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Published in final edited form as: Curr Psychiatry Rev. 2013 ; 9(1): 59–64. doi:10.2174/157340013805289699.
PSYCHIATRIC DISORDERS ASSOCIATED WITH FXTAS Andreea L. Seritan, M.D.1,2, Melina Ortigas2, Stefan Seritan3, James A. Bourgeois, O.D., M.D.4, and Randi J. Hagerman, M.D.2,5 1Department
of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, California 2Medical
Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California Davis Medical Center, Sacramento, California 3University
of California Santa Barbara, College for Creative Studies, Santa Barbara, California
4Department
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of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
5Department
of Pediatrics, University of California Davis Medical Center, Sacramento, California
Abstract
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Carriers of the FMR1 premutation (with 55-200 CGG repeats) may present with multiple medical and psychiatric disorders. Middle-aged carriers (males more often than females) may suffer from fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a newly discovered neurodegenerative disease characterized by intention tremor and ataxia, along with several other neurological features. Psychiatric manifestations are common in premutation carriers of both genders and include attention deficits, anxiety, depression, irritability, impulse dyscontrol, and substance abuse or dependence. Major depressive disorder, panic disorder with or without agoraphobia, generalized anxiety disorder, social phobia, and specific phobia are among the psychiatric diagnoses often encountered in premutation carriers, including those with FXTAS. Later in the course of the illness, cognitive deficits (including dementia) may occur. In this paper, we discuss common psychiatric phenotypes in FXTAS, based on a thorough review of the literature, as well as our own research experience. Symptomatic pharmacologic treatments are available, although disease modifying agents have not yet been developed.
Keywords anxiety; depression; FXTAS; FMR1 premutation; psychiatric disorders; substance abuse
BACKGROUND About one in 130-260 females and one in 250-810 males in the general population carry the fragile X mental retardation 1 (FMR1) gene premutation, with 55-200 CGG repeats [1]. Until recently, premutation carriers were believed to be clinically unaffected, as opposed to
Corresponding Author: Andreea L. Seritan, MD, 2230 Stockton Blvd., Sacramento, CA 95817, Phone: (916) 734-5764, Fax: (916) 734-0849, [email protected].
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those who have full mutations (> 200 CGG repeats), resulting in the fragile X syndrome (FXS). FXS is caused by the absence or severe deficiency of the FMR1 protein (FMRP) because the full mutation is methylated so transcription is inhibited. About a decade ago, astute clinical observations coupled with the discovery of elevated FMR1 mRNA in the premutation led to the report of neurological symptoms in aging premutation carriers, thus forcing a paradigm shift in thinking about clinical involvement in carriers [2-4]. Now we know that premutation carriers of both genders exhibit varied autoimmune, endocrine, neurological, and psychiatric symptoms. Later in life, carriers may develop a neurodegenerative disease which received its name from the characteristic movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is believed to be caused by RNA toxicity due to the intracellular accumulation of excess FMR1 mRNA, despite normal or slightly reduced FMRP levels [4]. The excess mRNA leads to dysregulation and sequestration of other molecules and formation of eosinophilic ubiquitinpositive intranuclear inclusions in neurons and astrocytes throughout the nervous system, as well as in other organs [5, 6].
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FXTAS affects 17% of male carriers in their 50's, up to 75% of male carriers in their 80's, and up to 16% of female carriers [7-9]. We have also seen FXTAS in individuals with the grey zone (45-54 CGG repeats) when it occurs in a family that has others with fragile X premutation or full mutation involvement. Clinical manifestations may include: intention tremor, ataxia, parkinsonism, peripheral neuropathy, autonomic dysfunction, psychiatric manifestations, and cognitive impairment [10]. Clinical and radiological diagnostic criteria for FXTAS have been established [11]. The presence of the premutation is a required criterion; results of fragile X DNA testing show the number of CGG repeats on each allele. Psychiatrists may suspect FXTAS and order the DNA test when the above clinical manifestations are present, along with family history of one or more of the following: movement disorder, unidentified neurological disorder or dementia, autism spectrum disorders or autistic-like behaviors (gaze avoidance, repetitive behaviors, hand-flapping, hand biting, touch avoidance), attention deficit hyperactivity disorder (ADHD), mental retardation, developmental delays, learning disorders, FXS, or FXTAS [12]. Neuroimaging studies show cerebellar atrophy, generalized cerebral atrophy, and white matter disease [13, 14]. Symmetrical hyperintensities in the middle cerebellar peduncles (MCP) on T2 MRI, called the MCP sign, are pathognomonic for FXTAS, even though present in only 60% of male and 13% of female carriers [13, 14]. This paper will review the psychiatric manifestations in FMR1 premutation carriers, focusing on individuals with FXTAS.
