Aging With Developmental Disabilities, Part 1: Fragile X–Associated Disorders

Table – Psychiatric disorders in FMR1 premutation carriers

Individuals with developmental disabilities encounter multiple difficulties as they age. Underlying molecular mechanisms may result in cascading changes at the neuronal level that, combined with the effects of aging, contribute to additional challenges, resulting in new psychiatric manifestations or exacerbations of preexisting conditions. At the same time, medical diseases, often comorbid with intellectual disabilities, may contribute to the development of cognitive deficits or psychiatric disorders in late life. For example, cerebrovascular risk factors, such as diabetes mellitus, hyperlipidemia, and hypertension, may cause microvascular ischemic changes, which are associated with vascular depression or cognitive disorders.

Several examples of neurodevelopmental disorders in older adults are discussed in this article. This is not intended to be an exhaustive review, but rather a quick guide to common neurodevelopmental conditions and their associated late-life neuropsychiatric manifestations. Here, we discuss the fragile X–associated disorders: fragile X–associated tremor/ataxia syndrome and fragile X syndrome (FXS). In part 2 of the article (in an upcoming issue of Psychiatric Times), the discussion will center on autism spectrum disorders, Down syndrome, and 22q deletion syndrome.

Before beginning our discussion, we emphasize that a common point for the conditions associated with intellectual disability is the need to establish a cognitive baseline (and to understand whether a decline from baseline occurred) in order to make an accurate diagnosis of major neurocognitive disorder later in life.

Fragile X–associated disorders

Fragile X–associated disorders are a fascinating group of neurodevelopmental disorders. Awareness of the complex molecular and clinical phenomena associated with these conditions is still an area of growth for many psychiatrists. The fragile X mental retardation 1 (FMR1) gene consists of successive CGG repeats in the promoter region of the gene. The number of CGG repeats determines the phenotype, as follows: neurotypical individuals have fewer than 45 repeats; those in the “gray zone” have 45 to 54 repeats (and may develop clinical problems similar to those with the premutation); 55 to 200 CGG repeats indicate the presence of a premutation; and the full mutation is found in those with over 200 repeats.

Approximately 1 in 150 to 200 females and 1 in 400 to 450 males in the general population have the premutation.¹ Almost half of FMR1 premutation carriers have anxiety and depressive disorders, along with other, less frequent, psychiatric comorbidities.^2-4 Some carriers also have neurodevelopmental disorders, such as autism spectrum disorders and/or intellectual disability, although most do not.¹

The Table illustrates common psychiatric diagnoses encountered in premutation carriers. Male carriers may also present with multiple medical problems, including type 2 diabetes mellitus, dyslipidemia, hypertension, obesity, and sleep apnea. Female carriers have been known to have primary ovarian insufficiency leading to premature menopause (20%); they may also have hypertension (50%), migraines (40%), thyroid problems (40%), fibromyalgia (40%), and autoimmune diseases (10%).⁵

Fragile X–associated tremor/ataxia syndrome (FXTAS). In late life, FMR1 gene premutation carriers may develop FXTAS, a neurodegenerative disease that was discovered relatively recently.⁶ Initially thought to affect men exclusively, FXTAS is now known to occur in approximately 40% of males in their 60s and up to 16% of females with the premutation.^5,7 FXTAS manifests with intention tremor, cerebellar ataxia, parkinsonism, neuropathy, psychiatric comorbidities, and progressive cognitive impairment, which can lead to a major neurocognitive disorder in some patients. Neuroimaging studies have shown generalized cerebral and cerebellar atrophy and white matter hyperintensities on T2 MRI in the middle cerebellar peduncles or in the splenium of the corpus callosum.^1,8

Cognitive deficits in premutation carriers include executive dysfunction (prominent and present early, even before the manifestation of FXTAS) and short-term memory deficits. FXTAS may occur in up to 30% of patients in advanced stages of disease, particularly men. This newly discovered major neurocognitive disorder has been described as a mixed cortical-subcortical picture, with psychomotor slowing, executive dysfunction, deficits in memory (recall and retrieval) and attention, and personality changes.⁹ The FXTAS major cognitive disorder is clinically and neuropathologically different from Alzheimer disease and all other known major neurocognitive disorders.

On pathological examination, eosinophilic ubiquitin-positive intranuclear inclusions are present in neurons and astrocytes throughout the brain, as well as in the peripheral nervous system and other organs. In a case series of 8 women with the premutation, all had these pathognomonic intranuclear inclusions. Three of the carriers also had amyloid plaques and neurofibrillary tangles sufficient to support a neuropathological diagnosis of Alzheimer disease.¹⁰ More research is needed to fully understand the major neurocognitive disorder of FXTAS. What is known indicates that the FMR1 premutation sometimes causes a neurodevelopmental disorder and more commonly causes late-life neurodegenerative changes, including FXTAS.

