-adrenergic blocker, use in the management of oversecretion of sweat glands, is the most effective medication for the treatment of ET and hypersalivation, and tremors (Cordivari et al 2004). On may help enhanced physiologic tremors as well (Caccia et al a trial basis, we applied BTX in one of our patients with 1989; Calzetti et al 1990); however, these medications are FXTAS with a disabling arm tremor. Under the guidance of contraindicated in patients with asthma, second-degree AV electromyography (EMG), 10–15 units of Botox (the type A block, and insulin dependent diabetes. Fatigability, impo- of BTX, BTX A) were injected into fl exor digitorum super- tence, lightheadedness, sedation and depressive symptoms fi cialis, fl exor digitorum profundus, and extensor digitorum. are common side effects. Primidone has also been shown The exact dosage of BTX injected was determined based to be effective in placebo controlled studies in ET (Koller on the real-time activities shown on EMG, which provides and Royse 1986), with its anti-tremor effect attributed to its anatomical guidance for injections. The injection protocol Clinical Interventions in Aging 0000:0(0) was repeated every three months on average. The patient tried with varying degrees of success. One is to reduce the experienced signifi cant functional improvement following physical tremor by mechanical means, such as adding mass the injections, with reduced tremor during action and at rest and/or some form of damping to the mouse. Although this one week later. The maximal effect of BTX was experienced can be helpful for some people, such a mouse can be physi- at 4–6 weeks post injections, and benefi t lasted up to three cally tiring to use. Furthermore, it is diffi cult to adjust the mass and damping to a particular individual’s needs, which Placebo controlled trials of BTX in essential tremor have may vary over time and circumstance. A second approach shown that in some cases there is signifi cant reduction of is to use a different type of pointing device, such as a track- tremor amplitude, but only mild functional improvement ball, job stick, or keyboard keys. This helps some people, associated with problematic limb weakness (Jankovic et al but not others. For example, using a trackball requires good 1996; Brin et al 2001; Cordivari et al 2004). Faced with the fi nger dexterity, while certain types of joysticks can actu- challenge of medical management of the disabling tremor in ally increase the tremor. A third approach, which was taken patients with FXTAS, further study in this disorder, including in a study completed at the University of Colorado Health Sciences Center, is to accept the mouse motion and apply a digital smoothing algorithm to reduce its effects. Researchers Deep brain stimulation
at the IBM Watson Research Center created the Assistive Only three persons with FXTAS that underwent bilateral Mouse Adapter (www.montrosesecan.com) algorithm which thalamic deep brain stimulation for tremor have been reported has demonstrated a positive difference in cursor movement, (Leehey et al 2003; Peters et al 2006). In one, a transient button clicking, and speed of use in patients with tremor microthalamotomy effect improved tremor greatly but speech although none had FXTAS (Bodine et al 2007).
was softer and gait ataxia worsened markedly (Leehey et al 2003). Tremor reoccurred in four months, and stimulation Treatment of ataxia
then was not benefi cial due to an open circuit on one side and Gait difficulties may be caused by cerebellar ataxia or suboptimal electrode placement on the other. The electrodes parkinsonism in FXTAS and can be exacerbated by were not corrected because of concern that further surgery peripheral neuropathy. In those with parkinsonism and may worsen speech and ataxia. There was no long-lasting gait abnormalities, subjective improvement was seen on cognitive dysfunction from the surgery. The two other people carbidopa/levodopa, dopamine agonists, and eldepryl as were cousins (Peters et al 2006). No informative clinical data mentioned above (Hall et al 2006). Ataxia improved in one were available on one; the other had a marked reduction in patient on amantadine in the Hall and colleagues (2006) tremor while gait ataxia persisted postoperatively. This latter report and in two patients reported by Jacquemont and patient had mild executive dysfunction prior to surgery and colleagues (2004). There is no universally effective treat- there was no mention about any changes in his mentation ment for cerebellar ataxia, but a small proportion of sub- jects on amantadine or buspirone will show improvement. Given these reports suggesting gait ataxia may worsen Unfortunately, these medications may be poorly tolerated in after surgery, the usefulness of this procedure in FXTAS may ataxia patients (Hassin-Baer et al 2000).