PSYCHIATRIC MANIFESTATIONS IN YOUNG PREMUTATION CARRIERS Young fragile X premutation carriers exhibit psychiatric and neurological problems that have been better studied in boys than in girls. Boys with the premutation have a higher incidence of ADHD, autism spectrum disorder (ASD), and seizures than boys without the premutation [15-17]. Farzin et al. studied a group of 43 males aged 4-22 (average 10.3 years, SD 5 years), of whom 27 were premutation carriers and 16 were sibling controls without the premutation [15]. The 27 premutation carriers included 14 probands that had been identified due to visible behavioral challenges and confirmed through genetic analysis, and 13 nonproband premutation carriers discovered through cascade testing in families of children
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with fragile X mutations. The premutation carriers had significantly higher rates of ADHD and ASD than the unaffected controls. Of the probands, 93% had symptoms of ADHD and 79% had ASD features. In the non-proband group, 38% had symptoms of ADHD and 8% had ASD symptoms which were not significantly increased compared to the controls, where 13% had ADHD symptoms and none had ASD [15]. However, non-proband premutation carriers had higher rates of social deficits as measured by a social communication questionnaire compared to controls. Chonchaiya and colleagues studied 50 premutation carrier boys (mean age 9 years 5 months, SD 4 years 8 months) and 32 male sibling controls (mean age 9 years 2 months SD 5 years 3 months) for differences in ASD and seizures rates [16]. Among premutation carriers, 14% had a history of seizures, 18% had autism, and 48% had ASD features, whereas none of the controls had any seizures, autism, or ASD [16]. One boy with the premutation also had ASD and repetitive behaviors, including skin picking and chewing on clothes or objects [17].
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In another study of 10 boys ages 4 to 15 years old who had either the premutation or gray zone (45-54 CGG repeats), four met criteria for pervasive developmental disorders, while three had symptoms of ADHD [18]. In a case series of three boys and two girls with the premutation, ages 3 to 10, four had autism and one met criteria for ASD [19]. Basuta et al. [20] described two siblings with the premutation (7 year old girl and 8 year old boy) both of whom had social anxiety and obsessive-compulsive symptoms, although the boy had more behavioral problems (attention deficits and hyperactivity). In a more heterogeneous group of 7 male and 43 female carriers ages 5-80, 14% of men and 5% of women met the Autism Diagnostic Observation Schedule-Generic criteria for ASD [21].
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Not much is known about psychiatric manifestations in young female carriers besides the scarce reports of anxiety symptoms and ASD and the emotional implications of being a carrier. Learning about the carrier status can be a difficult reality for adolescent girls, raising feelings of anxiety, guilt, and altered self-worth [22]. Moreover, 15-24% of female carriers may develop primary ovarian insufficiency (POI) with premature menopause (before age 40); approximately 3% of female carriers have their final menses before 29 years old, and 1%, prior to age 18 [22]. Premature menopause may be associated with multiple psychiatric symptoms including anxiety, depression, insomnia, irritability, mood swings, and sexual dysfunction. The threat to parental role due to early loss of child bearing capacity and the delay in diagnosis can cause additional stress [23, 24].
PSYCHIATRIC MANIFESTATIONS IN ADULT PREMUTATION CARRIERS WITHOUT FXTAS Premutation carriers seen in clinically research studies are usually individuals with solid educational attainments, most being college educated, some with graduate/doctoral degrees [25-27]. In our research work with carriers of both genders, we learned that many preferred small liberal arts colleges, and some even interrupted their education because of difficulty adjusting to large college environments. This may be due to the very high prevalence of social phobia (34%) in premutation carriers, significantly higher than in the age-matched general population controls (12.6%) [27]. Nevertheless, many have overcome this challenge (for example, by practicing public speaking) and become accomplished professionals. Hessl Curr Psychiatry Rev. Author manuscript; available in PMC 2015 January 23.
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et al. found higher levels of obsessive-compulsive symptoms in men with the premutation, compared to published norms [28]. Also, women with the premutation had significantly higher somatization and depression scores, compared to normative sample means [28]. Premutation carriers (especially women) may have a history of eating disorders; impulse control disorders and current or prior substance abuse or dependence may be present as well. Substances of abuse include: alcohol, cannabis, cocaine, opioids, stimulants, and designer drugs. This is consistent with previous studies, which have shown significantly higher rates of alcohol abuse in male carriers and age-matched family controls [29], as well as increased alcohol intake in female carriers, compared to controls [25]. A minority of carriers meet diagnostic criteria for psychotic or somatoform disorders [30]. Paranoid ideation may occur in later stages of illness and it may be due to the misinterpretation of other individuals’ actions. Interestingly, presence of paranoid ideation was negatively correlated with hippocampal volume in male carriers [31]. Table 1 summarizes less common psychiatric disorders in a sample of 184 premutation carriers with and without FXTAS.
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Women premutation carriers report chronic muscle pain, paresthesias, and tremor and may have thyroid problems, peripheral neuropathy, hypertension, fibromyalgia, autoimmune disease, migraines, and POI [8, 9, 25, 32-34]. Men with the premutation often have type II diabetes, hypertension, sleep apnea, migraine headaches, and cardiac disease [3, 35, 36]. Chonchaiya et al. [37] surveyed daughters of men with FXTAS (who are obligate carriers, since they received the X chromosome from their fathers) and found higher rates of neurological symptoms including tremor, balance, and memory problems, as well as higher rates of psychiatric problems (anxiety and insomnia) than age matched, non-carrier control women.