Fragile X syndrome. FMR1 full mutations lead to gene methylation and silencing and thus the absence of the FMR1 protein, which is an RNA-binding protein that plays an important role in synaptic plasticity and is thus critical in brain development and aging processes. The absence of the FMR1 protein leads to FXS, the most common cause of inherited intellectual disability, with an estimated prevalence of 1 per 3600 to 1 per 6000 in the general population.¹¹

Psychiatric manifestations of FXS include anxiety, ADHD, autism spectrum disorders, mood instability, and aggression. In fact, FXS is the most common single gene cause of autism spectrum disorders, which are present in 30% of males with the FMR1 mutation.¹² FMR1 protein represses amyloid precursor protein translation, which leads to excess amyloid precursor protein and in turn results in formation of β-amyloid plaques. Few studies have focused on aging adults with FXS. In a review of 62 individuals with FXS (44 males, 18 females) aged 40 years or older, 6 (10%) reported cognitive decline or had received a diagnosis of a major neurocognitive disorder.¹³ Approximately 40% of participants also had neurological problems, including tremor, ataxia, parkinsonism, seizures, tardive dyskinesia, and tics. Other medical conditions included gastrointestinal symptoms, obesity, hypertension, and cardiac problems.

Treatment considerations

Treatment strategies for late-life manifestations of neurodevelopmental disorders include psychosocial approaches and management of symptoms such as agitation, anxiety, apathy, depression, insomnia, irritability, and psychosis. Psychosocial strategies include behavior modification based on the antecedent-behavior-consequence model, cognitive-behavioral therapy, social skills training, supportive psychotherapy, and family caregiver support and education interventions.

Targeted treatments are being explored for FXS (antagonists of the metabotropic glutamate receptor mGluR5, GABA A and B receptor antagonists, minocycline, and others), although these agents have not been studied specifically in older adults with FXS. The NMDA antagonist memantine has been used off-label for maladaptive behaviors in FXS.14 One randomized, double-blind, placebo-controlled trial that evaluated the effects of memantine on the cognitive and motor symptoms of FXTAS did not reveal any significant benefit.¹⁵ Clearly, more research is needed to identify effective treatments for neurodevelopmental disorders in late life.

The majority of adults with neurodevelopmental disorders are physically, emotionally, and financially dependent on their families throughout their lives; many are cared for at home by unpaid family caregivers. In fragile X families the same individual (who may also be a premutation carrier) may care for young children with FXS and aging parents with FXTAS. Clinicians should be vigilant and assess for caregiver burden at every visit and be familiar with local and national resources that can provide support and respite to families.

Acknowledgment-The authors acknowledge the American Association for Geriatric Psychiatry (AAGP) for helping to bring this article to fruition. The AAGP is a national association representing and serving its members and the field of geriatric psychiatry. The AAGP promotes the mental health and well-being of older people through professional education, public advocacy, and support of career development for clinicians, educators, and researchers in geriatric psychiatry and mental health.

Disclosures:

Dr Seritan is a Geriatric Psychiatrist in the Department of Psychiatry, University of California, San Francisco, San Francisco, CA. Mr Ligsay is a medical student at the University of California, Davis School of Medicine, Sacramento, CA. Dr Hagerman is Distinguished Professor and Endowed Chair in Fragile X Research in the Department of Pediatrics, University of California, Davis Medical Center, Sacramento, CA and Medical Director of the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, CA. Dr Seritan and Mr Ligsay report no conflicts of interest concerning the subject matter of this article; Dr Hagerman reports that he has received support from the NIH for genotype-phenotype study in fragile X premutation disorders.

References:

1. Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome. Ann NY Acad Sci. 2015;1338:58-70.

2. Roberts JE, Bailey D, Mankowski J, et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:130-139.

3. Bourgeois JA, Seritan AL, Casillas M, et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry. 2011;72:175-182.

4. Seritan AL, Ortigas M, Seritan S, et al. Psychiatric disorders associated with FXTAS. Curr Psychiatry Rev. 2013;9:59-64.

5. Coffey SM, Cook K, Tartaglia N, et al. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet. 2008;146:1009-1016.

6. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127-130.

7. Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA. 2004;291:460-469.

8. Apartis E, Blancher A, Meissner WG, et al. FXTAS: new insights and the need for revised diagnostic criteria. Neurology. 2012;79:1898-1907.

9. Seritan AL, Nguyen DV, Farias ST, et al. Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): comparison with Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1138-1144.

10. Tassone F, Greco CM, Hunsaker MR, et al. Neuropathological, clinical, and molecular pathology in female fragile X premutation carriers with and without FXTAS. Genes Brain Behav. 2012;11:577-585.

11. Schneider A, Ligsay A, Hagerman RJ. Fragile X syndrome: an aging perspective. Dev Disabil Res Rev. 2013;18:68-74.

12. Richards C, Jones C, Groves L, et al. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2015;2:909-916.

13. Utari A, Adams E, Berry-Kravis E, et al. Aging in fragile X syndrome. J Neurodev Disord. 2010;2:72-76.

14. Erickson CA, Mullett JE, McDougle CJ. Open-label memantine in fragile X syndrome. J Autism Dev Disord. 2009;39:1629-1635.

15. Seritan AL, Nguyen DV, MuY, et al. Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double blind, placebo-controlled trial. J Clin Psychiatry. 2014;75:264-271.