Fragile X Syndrome and Premutation Disorders: New Developments and Treatments

This book covers both molecular and clinical aspects of Fragile X Syndrome (FXS) and premutation disorders so that new targeted treatments can be understood by clinicians and parents. It covers all premutation disorders including FXTAS, FXPOI and FXAND problems. The main focus is to help clinicians to give the best care possible to patients with FXS and to understand a multidisciplinary treatment approach. Underserved populations such as babies and toddlers with FXS and mothers with the full mutation are highlighted, including the treatments that can be beneficial to them. This book also discuss fragile X associated disorders as they impact the family whose proband has FXS. A highlight of this book is the international perspective on how different cultures deal with FXS and targeted treatments.

• Language: English
• Publisher: Mac Keith Press
• Release date: Nov 10, 2020
• ISBN: 9781911612391

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PhD

Overview of FXS and Fragile X Spectrum Disorders

Randi J Hagerman

This book is written for families with fragile X mutations and physicians/healthcare providers/therapists and teachers who treat these families and their children. Previous books have been written and edited for clinicians and scientists to promote further research and advance our progress in treatment issues. However, the current state of the science in fragile X studies is complex and basic information needs to go to families so that they can educate their healthcare providers and therapists who may not be knowledgeable about the current literature. Most doctors have heard of fragile X but what comes to their mind is fragile X syndrome (FXS) and not premutation disorders. I have heard several times about doctors who are seeing someone with the fragile X-associated tremor ataxia syndrome (FXTAS) and remarking that they are surprised that the patient is not intellectually impaired. So the confusion between FXS and FXTAS continues and this book will help to arm families in educating their doctors, therapists and other healthcare providers about all of the fragile X disorders.

The contributors to this volume are seasoned clinicians and scientists who have years of experience and have worked with us directly or collaborated with us for the benefit of families so that their care is improved. This volume covers those with FXS (full mutation of >200 repeats) in addition to premutation (55–200 CGG repeats) disorders of which there are many. Although many carriers will not experience problems related to the premutation, the majority will experience at least one of the following problems. FXTAS is a disorder of aging carriers that is experienced by approximately 40% of male carriers and 13–16% of female carriers. FXTAS usually begins in those aged in their 60s but may become more prevalent with age and involves up to 75% of male carriers by the time they are 80. Another 16–20% of female carriers will experience fragile X-associated primary ovarian insufficiency (FXPOI) meaning ovarian dysfunction and cessation of menses prior to age 40. For many this is menopause; however, a small percentage of women will become pregnant after FXPOI so the name was changed from ovarian failure to ovarian insufficiency.

The most common set of problems that carriers may experience is called fragile X-associated neuropsychiatric disorders (FXAND). FXAND represents an umbrella term of many neuropsychiatric disorders and one or more of these problems are experienced by carriers more commonly than either FXTAS or FXPOI or age-matched individuals without the premutation. These problems can be experienced by approximately 50% of carriers and their etiology relates to the molecular dysfunction caused by the premutation including mitochondrial dysfunction, RNA toxicity, micro RNA dysregulation, etc. This is explained in great detail in Chapter 4 for those who seek molecular answers. We named this set of disorders with a diagnostic label because many clinicians have felt that the problems of anxiety and depression are all secondary to raising a child with FXS and have not treated these problems in clinic. Although raising a child with FXS can be stressful and can exacerbate anxiety and depression, these neuropsychiatric problems have a molecular basis and they can be present long before a child with FXS enters a family and long after they move out of the home. In childhood, FXAND problems include ADHD, anxiety and/or social deficits or, on occasion, autism spectrum disorder (ASD). In adulthood, FXAND problems include insomnia, chronic fatigue, chronic pain, obsessive-compulsive behavior or disorder (OCD), panic disorder, social deficits, broad autism spectrum phenotype, and social phobia in addition to other types of anxiety or depression. Because chronic pain, insomnia and chronic fatigue have neuropsychiatric disorders associated with them and they are listed in the Diagnostic and Statistical Manual of Psychiatry (DSM 5) as disorders they are included in FXAND. If the neuropsychiatric symptoms are mild and do not meet the diagnostic criteria in the DSM5 for a disorder then they would not meet criteria for FXAND. The FXAND umbrella was named to stimulate more research into the etiology and treatment of these problems. The European families with a fragile X mutation wanted to have a more general term for neuropsychiatric and other conditions associated with the premutation and so the term fragile X-premutation associated conditions (FXPAC) was created. This term also alleviates the stigma of having a disorder associated with the premutation which is important for many carriers.