be limited. Moreover, persons with preexisting cognitive dys- In addition to pharmacological treatment, physical function tend to dement after bilateral deep brain stimulation therapy can be helpful for improving strength and gait in (Aybek and Vingerhoets 2007), and persons with FXTAS treatment of patients with ataxia and parkinsonism, particu- frequently have signifi cant cognitive dysfunction, further larly as these patients continue to age (Ellis et al 2005; Cao dampening enthusiasm for using this procedure in this popu- et al 2007). Patients with cerebellar ataxia tend to exhibit lation. However, persons with little or no ataxia or cognitive gait abnormalities including slower walking velocity with defi cits, but with disabling medically resistant tremor may still reduced step length and high variability in step timing and be candidates, at least for unilateral surgery, which is less likely amplitude (Ebersbach et al 1999). Researchers have found to worsen ataxia and cognition than bilateral surgery.
that the variability in gait speed is more attributable to bal- ance-related defi cits than intra-limb coordination of leg Computer modifi cations
placement during walking (Morton and Bastian 2003; Ilg Several approaches to the problem of the use of the com- et al 2007). Traditionally, patients with Parkinsonism have puter mouse by individuals with essential tremor have been responded well to step and gait training in physical therapy. Clinical Interventions in Aging 0000:0(0) Lasting improvements in overground walking speed, stride brain atrophy with dilatation of the ventricles, which may length, cadence, and fall reduction have been seen with physi- be mistaken for normal pressure hydrocephalus (NPH). cal therapy and particularly with body-weight-supported However, surgery for presumed NPH has been disastrous in treadmill training (Miyai et al 2002; Pohl et al 2003; Protas cases of FXTAS (Jacquemont et al 2004). Typically patients et al 2005). In our experience these approaches have been with FXTAS do not tolerate surgery with general anesthesia helpful for individuals with FXTAS, but no studies of effi cacy well and further deterioration in both motor and cognitive abilities is typically seen (Jacquemont et al 2004). There- fore, surgery should be avoided if at all possible. Support Treatment of cognitive defi cits
for family caretakers during the dementia process is crucial, and dementia
and the decision to place a patient with FXTAS in a center The treatment of cognitive impairment in FXTAS is based on that delivers specialty care for dementia patients is often off-label application of dementia treatments conventionally eventually necessary in late-stage disease.
used in Alzheimer’s disease (Farlow and Cummings 2007). Nutrition and exercise studies
Cautious dosing of donepezil and other cholinesterase inhibi- tors can be considered for the memory impairment; in the in related conditions
early weeks and months of treatment memory function may Many studies have investigated the possible role of diet and be enhanced. Even if the eventual course of memory and exercise in Alzheimer’s disease (AD), dementia, and related other cognitive decline is not substantially altered, short-term conditions. It is likely that the defi ciencies discussed here will improvement in quality of life can result (Bourgeois et al impact patients with FXTAS just as they do other causes of 2006). In addition, the frequent co-morbidities of depressive, dementia. Defi ciencies in B vitamins, particularly folate and anxiety, and psychotic disorders may lead the clinician to vitamin B12, are common in elderly populations and have treat with antidepressants and/or antipsychotics. The positive been associated with increased risk of cognitive impairment treatment effects on mood, anxiety, and psychosis can also and dementia (Clarke et al 1998; Ramos et al 2005; de Lau result in improved cognitive symptoms and performance et al 2007; Durga et al 2007). Of particular interest is the as seen in a case report of FXTAS (Bourgeois et al 2006). sulfur amino acid homocysteine, which becomes elevated