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In a study by Hunter et al. [25] female premutation carriers reported increased ADHD, anxiety, and depression symptoms compared to non-carrier controls, although differences were not statistically significant. These authors used the self-report Conners’ Adult ADHD Rating Scales and found significantly elevated scores of ADHD symptoms including inattention, problems with memory and self concept, impulsivity, and emotional lability when compared to controls without the FMR1 premutation [38]. Roberts et al. compared female carriers between the ages of 20-46 to women from the National Comorbidity Survey Replication (NCS-R) and found higher rates for any mood disorder in the premutation group. Women carriers with a mid-range CGG repeat length or who had never been married appeared to have a higher risk of major depressive disorder (MDD) [26]. Premutation carriers were less likely to meet criteria for a life-time anxiety disorder but those with children had an increased likelihood of being diagnosed with lifetime panic disorder and current agoraphobia without panic disorder compared to the NCS-R sample [26]. Spanish researchers examined mood and anxiety disorders across three groups: female premutation carriers with children with FXS and mental retardation (MR), mothers of children with MR without FXS, and mothers in the general population [39]. Mothers of children with FXS and MR scored higher in hostility and depression when compared to mothers of mentally retarded children without FXS and to controls [39].
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PSYCHIATRIC MANIFESTATIONS IN ADULT PREMUTATION CARRIERS NIH-PA Author Manuscript
WITH FXTAS
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Patients with FXTAS were found to have a 65% lifetime prevalence of mood disorders and 52% lifetime prevalence of anxiety disorders; specifically, there was a significantly higher prevalence of MDD, panic disorder, specific phobia, and posttraumatic stress disorder (PTSD) when compared with age-matched general population controls [27]. In a sample of 55 patients with FXTAS (36 men and 19 women), 44% had MDD, 2% had dysthymic disorder, 13% met criteria for depressive disorder NOS, 4% presented with adjustment disorders, and 4% had bipolar spectrum disorders [40]. Mood swings, irritability, and anger outbursts were frequent, especially as the illness progressed, but true bipolar disorders (type I or II) were less common. Among the anxiety disorders studied, generalized anxiety disorder was present in 11% of the sample, panic disorder in 5%, PTSD in 9%, 15% of patients had social phobia, and the most common diagnosis was specific phobia (22%) [40]. Similar to data on carriers without FXTAS, we found that 14% of these patients had either alcohol abuse or dependence or polysubstance dependence, as established through the Structured Clinical Interview for DSM-IV-TR (SCID) [41]. Both men and women with FXTAS met criteria for somatoform disorders (see Table 1). The lifetime sequencing of neuropsychiatric illness in FXTAS awaits validation, but patients often report that the anxiety and depressive symptoms preceded the onset of motor and then cognitive deficits, suggesting that the anxiety and mood disorders may represent a psychiatric prodrome of later motor and cognitive impairments (also see Ages of onset of mood and anxiety disorders in fragile X premutation carriers in this issue).
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Suicidality is an aspect of psychiatric care in FXTAS that requires close monitoring. In our experience, at least 5% of patients with FXTAS and comorbid psychiatric disorders have reported suicidal ideation. In our sample of 135 participants with FXTAS of both genders, one man attempted suicide twice. Patients with FXTAS and MDD and/or panic disorder are at increased risk for suicide particularly in the early stages of FXTAS dementia, due to impulsive behavior combined with a sense of loss of cognitive and motor function. Suicidal risk assessment should include the prior history of suicidal behavior, access to means of selfharm, also the impact of male gender, increased age, substance abuse, psychosocial losses (such as loss of employment due to functional impairment), and psychodynamic conflicts (e.g., sense of guilt at being “responsible” for transmission of a genetically-determined illness to family members). The risk of suicide may be even higher than what we have observed to date, given that other neuropsychiatric illnesses with movement disorders are fraught with very high suicidality rates. For example, about 20% of patients with Huntington’s disease endorse suicidal ideation, with depression/anxiety, aggression/ irritability, and substance abuse being significant predictors [42].
TREATMENT The management of psychiatric disturbances associated with FXTAS is determined by the illness stage and comorbidities. First, a thorough workup should be done to rule out thyroid disease, testosterone deficiency, perimenopause, POI, vitamin deficits, or other contributory factors, which should be appropriately addressed [43]. Curr Psychiatry Rev. Author manuscript; available in PMC 2015 January 23.
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A. Psychotherapy
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Useful psychotherapeutic approaches include: supportive, cognitive-behavioral (CBT), and problem-solving therapy (PST). Supportive psychotherapy can address adjustment reactions to having a genetic neurodegenerative disease and the resulting disability, feelings of guilt associated with passing the defective gene on to offspring, issues of infertility and altered expectations in women with POI, as well as living in families with multiple members affected by FXS or premutation involvement. CBT is indicated for social phobia, other anxiety disorders, depression, and somatoform disorders [44, 45]. PST can be delivered in primary care settings and is helpful in addressing depression, even in individuals with executive dysfunction, which is the major cognitive deficit in carriers [46, 47]. Couples therapy is indicated at times, especially in situations where patients with FXTAS become distrustful of their spouse’s actions and may alienate themselves through angry outbursts directed at their caregivers. Family therapy often complements genetic counseling for multigenerational fragile X-spectrum affected families [48]. In advanced disease stages, we counsel all patients to minimize or stop driving which becomes unsafe due to neurological and/or cognitive deficits. We strongly recommend assessing safety issues, including access to means of self-harm, since patients with FXTAS may become despondent and attempt suicide. B. Psychopharmacological management General principles of psychopharmacological management in late life apply, including starting medications at low doses and titrating as tolerated, minimizing benzodiazepines and opioids in cognitively impaired individuals, and paying attention to drug-drug interactions. A high risk of falls is part of the FXTAS picture, due to ataxia and autonomic instability, therefore sedating medications, drugs that may cause or worsen parkinsonism (typical antipsychotics or risperidone at higher doses than 3 mg/day), and agents that may cause orthostatic hypotension (including but not limited to tricyclic antidepressants and trazodone) are not recommended. At this time, no medication directly addresses the disease mechanisms however modest improvements have been noted with symptomatic treatments [49, 50].