Some problems associated with the premutation are not covered by FXTAS, FXPOI, and FXAND such as connective tissue problems, hypertension or autoimmune problems but can still cause significant difficulties in some carriers. It is likely that all of the premutation problems are associated with the molecular finding of elevated FMR1 mRNA (discovered by Dr Flora Tassone in 2000) and leading to Ca++ dysregulation and mitochondrial dysfunction. This is a very different mechanism compared with the absence or deficiency of FMRP that occurs in those with FXS. Even though we try to make a clear distinction between the full mutation disorders and the premutation disorders, there is some overlap that can lead to further confusion. For instance, FMRP, the protein that is produced by the FMR1 gene, is typically normal or high in carriers compared with the general population without a premutation; but in the upper end of the premutation (>120 repeats) FMRP may drop somewhat and this can lead to problems with loose connective tissue, such as prominent ears or hyperextensible finger joints. Another area of overlap occurs in those individuals with a full mutation that is unmethylated because this leads to low FMRP but typically elevated levels of FMR1 mRNA. Therefore, these individuals are at risk for FXTAS because the elevated mRNA can cause RNA toxicity. A few cases of men with an unmethylated full mutation who have experienced FXTAS have been reported but they typically have a higher IQ than men with a full mutation that is completely methylated.

Another area of controversy is the association of ASD and FXS. Although in years past those with FXS were not considered to have ‘true autism’, researchers and clinicians realize that ASD is a heterogeneous disorder and there are hundreds of genes that when mutated cause ASD. What many do not appreciate is that FMRP is a regulator of translation for many of the ASD genes and the absence of FMRP leads to dysregulation of many of these same pathways associated with other types of ASD. Also, there is deficiency of FMRP in the brains of those with ASD who do not have an FMR1 mutation and, in addition, a deficiency of FMRP in schizophrenia and some other neuropsychiatric disorders. Therefore, the targeted treatments that are discussed in this volume may be helpful for other forms of ASD besides FXS.

Approximately 60% of those with FXS have ASD by the behavioral definition set forth in the Diagnostic and Statistical Manual of Psychiatry, the DSM 5. However, now that FXS is well accepted as a cause of ASD, we can appreciate the differences between the FXS subtype of ASD and many other forms of ASD. One area of strength for many of those with FXS is their ability to stimulate endearment from others. This is especially true if individuals are mainstreamed in the regular education classroom. Several families have told me that when their son graduated from high school they were the only student who received a standing ovation. Many of my patients have been voted Homecoming King by their school as a measure of the friendships that they had developed even when they had a diagnosis of ASD (Fig. 1.1). This has never happened to any my patients with idiopathic ASD.

There is a social essence that can be part of the FXS phenotype and it is best described by the family of Max, a teenager with FXS, as the ‘Max Factor’. Max lives in Fresno and he is known citywide because of his intense interest in country music. At concerts he is often sitting in the front row and he sometimes stands up and dances. He likes to go to the local radio stations and help the DJs announce songs. He is an encyclopedia of information about country music so he can answer any question on this topic. He is also a member of the cheerleaders of his high school. He cannot do the cheerleading routines as well as the girls, but when he comes out as part of the cheerleading squad everybody cheers him. He is like a mascot for the team and well loved by all because of his personality and we call this the ‘Max Factor’. A famous country music singer came to town for a concert and Max was in a greeting line. When the star came to Max he just bowed down in deference to Max’s fame. Although many boys with FXS have the ‘Max Factor’, some do not and there is a broad spectrum of involvement in FXS that is not only influenced by the molecular status and FMRP level, but also by additional genetic and environmental factors. To optimize one’s potential it takes a multimodality intervention plan that is characterized in the chapters of this book. The plan includes multiple therapies, medications including targeted treatments, and guided environmental stimulation that many families excel in giving to their children.