in Anecdotal information also suggests that memantine, which the blood (hyperhomocysteinemia) when folate or vitamin may decrease glutamate-mediated neurotoxicity (Choi et al B12 is defi cient (Selhub and Miller 1992). Hyperhomocys- 1988), is helpful in FXTAS, but controlled studies have not teinemia is an independent risk factor for vascular disease, been carried out. Memantine is typically well tolerated when including cerebrovascular disease (Refsum et al 1998), and started at low-dose (ie, 5 mg every morning) with a gradual is associated with both an increased prevalence and incidence increase to 10 mg twice a day (Reisberg et al 2003). Ran- of AD and dementia (Clarke et al 1998; Miller et al 2002; domized trials are currently being planned for cholinesterase Seshadri et al 2002; Haan et al 2007). Lowering plasma inhibitors, memantine, and other putatively neuroprotective homocysteine levels with B vitamin supplements may reduce (eg, lithium) agents to address the effect of these medications the risk, though clinical trials are necessary to determine on both the clinical symptoms and the eventual prognosis for if such interventions will ultimately benefi t patients with the cognitive aspects of FXTAS (Bauer et al 2003; Chuang FXTAS or AD (Luchsinger et al 2007). It may be the case that preventing hyperhomocysteinemia before cognitive While it has yet to be established in clinical trials, using defi cits appear will be more benefi cial than intervening after the example of other neurodegenerative diseases (Scarmeas cognitive impairment has been manifested.
et al 2005; Aggarwal et al 2006), it may be that progression Alternatively, defi ciencies of folate and vitamin B12 in the motor symptoms predicts similar deterioration in the may have effects on brain function independent of homo- cognitive symptoms. Thus, clinicians should be particularly cysteine. Both vitamins are involved in the synthesis of vigilant for cognitive symptoms if the tremor and ataxia S-adenosylmethionine (SAM), which serves as the universal symptoms are in a period of progression.
methyl donor for a wide variety of methylation reactions, Evaluation for other causes of dementia, particularly including those involving neurotransmitters, membrane reversible contributing causes, such as hypothyroidism, HIV, phospholipids, myelin, and DNA (Selhub and Miller 1992). syphilis, B12 defi ciency, thiamine, B6, or folate defi ciency, is Of note is that both folate and vitamin B12 defi ciencies have essential. Patients with FXTAS will usually have signifi cant been associated with depression (Alpert and Fava 1997), Clinical Interventions in Aging 0000:0(0) and oral supplements of SAM have been shown to alleviate FXTAS (Franke et al 1996; Hagerman and Hagerman 2002; depressive symptoms (Mischoulon and Fava 2002). There Hessl et al 2005). In addition, the use of selective serotonin is also some evidence that folate has antioxidant properties reuptake inhibitors (SSRIs) to treat depression or anxiety can (Stanger et al 2002), though this is not currently considered stimulate neurogenesis in the aging brain and may therefore a major property of the vitamin. Nonetheless, neurons with be neuroprotective for later cognitive decline (Jacobs et al the FXTAS premutation will die more easily with oxidative 2000; Santarelli et al 2003). Neurogenesis, the making of stress, and we recommend folate and B complex supplemen- new neurons in adulthood, only occurs in the olfactory bulb tation (to avoid defi ciencies). However, the prevalences of and in the dentate gyrus of the hippocampus. The latter is folate, vitamin B12, and other B vitamin defi ciencies, as well important for learning and memory (Jacobs et al 2000). A as hyperhomocysteinemia in FXTAS patients are not well- stimulating environment that includes regular exercise may documented and it is unknown if B vitamin supplements in enhance neurogenesis, but increased stress or increased levels FXTAS patients will protect against the cognitive impairment of glucocorticoid hormones (cortisol) is expected to inhibit and depression associated with the disorder.