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Depressive and anxiety symptoms can be targeted with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, or mirtazapine, which may also help reduce the neuropathic pain [10, 25, 49-52]. SSRIs provide the additional benefit of increased hippocampal neurogenesis, which has been shown in Alzheimer’s disease and in depression [53-55]. This effect may be helpful to carriers as they age, since brain atrophy is a significant finding in those with FXTAS and even premutation carriers without FXTAS. Low dose benzodiazepines are effective for panic disorder, with the above caveat for their safety of use. Pregabalin or gabapentin are useful for peripheral neuropathy [10, 49]. Antiepileptic mood stabilizers (valproate, oxcarbazepine, lamotrigine) are generally ideal for impulse control disorder and bipolar spectrum disorders. Lamotrigine is an effective mood stabilizer which has also been used for migraines and neuropathic pain [56], both of which may occur in FXTAS. However, not enough evidence exists to support their widespread use since they may worsen the mitochondrial dysfunction that occurs in patients with FXTAS [57, 58]. Lithium has been proposed as therapeutic agent but is less favored in the elderly
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due to possible cognitive and renal side effects. Atypical antipsychotics may help treat the paranoid ideation or psychotic symptoms and can be used as alternate mood stabilizers. Weight-neutral agents, such as aripiprazole or ziprasidone (under QTc monitoring), are preferred because patients with FXTAS often become sedentary due to their neurologic deficits [50]. Quetiapine has the lowest risk of extrapyramidal side effects, but it may cause orthostatic hypotension and metabolic side effects. Stimulants or the norepinephrine reuptake inhibitor atomoxetine have been used to address ADHD symptoms [25]. Anecdotal reports have shown cognitive benefit from cholinesterase inhibitors or memantine [49, 51, 59]. Case reports have also suggested memantine might be helpful for neuropathic pain, although a recent meta-analysis did not find conclusive evidence regarding NMDA receptor antagonist efficacy for this indication [60].
CONCLUSION
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FXTAS is a genetically determined, molecularly based disorder with significant systemic and neuropsychiatric manifestations. Neuropsychiatric aspects of FXTAS may include anxiety, mood, cognitive, and other psychiatric disorders. These problems can begin in childhood for a subgroup of carriers, although why some are affected and others are not is unknown. It is important to carry out fragile X DNA testing when managing patients who have a family history consistent with FXS. A thorough clinical evaluation, including neuroimaging, is crucial. Symptomatic treatments are available, although disease modifying agents have not yet been developed. Psychotherapy is a very important aspect of treatment for families affected by fragile X-associated disorders.
ACKNOWLEDGMENT This work was supported by the National Institutes of Health (NIH) Roadmap Interdisciplinary Research Consortium Grant AG032115 and the NIH Grant MH078041.
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[50]. Hagerman RJ, Hall DA, Coffey S, et al. Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems. Clin Interv Aging. 2008; 3:251–62. [PubMed: 18686748] [51]. Bourgeois JB, Farzin F, Brunberg JA, et al. Dementia with mood symptoms in a carrier of the fragile X-associated tremor/ataxia syndrome (FXTAS): clinical intervention with donepezil and venalafaxine. J Neuropsychiatry Clin Neurosci. 2006; 18:171–7. [PubMed: 16720793] [52]. Berry-Kravis, E.; Hall, DA.; Leehey, MA.; Hagerman, RJ. Treatment and management of FXTAS. In: Tassone, F.; Berry-Kravis, E., editors. The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS). Springer; New York: 2010. p. 137-54. [53]. Chow TW, Pollock BG, Milgram NW. Potential cognitive enhancing and disease modification effects of SSRIs for Alzheimer’s disease. Neuropsychiatr Dis Treat. 2007; 3:627–36. [PubMed: 19300592] [54]. Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008; 33:73–83. [PubMed: 17882234] [55]. Boldrini M, Underwood MD, Hen R, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009; 34:2376–89. [PubMed: 19606083] [56]. Malik S, Arif H, Hirsch LJ. Lamotrigine and its applications in the treatment of epilepsy and other neurological and psychiatric disorders. Expert Rev Neurother. 2006; 6:1609–27. [PubMed: 17144777] [57]. Berger I, Segal I, Shmueli D, Saada A. The effect of antiepileptic drugs on mitochondrial activity: a pilot study. J Child Neurol. 2010; 25:541–5. [PubMed: 20413803] [58]. Napoli E, Ross-Inta C, Wong S, et al. Altered zinc transport disrupts mitochondrial protein processing/import in fragile X-associated tremor/ataxia syndrome. Hum Mol Genet. 2011; 20:3079–92. [PubMed: 21558427] [59]. Ortigas MC, Bourgeois JA, Schneider A, et al. Improving fragile X-associated tremor/ataxia syndrome symptoms with memantine and venlafaxine. J Clin Psychopharmacol. 2010; 30:642–4. [PubMed: 20841969] [60]. Collins S, Sigtermans MJ, Dahan A, Zuurmond WA, Perez R. NMDA receptor antagonists for the treatment of neuropathic pain. Pain Medicine. 2010; 11:1726–42. [PubMed: 21044263]
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Table 1
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Less Common Psychiatric Disorders in 184 Premutation Carriers. Psychiatric disorder
Men (n = 95)
Women (n = 89)
FXTAS
No FXTAS
FXTAS
No FXTAS
0
0
3
3
1
0
0
0
Psychotic disorders NOS
3
0
2
0
Substance abuse/dependence
24
4
6
9
Alcohol
14
1
4
5
Cannabis
1
1
2
1
Cocaine
2
2
0
2
Opioid
1
0
0
0
Sedative/hypnotic
2
0
0
0
Stimulant
1
0
0
1
3
0
0
0
4
0
4
4
Eating disorders
a
Impulse control disorder
Polysubstance
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Somatoform disorders
b
a
Include anorexia, bulimia, binge eating disorder
b
Include hypochondriasis, pain disorder, somatization disorder, somatoform disorder NOS.