Many families find the transition from high school into the working world difficult for their children with FXS. However, new programs for vocational training and the college experience have been developed. In Figure 1.2 there are two brothers who were voted homecoming king at their graduation from high school and they have had a unique experience for their education at college level. The vast majority of boys with FXS do not go to college but when the education is geared to their strengths and their needs at the adult level they can be successful. Their Advancing Students Toward Education and Employment Program (ASTEP) at Minot State University in North Dakota serves as a model to what we need to strive toward. This program is for young adults aged 18 to 26 with intellectual disabilities to learn about employment and independent living skills in addition to academic subjects in two different tracks depending on their reading and skill level. Special education teachers and therapists are involved and each student has individual mentors who help them choose courses based on their interests and skill level and they live in the dorms for the college so they participate in the campus life. Both of these brothers have been successful and this program has enhanced their self-image and their ability level for successful employment and independent living.

Figure 1.1 Two teenage brothers with FXS have been voted homecoming king in their respective high school graduating class. Here, the older brother was voted homecoming king. Published with consent.

Figure 1.2 The older brother is standing beside his younger brother who was also voted homecoming king when he graduated. Published with consent.

Figure 1.3 These brothers are standing outside of their college dorm at Minot State University in North Dakota. Published with consent.

We are entering a new age of genetic interventions and this is an exciting time to consider a future molecular or cellular intervention for FXS and even premutation involvement. However, the stem cell therapies that are currently advertised are not efficacious and not specific for FXS, and in some instances can be dangerous. There are many animal studies that are currently in progress and others that need to be done for gene therapy and stem cell therapy for FXS but they are not yet ready for human trials. The new tools for gene editing (CRISPR/Cas9) are phenomenal and the research is progressing but it will take a few years for studies in patients with FXS and premutation disorders. The future is bright but before genetic interventions are available you can take advantage of the interventions described in this volume.

Autism Spectrum Disorder and Fragile X Syndrome

Intertwined and Guiding Interventions

Leonard Abbeduto, Angela John Thurman, and Jenniffer Villarreal

Unlike fragile X syndrome (FXS), which can be diagnosed with virtually 100% accuracy from a set of tests performed on a blood sample, autism spectrum disorder (ASD) is a behaviorally defined condition, meaning that clinicians decide whether a person displays behaviors that meet certain predetermined criteria regardless of the etiology, or cause, of those behaviors. The criteria for ASD are (1) persistent impairments in social communication and social interaction that are severe enough to negatively impact everyday functioning in multiple situations and (2) presence of narrow and repetitive interests, behaviors, and/or activities (American Psychiatric Association 2013). Because ASD is a behavioral disorder, it can have many different causes, and it can co-occur with other disorders, including FXS. In this chapter, we discuss the occurrence of ASD among people with FXS. Table 2.1 provides examples of some of the behaviors that clinicians would consider evidence of ASD.

DIAGNOSING ASD

ASD is typically diagnosed by (1) conducting an interview with a parent or caregiver to learn about the developmental history and behavior of the individual in question and (2) observing that individual in a semi-structured situation. In order to systematize the interview and observational process, researchers have developed instruments that are often used to help gather and organize the information needed to diagnose ASD. The Autism Diagnostic Interview-Revised (ADI-R; Rutter, LeCouteur and Lord 2003) and the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2; Lord et al. 2012) are two such commonly used measures, although there are others. The ADI-R is a structured interview that includes questions about both past and current functioning and leads to categorizing the targeted individual as having or as not having concerns suggesting the presence of ASD. The ADOS-2 consists of a series of examiner-initiated activities and probes designed to produce desired social behaviors or, in the case of individuals with ASD, the expected atypical responses or behaviors. The ADOS-2 leads to a categorization as having or not having concerns suggesting the presence of ASD, in addition to allowing the computation of a quantitative ASD severity score. Importantly, the ADI-R and ADOS-2 outcomes are not simply taken blindly by the clinician in terms of the appropriate diagnosis; instead, the results and observations generated through the administration of these two measures, and/or others, are combined with the expert opinion of the clinician to arrive at a diagnosis.