neurogenesis (Jacobs et al 2000). Therefore teaching patients Other dietary factors may be important in FXTAS. Treat- to reduce stress and increase exercise as described above ment with antioxidants, such as vitamins C and E, may help may be benefi cial for neurogenesis and may be particularly prevent and treat the oxidative damage in neuronal cells Integrated psychopharmacological approaches with Exercise can also affect the outcomes of patients with antidepressants and antipsychotics (if needed) along with AD, FXTAS, and other neurodegenerative diseases and it can cognition enhancers (discussed above) are indicated. Among stimulate neurogenesis. Aerobic exercise has been found to antidepressants, tricyclics (TCAs) and MAOIs have a pro- modify cognition, such as executive functioning, and reduce pensity for systemic side effects (anticholinergic effects of symptoms of depression and behavioral problems in AD TCAs may also further compromise cognition) and are best patient populations (Yu et al 2006; Rolland et al 2007). We avoided. SSRIs with minimal drug-drug interaction profi les recommend exercise for patients with FXTAS, because in (eg, sertraline, citalopram, escitalopram) are preferred; our clinical experience it has been helpful. An exercise rou- paroxetine, fl uoxetine, and fl uvoxamine are discouraged tine that includes walking, strength, balance, and fl exibility due to drug-drug interaction risk. The selective serotonin training may be therapeutic (Rolland et al 2007). For patients norepinephrine reuptake inhibitors (SNRIs; venlafaxine experiencing signifi cant tremor, this should be guided by a and duloxetine) are to be considered, as their noradrenergic physical therapist, as described above.
activity may be desirable. Duloxetine may have the added benefi t of reducing pain as described below. Both of these Treatment of psychiatric problems
medications are used only with caution in renal failure, Psychiatric problems can occur prior to the onset of FXTAS, and they have CYP2D6 inhibitory effects so there can be and include ADHD, anxiety disorders, and depression in interactions with other medications. Mirtazapine is helpful a subgroup of carriers. Females have been studied to the especially for sedation and appetite stimulation; its dose is greatest extent, although the stress of raising a child with usually decreased in renal failure. For psychotic symptoms, fragile X syndrome may exacerbate any underlying pathol- cautious use of atypical antipsychotics is recommended with ogy related to the premutation (Franke et al 1996, 1998). The close follow-up; olanzapine is problematic in diabetes, while limbic system has a higher transcription rate for the FMR1 ziprasidone can be problematic in patients with increased mutation than most other areas of the brain and therefore it QTc. There have been no cases of serious cardiac events may be the most vulnerable to the RNA toxicity effect of the with any of the atypical antipsychotic drugs (Tandon 2002; premutation (Hagerman and Hagerman 2004; Tassone et al Harrigan et al 2004). The newer antipsychotic, aripiprazole, 2004). Recent evidence of the association of depression with may have the least metabolic side effects and may be a useful Alzheimer disease suggests that early treatment of psychi- choice when needed in patients with FXTAS.
atric problems, particularly depression and anxiety, which Treatment of autonomic
can lead to neuronal cell death in the hippocampus, should be treated early (Sapolsky 2000). This is likely true for all dysfunction
brain diseases but there is a predisposition to depression in Urinary urgency and frequency can be irritating symptoms, individuals with the premutation even before the onset of starting in the early 40’s and slowly become debilitating as Clinical Interventions in Aging 0000:0(0) the FXTAS patient ages. The normal micturition rate for Pyridostigmine can also be used for orthostatic most men is about every three hours with average fl uid intake hypotension (Gales and Gales 2007), which is also common but may progress to every 20 minutes in severely affected in FXTAS. It also enhances sympathetic signal transduction, individuals. Micturition is associated with diffi culty starting which increases peripheral vascular resistance and increases the stream, diffi culty emptying the bladder and dribbling. baroreceptor sensitivity, which helps with orthostatic symp- Detailed urodynamic studies have not been conducted, but toms without exacerbating supine hypertension. Other agents hyperactive detrusor activity is possible since some patients that may be helpful in some cases for patients with FXTAS respond well to tricyclic antidepressants or muscarinic and orthostatic hypotension, include those often used in receptor antagonists. Patients who do not respond well to patients with multiple system atrophy or Parkinson disease this therapy may be experiencing poor bladder contractility such as midodrine and fl udrocortisone. Increasing fl uid and or sphincter dyssynergia. In many patients a more effective salt intake can also be helpful if there are no medical contra- treatment is cystoscopy under local anesthetic with injections indications (eg, coexisting heart disease or hypertension).