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Published in final edited form as: Curr Psychiatry Rev. 2013 ; 9(1): 59–64. doi:10.2174/157340013805289699.
PSYCHIATRIC DISORDERS ASSOCIATED WITH FXTAS Andreea L. Seritan, M.D.1,2, Melina Ortigas2, Stefan Seritan3, James A. Bourgeois, O.D., M.D.4, and Randi J. Hagerman, M.D.2,5 1Department
of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, California 2Medical
Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California Davis Medical Center, Sacramento, California 3University
of California Santa Barbara, College for Creative Studies, Santa Barbara, California
4Department
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of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
5Department
of Pediatrics, University of California Davis Medical Center, Sacramento, California
Abstract
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Carriers of the FMR1 premutation (with 55-200 CGG repeats) may present with multiple medical and psychiatric disorders. Middle-aged carriers (males more often than females) may suffer from fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a newly discovered neurodegenerative disease characterized by intention tremor and ataxia, along with several other neurological features. Psychiatric manifestations are common in premutation carriers of both genders and include attention deficits, anxiety, depression, irritability, impulse dyscontrol, and substance abuse or dependence. Major depressive disorder, panic disorder with or without agoraphobia, generalized anxiety disorder, social phobia, and specific phobia are among the psychiatric diagnoses often encountered in premutation carriers, including those with FXTAS. Later in the course of the illness, cognitive deficits (including dementia) may occur. In this paper, we discuss common psychiatric phenotypes in FXTAS, based on a thorough review of the literature, as well as our own research experience. Symptomatic pharmacologic treatments are available, although disease modifying agents have not yet been developed.
Keywords anxiety; depression; FXTAS; FMR1 premutation; psychiatric disorders; substance abuse
BACKGROUND About one in 130-260 females and one in 250-810 males in the general population carry the fragile X mental retardation 1 (FMR1) gene premutation, with 55-200 CGG repeats [1]. Until recently, premutation carriers were believed to be clinically unaffected, as opposed to
Corresponding Author: Andreea L. Seritan, MD, 2230 Stockton Blvd., Sacramento, CA 95817, Phone: (916) 734-5764, Fax: (916) 734-0849, [email protected].
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those who have full mutations (> 200 CGG repeats), resulting in the fragile X syndrome (FXS). FXS is caused by the absence or severe deficiency of the FMR1 protein (FMRP) because the full mutation is methylated so transcription is inhibited. About a decade ago, astute clinical observations coupled with the discovery of elevated FMR1 mRNA in the premutation led to the report of neurological symptoms in aging premutation carriers, thus forcing a paradigm shift in thinking about clinical involvement in carriers [2-4]. Now we know that premutation carriers of both genders exhibit varied autoimmune, endocrine, neurological, and psychiatric symptoms. Later in life, carriers may develop a neurodegenerative disease which received its name from the characteristic movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is believed to be caused by RNA toxicity due to the intracellular accumulation of excess FMR1 mRNA, despite normal or slightly reduced FMRP levels [4]. The excess mRNA leads to dysregulation and sequestration of other molecules and formation of eosinophilic ubiquitinpositive intranuclear inclusions in neurons and astrocytes throughout the nervous system, as well as in other organs [5, 6].
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FXTAS affects 17% of male carriers in their 50's, up to 75% of male carriers in their 80's, and up to 16% of female carriers [7-9]. We have also seen FXTAS in individuals with the grey zone (45-54 CGG repeats) when it occurs in a family that has others with fragile X premutation or full mutation involvement. Clinical manifestations may include: intention tremor, ataxia, parkinsonism, peripheral neuropathy, autonomic dysfunction, psychiatric manifestations, and cognitive impairment [10]. Clinical and radiological diagnostic criteria for FXTAS have been established [11]. The presence of the premutation is a required criterion; results of fragile X DNA testing show the number of CGG repeats on each allele. Psychiatrists may suspect FXTAS and order the DNA test when the above clinical manifestations are present, along with family history of one or more of the following: movement disorder, unidentified neurological disorder or dementia, autism spectrum disorders or autistic-like behaviors (gaze avoidance, repetitive behaviors, hand-flapping, hand biting, touch avoidance), attention deficit hyperactivity disorder (ADHD), mental retardation, developmental delays, learning disorders, FXS, or FXTAS [12]. Neuroimaging studies show cerebellar atrophy, generalized cerebral atrophy, and white matter disease [13, 14]. Symmetrical hyperintensities in the middle cerebellar peduncles (MCP) on T2 MRI, called the MCP sign, are pathognomonic for FXTAS, even though present in only 60% of male and 13% of female carriers [13, 14]. This paper will review the psychiatric manifestations in FMR1 premutation carriers, focusing on individuals with FXTAS.