of 200 cc of Botox into the submucosal lining of the blad- Systemic hypertension is seen in the majority of both der in 10 cc aliquots. If a small diameter cystoscope is used male and female patients with FXTAS (Jacquemont et al the procedure is relatively well tolerated. A rare patient will 2003; Coffey et al in press), and it is thought to be related to develop an inability to urinate, and self-catheterization can autonomic dysfunction. It is often seen early, prior to the onset easily be taught. After Botox injections patients are treated of tremor and or ataxia. Because hypertension can lead to with an antibiotic and infections are rare. Mild hematuria usu- hypertensive encephalopathy, it is important to treat it early to ally resolves within 3 to 5 days. The effects of the botulinum avoid any exacerbation of CNS disease related to FXTAS.
can last from 3 to 4 months or longer.
Bowel incontinence is a late effect of FXTAS and may Treatment of hormonal dysfunction
start as a slowly progressive dilated and tortuous large bowel Hypothyroidism is a common problem among females with and result in chronic megacolon as the patient ages. No defi ni- the premutation. A recent study demonstrated that 17% of tive research has been done on patients with FXTAS but it is adult women with the premutation had thyroid dysfunction, presumed that autonomic anomalies are responsible for these usually hypothyroidism, while 50% of women who had signs and symptoms as well as overactive bladder (OAB). FXTAS had thyroid dysfunction, and this was signifi cantly The treatment of chronic megacolon is laxatives to prevent different from aged matched controls without the premutation constipation and high fi ber supplements to encourage normal (Coffey et al in press). Therefore, routinely testing for thyroid peristalsis. A new laxative regimen that is usually reserved dysfunction is indicated on a yearly basis in women with the for short 1–2 week treatments consists of polyethylene glycol premutation who are older than 50 years and particularly (17 g in 250 cc of fl uid) once or twice a day, which may need those who have neurological problems. Replacement is indi- to be used for up to a year. Side effects of diarrhea might cated for hypothyroidism because if left untreated cognitive require modifying the dose. The medication is not absorbed defi cits may occur, and psychiatric problems could be ampli- by the small bowel or colon but acts as an osmotic laxative fi ed over those that may already be present in premutation bringing water into the bowel and softening the stool. The rationale behind the treatment is to slowly train the bowel We have noted testosterone defi ciency in some patients to constrict down to a more normal size. Further studies of with FXTAS, although no large studies have been conducted this problem in FXTAS are warranted.