PSYCHIATRIC MANIFESTATIONS IN YOUNG PREMUTATION CARRIERS Young fragile X premutation carriers exhibit psychiatric and neurological problems that have been better studied in boys than in girls. Boys with the premutation have a higher incidence of ADHD, autism spectrum disorder (ASD), and seizures than boys without the premutation [15-17]. Farzin et al. studied a group of 43 males aged 4-22 (average 10.3 years, SD 5 years), of whom 27 were premutation carriers and 16 were sibling controls without the premutation [15]. The 27 premutation carriers included 14 probands that had been identified due to visible behavioral challenges and confirmed through genetic analysis, and 13 nonproband premutation carriers discovered through cascade testing in families of children
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with fragile X mutations. The premutation carriers had significantly higher rates of ADHD and ASD than the unaffected controls. Of the probands, 93% had symptoms of ADHD and 79% had ASD features. In the non-proband group, 38% had symptoms of ADHD and 8% had ASD symptoms which were not significantly increased compared to the controls, where 13% had ADHD symptoms and none had ASD [15]. However, non-proband premutation carriers had higher rates of social deficits as measured by a social communication questionnaire compared to controls. Chonchaiya and colleagues studied 50 premutation carrier boys (mean age 9 years 5 months, SD 4 years 8 months) and 32 male sibling controls (mean age 9 years 2 months SD 5 years 3 months) for differences in ASD and seizures rates [16]. Among premutation carriers, 14% had a history of seizures, 18% had autism, and 48% had ASD features, whereas none of the controls had any seizures, autism, or ASD [16]. One boy with the premutation also had ASD and repetitive behaviors, including skin picking and chewing on clothes or objects [17].
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In another study of 10 boys ages 4 to 15 years old who had either the premutation or gray zone (45-54 CGG repeats), four met criteria for pervasive developmental disorders, while three had symptoms of ADHD [18]. In a case series of three boys and two girls with the premutation, ages 3 to 10, four had autism and one met criteria for ASD [19]. Basuta et al. [20] described two siblings with the premutation (7 year old girl and 8 year old boy) both of whom had social anxiety and obsessive-compulsive symptoms, although the boy had more behavioral problems (attention deficits and hyperactivity). In a more heterogeneous group of 7 male and 43 female carriers ages 5-80, 14% of men and 5% of women met the Autism Diagnostic Observation Schedule-Generic criteria for ASD [21].
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Not much is known about psychiatric manifestations in young female carriers besides the scarce reports of anxiety symptoms and ASD and the emotional implications of being a carrier. Learning about the carrier status can be a difficult reality for adolescent girls, raising feelings of anxiety, guilt, and altered self-worth [22]. Moreover, 15-24% of female carriers may develop primary ovarian insufficiency (POI) with premature menopause (before age 40); approximately 3% of female carriers have their final menses before 29 years old, and 1%, prior to age 18 [22]. Premature menopause may be associated with multiple psychiatric symptoms including anxiety, depression, insomnia, irritability, mood swings, and sexual dysfunction. The threat to parental role due to early loss of child bearing capacity and the delay in diagnosis can cause additional stress [23, 24].
PSYCHIATRIC MANIFESTATIONS IN ADULT PREMUTATION CARRIERS WITHOUT FXTAS Premutation carriers seen in clinically research studies are usually individuals with solid educational attainments, most being college educated, some with graduate/doctoral degrees [25-27]. In our research work with carriers of both genders, we learned that many preferred small liberal arts colleges, and some even interrupted their education because of difficulty adjusting to large college environments. This may be due to the very high prevalence of social phobia (34%) in premutation carriers, significantly higher than in the age-matched general population controls (12.6%) [27]. Nevertheless, many have overcome this challenge (for example, by practicing public speaking) and become accomplished professionals. Hessl Curr Psychiatry Rev. Author manuscript; available in PMC 2015 January 23.
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et al. found higher levels of obsessive-compulsive symptoms in men with the premutation, compared to published norms [28]. Also, women with the premutation had significantly higher somatization and depression scores, compared to normative sample means [28]. Premutation carriers (especially women) may have a history of eating disorders; impulse control disorders and current or prior substance abuse or dependence may be present as well. Substances of abuse include: alcohol, cannabis, cocaine, opioids, stimulants, and designer drugs. This is consistent with previous studies, which have shown significantly higher rates of alcohol abuse in male carriers and age-matched family controls [29], as well as increased alcohol intake in female carriers, compared to controls [25]. A minority of carriers meet diagnostic criteria for psychotic or somatoform disorders [30]. Paranoid ideation may occur in later stages of illness and it may be due to the misinterpretation of other individuals’ actions. Interestingly, presence of paranoid ideation was negatively correlated with hippocampal volume in male carriers [31]. Table 1 summarizes less common psychiatric disorders in a sample of 184 premutation carriers with and without FXTAS.