(Greco et al 2007). We have even seen affected individuals Swallowing diffi culties are a common, typically late become aware of erectile dysfunction before the onset of symptom in FXTAS. We have seen one recent case of other neurological signs. Low testosterone is only one of FXTAS with swallowing diffi culties who had an excellent many causes of male impotence, but it is logical to speculate response to pyridostigmine bromide, a reversible acety- that testosterone replacement may improve libido and sexual cholinesterase inhibitor, which is typically used to enhance function in FXTAS patients. Other problems associated with muscurinic signal transmission in the management of myas- FXTAS which might improve include cognition, memory, thenia gravis. Adverse effects are from stimulation of the energy level and mood (Cherrier et al 2003; Hagerman and parasympathetic nervous system via muscarinic receptors Hagerman 2004). Further studies of testosterone defi ciency and they can include sweating, salivation, nausea, vomiting, in FXTAS are warranted and the benefi ts of testosterone Clinical Interventions in Aging 0000:0(0) Treatment of pain
point massage versus Swedish massage in improving pain Pain is a common problem in patients with FXTAS and it in fi bromyalgia and chronic pain conditions (Tsao 2007). In includes neuropathic pain, particularly in the lower extremi- 2007, Mannerkorpi and Henriksson (2007) demonstrated a ties seen in both males and females (Hagerman et al 2007), controlled trial of pain relief with massage. Neuromuscular and fi bromyalgia pain which is more common in females therapies (NMT) have shown effi cacy when treating motor with FXTAS (Coffey et al in press). Although neuropathic symptoms like spasticity and rigidity, which can occur pain is diffi cult to treat, available pharmacologic treatments in FXTAS (Svircev et al 2005). This type of therapeutic provide meaningful relief for many patients. Neuropathic approach may also help with gait diffi culties seen in FXTAS. pain is typically refractory to acetaminophen and nonsteroi- For the elderly, massage therapies are an important alterna- dal anti-infl ammatory drugs. Effective treatments include tive or additive therapy to pharmacological agents described antidepressants, antiepileptics, and topical analgesics (Gilron above, particularly when side effects of medications are et al 2006). In our experience, treatment with gabapentin or pregabalin has proven benefi cial for patients with FXTAS and neuropathic pain. In addition, application of Lidoderm Psychosocial approaches
(lidocaine 5%) patches can provide symptomatic relief Psychoeducation, supportive intervention for the patient and for peripheral neuropathic pain in the lower extremities their family, and delivering psychiatric care in the context (Herrmann et al 2005). Up to three patches can be applied of a multidisciplinary team, are all helpful approaches. over intact skin on the affected areas and left in place for up Given the fact that several members in the same family are to 12 hours over a 24-hour period. Fibromyalgia, chronic often affected, the intervention may target the patient and fatigue syndrome, and irritable bowel syndrome occur com- the family, with consistent longitudinal follow-up being a monly in female subjects with FXTAS (Coffey et al in press). There is no clear separation of these syndromes, which are Problem-solving therapy (PST) is a therapeutic modality often co-morbid with mood disturbances. Initial treatment which has been shown to improve depressive symptoms and for fi bromyalgia should include nonpharmacologic treat- functioning in depressed elderly patients with executive dys- ments such as cardiovascular exercise, cognitive-behavioral function, and cognitively unimpaired, depressed elderly and therapy and/or structured patient education (Goldenberg et al adults with minor and major depression in the primary care 2004). The most effective pharmacologic treatments include setting (Arean et al 1993; Unutzer et al 2002; Alexopoulos antidepressant, anticonvulsant and/or muscle relaxant medi- et al 2003; Haverkamp et al 2004; Steffens et al 2006). In the cations (Goldenberg et al 2004). If the above treatments do last decade, strong empirical evidence has been gathered to not provide acceptable pain relief, patients should be referred support this novel psychotherapy type (Mackin and Arean to a pain specialty clinic for consideration of interventional 2005). Problem-solving therapy may be used in FXTAS treatments, pain rehabilitation programs and/or chronic treat- patients without dementia, as they have signifi cant executive function defi cits (Grigsby et al 2007). Executive dysfunction increases the risk of poor response of geriatric depression Massage therapy