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Women premutation carriers report chronic muscle pain, paresthesias, and tremor and may have thyroid problems, peripheral neuropathy, hypertension, fibromyalgia, autoimmune disease, migraines, and POI [8, 9, 25, 32-34]. Men with the premutation often have type II diabetes, hypertension, sleep apnea, migraine headaches, and cardiac disease [3, 35, 36]. Chonchaiya et al. [37] surveyed daughters of men with FXTAS (who are obligate carriers, since they received the X chromosome from their fathers) and found higher rates of neurological symptoms including tremor, balance, and memory problems, as well as higher rates of psychiatric problems (anxiety and insomnia) than age matched, non-carrier control women.
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In a study by Hunter et al. [25] female premutation carriers reported increased ADHD, anxiety, and depression symptoms compared to non-carrier controls, although differences were not statistically significant. These authors used the self-report Conners’ Adult ADHD Rating Scales and found significantly elevated scores of ADHD symptoms including inattention, problems with memory and self concept, impulsivity, and emotional lability when compared to controls without the FMR1 premutation [38]. Roberts et al. compared female carriers between the ages of 20-46 to women from the National Comorbidity Survey Replication (NCS-R) and found higher rates for any mood disorder in the premutation group. Women carriers with a mid-range CGG repeat length or who had never been married appeared to have a higher risk of major depressive disorder (MDD) [26]. Premutation carriers were less likely to meet criteria for a life-time anxiety disorder but those with children had an increased likelihood of being diagnosed with lifetime panic disorder and current agoraphobia without panic disorder compared to the NCS-R sample [26]. Spanish researchers examined mood and anxiety disorders across three groups: female premutation carriers with children with FXS and mental retardation (MR), mothers of children with MR without FXS, and mothers in the general population [39]. Mothers of children with FXS and MR scored higher in hostility and depression when compared to mothers of mentally retarded children without FXS and to controls [39].
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PSYCHIATRIC MANIFESTATIONS IN ADULT PREMUTATION CARRIERS NIH-PA Author Manuscript
WITH FXTAS
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Patients with FXTAS were found to have a 65% lifetime prevalence of mood disorders and 52% lifetime prevalence of anxiety disorders; specifically, there was a significantly higher prevalence of MDD, panic disorder, specific phobia, and posttraumatic stress disorder (PTSD) when compared with age-matched general population controls [27]. In a sample of 55 patients with FXTAS (36 men and 19 women), 44% had MDD, 2% had dysthymic disorder, 13% met criteria for depressive disorder NOS, 4% presented with adjustment disorders, and 4% had bipolar spectrum disorders [40]. Mood swings, irritability, and anger outbursts were frequent, especially as the illness progressed, but true bipolar disorders (type I or II) were less common. Among the anxiety disorders studied, generalized anxiety disorder was present in 11% of the sample, panic disorder in 5%, PTSD in 9%, 15% of patients had social phobia, and the most common diagnosis was specific phobia (22%) [40]. Similar to data on carriers without FXTAS, we found that 14% of these patients had either alcohol abuse or dependence or polysubstance dependence, as established through the Structured Clinical Interview for DSM-IV-TR (SCID) [41]. Both men and women with FXTAS met criteria for somatoform disorders (see Table 1). The lifetime sequencing of neuropsychiatric illness in FXTAS awaits validation, but patients often report that the anxiety and depressive symptoms preceded the onset of motor and then cognitive deficits, suggesting that the anxiety and mood disorders may represent a psychiatric prodrome of later motor and cognitive impairments (also see Ages of onset of mood and anxiety disorders in fragile X premutation carriers in this issue).
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Suicidality is an aspect of psychiatric care in FXTAS that requires close monitoring. In our experience, at least 5% of patients with FXTAS and comorbid psychiatric disorders have reported suicidal ideation. In our sample of 135 participants with FXTAS of both genders, one man attempted suicide twice. Patients with FXTAS and MDD and/or panic disorder are at increased risk for suicide particularly in the early stages of FXTAS dementia, due to impulsive behavior combined with a sense of loss of cognitive and motor function. Suicidal risk assessment should include the prior history of suicidal behavior, access to means of selfharm, also the impact of male gender, increased age, substance abuse, psychosocial losses (such as loss of employment due to functional impairment), and psychodynamic conflicts (e.g., sense of guilt at being “responsible” for transmission of a genetically-determined illness to family members). The risk of suicide may be even higher than what we have observed to date, given that other neuropsychiatric illnesses with movement disorders are fraught with very high suicidality rates. For example, about 20% of patients with Huntington’s disease endorse suicidal ideation, with depression/anxiety, aggression/ irritability, and substance abuse being significant predictors [42].
TREATMENT The management of psychiatric disturbances associated with FXTAS is determined by the illness stage and comorbidities. First, a thorough workup should be done to rule out thyroid disease, testosterone deficiency, perimenopause, POI, vitamin deficits, or other contributory factors, which should be appropriately addressed [43]. Curr Psychiatry Rev. Author manuscript; available in PMC 2015 January 23.