to medications (Alexopoulos et al 2005). By addressing the Tremors can be exacerbated by anxiety and stress, as noted executive dysfunction, the patients’ daily functioning may earlier, so an important approach to treatment of these improve and their response to antidepressants will be ampli- symptoms would be the reduction of these tremor stimula- fi ed. Furthermore, the caregivers’ wellbeing may be enhanced tors. Massage has been shown to be effective in reducing along with the patients’ mood and anxiety symptoms. Women cortisol levels, stress and anxiety, as well as improving constitute the majority of caregivers for patients with FXTAS overall mental health (Balint et al 2002; Mannerkorpi and and 70% of the care-giving population. Women were found Henriksson 2007; Sharpe et al 2007; Tsao 2007). Pain and to have signifi cantly higher odds than male caregivers of hav- discomfort, also associated with fi bromyalgia, stiffness (eg, ing a high score on the Zarit Burden Interview (ZBI). Poor with parkinsonism), and fatigue are also contributors to perceived physical health and more behavior disturbance in stress and anxiety. Massage therapy can lessen these types of the patient were associated with higher odds of high levels discomforts, as well as decrease uncomfortable sleep move- of caregiver burden and depression (Gallicchio et al 2002). ments and lengthen the sleeping span (Field et al 2002). A In our clinical experience depression is very common in the recent study demonstrated effi cacy with acupressure/pressure wives of men with FXTAS and they typically do well with Clinical Interventions in Aging 0000:0(0) supportive counseling and the addition of an SSRI agent for Conclusions and future directions
A number of medications and therapies have been noted to be helpful for the symptoms of FXTAS, although no controlled Genetic counseling
trials of effi cacy have been carried out. Therefore, it is critical Genetic counseling for FXTAS is complicated. In addition that controlled trials be undertaken with existing therapeutic to the genetic information and obtaining the family pedigree, agents or modalities where anecdotal evidence in patients there are many psychosocial features to be addressed that are, with FXTAS, or controlled studies with related disorders, themselves, a consequence of the neuropsychiatric features suggests that such approaches would be effi cacious.
(Bourgeois et al 2006; Grigsby et al 2006). When addressing Since FXTAS is a progressive neurodegenerative the family history, questions regarding neurological, immu- disorder, and because none of the current therapies target nological, and endocrine issues must be asked in addition FXTAS pathogenesis, such approaches will, at best, stall or to a family history of mental impairment, autism, ADHD, transiently improve the symptoms of the disorder. Therefore, behavioral and emotional problems. It is suggested that the development of therapeutic interventions that target the family history be obtained from the spouse of the patient core molecular processes that underlie FXTAS is essential. with FXTAS as the patient is likely to be overwhelmed with Such therapeutics would, in principle, target either the too much information and with recommendations that affect pathogenic trigger, the expanded-CGG-repeat mRNA itself quality of life, such as the cessation of driving or need for (“toxic RNA”), or downstream pathways that are altered as a cane, walker or wheelchair. In addition, the patient may a consequence of the abnormal FMR1 mRNA expression. not be aware of the severity of his FXTAS-related clinical Whereas the simplest approach, conceptually, would be to fi ndings and fi nd it depressing and threatening to have these use antisense or RNA interference methods to knock down addressed. Impotency and incontinence also have the poten- the pathogenic RNA itself, such approaches remain diffi cult tial to threaten self-esteem and the genetic counselor needs due to the general inability of such agents to traverse the to be aware of and sensitive to all these issues.
blood brain barrier. However, as we learn more about the The patient with FXTAS cannot be treated in isolation. other molecular abnormalities, and proteins involved, with The questions, concerns, and needs of the caregiver/spouse the downstream pathways (Jin et al 2004; Arocena et al 2005; must be addressed, as Bacalman and colleagues (2006) Iwahashi et al 2006), additional opportunities for targeted has shown that these individuals experience varying interventions will hopefully become available.
degrees of stress. Therefore, we recommend meeting with the caregiver separately from the patient in order to obtain a Acknowledgment
more accurate understanding of the patient’s condition and This work was supported by grants from the Coleman Foun- progression and to explore the caregiver’s emotional state and dation, National Institutes of Health HD036071, HD02274, understanding of FXTAS. As in Alzheimer disease, the care- NS044299, NS052487, UL1RR024922, RL1AG032115, and giver is prone to depression, feelings of being overwhelmed, Centers for Disease Control and Prevention U10/CCU925123. grief over the loss of a planned future, anger regarding the The authors report no other confl icts of interest.
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