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A. Psychotherapy
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Useful psychotherapeutic approaches include: supportive, cognitive-behavioral (CBT), and problem-solving therapy (PST). Supportive psychotherapy can address adjustment reactions to having a genetic neurodegenerative disease and the resulting disability, feelings of guilt associated with passing the defective gene on to offspring, issues of infertility and altered expectations in women with POI, as well as living in families with multiple members affected by FXS or premutation involvement. CBT is indicated for social phobia, other anxiety disorders, depression, and somatoform disorders [44, 45]. PST can be delivered in primary care settings and is helpful in addressing depression, even in individuals with executive dysfunction, which is the major cognitive deficit in carriers [46, 47]. Couples therapy is indicated at times, especially in situations where patients with FXTAS become distrustful of their spouse’s actions and may alienate themselves through angry outbursts directed at their caregivers. Family therapy often complements genetic counseling for multigenerational fragile X-spectrum affected families [48]. In advanced disease stages, we counsel all patients to minimize or stop driving which becomes unsafe due to neurological and/or cognitive deficits. We strongly recommend assessing safety issues, including access to means of self-harm, since patients with FXTAS may become despondent and attempt suicide. B. Psychopharmacological management General principles of psychopharmacological management in late life apply, including starting medications at low doses and titrating as tolerated, minimizing benzodiazepines and opioids in cognitively impaired individuals, and paying attention to drug-drug interactions. A high risk of falls is part of the FXTAS picture, due to ataxia and autonomic instability, therefore sedating medications, drugs that may cause or worsen parkinsonism (typical antipsychotics or risperidone at higher doses than 3 mg/day), and agents that may cause orthostatic hypotension (including but not limited to tricyclic antidepressants and trazodone) are not recommended. At this time, no medication directly addresses the disease mechanisms however modest improvements have been noted with symptomatic treatments [49, 50].
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Depressive and anxiety symptoms can be targeted with selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, or mirtazapine, which may also help reduce the neuropathic pain [10, 25, 49-52]. SSRIs provide the additional benefit of increased hippocampal neurogenesis, which has been shown in Alzheimer’s disease and in depression [53-55]. This effect may be helpful to carriers as they age, since brain atrophy is a significant finding in those with FXTAS and even premutation carriers without FXTAS. Low dose benzodiazepines are effective for panic disorder, with the above caveat for their safety of use. Pregabalin or gabapentin are useful for peripheral neuropathy [10, 49]. Antiepileptic mood stabilizers (valproate, oxcarbazepine, lamotrigine) are generally ideal for impulse control disorder and bipolar spectrum disorders. Lamotrigine is an effective mood stabilizer which has also been used for migraines and neuropathic pain [56], both of which may occur in FXTAS. However, not enough evidence exists to support their widespread use since they may worsen the mitochondrial dysfunction that occurs in patients with FXTAS [57, 58]. Lithium has been proposed as therapeutic agent but is less favored in the elderly
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due to possible cognitive and renal side effects. Atypical antipsychotics may help treat the paranoid ideation or psychotic symptoms and can be used as alternate mood stabilizers. Weight-neutral agents, such as aripiprazole or ziprasidone (under QTc monitoring), are preferred because patients with FXTAS often become sedentary due to their neurologic deficits [50]. Quetiapine has the lowest risk of extrapyramidal side effects, but it may cause orthostatic hypotension and metabolic side effects. Stimulants or the norepinephrine reuptake inhibitor atomoxetine have been used to address ADHD symptoms [25]. Anecdotal reports have shown cognitive benefit from cholinesterase inhibitors or memantine [49, 51, 59]. Case reports have also suggested memantine might be helpful for neuropathic pain, although a recent meta-analysis did not find conclusive evidence regarding NMDA receptor antagonist efficacy for this indication [60].
CONCLUSION
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FXTAS is a genetically determined, molecularly based disorder with significant systemic and neuropsychiatric manifestations. Neuropsychiatric aspects of FXTAS may include anxiety, mood, cognitive, and other psychiatric disorders. These problems can begin in childhood for a subgroup of carriers, although why some are affected and others are not is unknown. It is important to carry out fragile X DNA testing when managing patients who have a family history consistent with FXS. A thorough clinical evaluation, including neuroimaging, is crucial. Symptomatic treatments are available, although disease modifying agents have not yet been developed. Psychotherapy is a very important aspect of treatment for families affected by fragile X-associated disorders.
ACKNOWLEDGMENT This work was supported by the National Institutes of Health (NIH) Roadmap Interdisciplinary Research Consortium Grant AG032115 and the NIH Grant MH078041.
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Table 1
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Less Common Psychiatric Disorders in 184 Premutation Carriers. Psychiatric disorder
Men (n = 95)
Women (n = 89)
FXTAS
No FXTAS
FXTAS
No FXTAS
0
0
3
3
1
0
0
0
Psychotic disorders NOS
3
0
2
0
Substance abuse/dependence
24
4
6
9
Alcohol
14
1
4
5
Cannabis
1
1
2
1
Cocaine
2
2
0
2
Opioid
1
0
0
0
Sedative/hypnotic
2
0
0
0
Stimulant
1
0
0
1
3
0
0
0
4
0
4
4
Eating disorders
a
Impulse control disorder
Polysubstance
NIH-PA Author Manuscript
Somatoform disorders
b
a
Include anorexia, bulimia, binge eating disorder
b
Include hypochondriasis, pain disorder, somatization disorder, somatoform disorder NOS.
NIH-PA Author Manuscript Curr Psychiatry Rev. Author manuscript; available in PMC 2015 January 23.