A few caveats about the ASD diagnostic process: first, the measures used to help clinicians diagnose ASD do not always ‘agree’ in that it is not unusual for one measure, such as the ADI-R, to indicate that an individual has ASD, whereas another measure, such as the ADOS-2, might suggest that the same individual does not meet the criteria for ASD. This is also true when diagnosing ASD in FXS. As an example, McDuffie et al. (2012) found that the two measures disagreed for 29% of the 10to 15-yearolds with FXS they studied. Second, the ADI-R, ADOS-2, and other measures used in the diagnostic process are typically designed to avoid confusing the impairments that reflect ASD with impairments that reflect an intellectual disability or limitations in language ability. In other words, the goal of these measures is to assign a diagnosis of ASD because the individual truly has ASD and not because his or her cognitive or language limitations make it ‘look’ like he or she has ASD. Although the measures are largely successful in achieving this goal for the vast majority of individuals evaluated, it appears that this is less true for individuals with FXS. Indeed, cognitive and language impairments have significant influences on scores and decisions about the ASD diagnosis for individuals with FXS (e.g. Abbeduto et al. 2019). Third, because the ASD diagnosis requires interpretation and decision-making by a clinician, a clinician’s experience with both individuals with FXS and individuals with ASD not due to FXS or another genetic condition (hereafter referred to as ‘nonsyndromic’ ASD) may play a particularly important role in the diagnostic process for individuals with FXS. Unfortunately, not all clinicians will have adequate experience with both disorders, and clinicians may differ in their perspective about the evidence needed to assign an ASD diagnosis to an individual with FXS. The bottom line is that it may be more difficult to decide whether an individual with FXS truly meets the criteria for ASD than for individuals without FXS and the diagnosis may not always be accurate.

ASD IN FXS

More than half of people with FXS also meet criteria for having ASD (hereafter referred to has FXS+ASD), although ASD is more common among males than females with FXS (Kaufmann et al. 2004; Harris et al. 2005; Clifford et al. 2007; McDuffie et al. 2010; Budimirovic and Kaufmann 2011; Klusek, Martin and Losh 2014; Kaufmann et al. 2017). Even those individuals with FXS who do not meet criteria for ASD (hereafter referred to as FXS only) are thought to display behaviors that are often seen in individuals with nonsyndromic ASD. In fact, many of the behaviors thought to be typical of FXS also ‘fit’ the definition of ASD, including perseverative, or repetitive, speech (Belser and Sudhalter 2001; Murphy and Abbeduto 2007; Martin et al. 2012), poor eye contact (Merenstein et al. 1996; Roberts et al. 2007), and repetitive motor movements (Wolff et al. 2012). Indeed, the FMR1 full mutation that causes FXS is also the leading single-gene cause of ASD, accounting for 3–5% of all cases of ASD (Kaufmann et al. 2017).

The symptoms of ASD emerge in the first year of life for individuals with FXS and remain stable and equally impairing during the preschool years (Roberts et al. 2016). As children with FXS move into the school years, however, their ASD symptoms begin to change. In particular, some ASD symptoms seem to worsen during middle to late childhood (Hatton et al. 2006; Thurman et al. 2015; Lee et al. 2016). Interestingly, there is evidence of an improvement in ASD symptoms in adolescence at least for males with FXS, although largely only in the social communication domain, and not the restricted and repetitive interests and behaviors domain (McDuffie et al. 2010). It is likely that this improvement in adolescence results from the cumulative effects of education, behavioral therapies, and pharmacological treatments, which should be encouraging for families.

The high rate of co-occurrence, or comorbidity, of FXS+ASD has led many researchers and clinicians to suggest treatments that are found to be effective for individuals with nonsyndromic ASD might also be effective for individuals with FXS and vice versa (e.g. Belmonte and Bourgeron 2006; Berry-Kravis et al. 2012; Gurkan and Hagerman 2012; Hagerman et al. 2012). There is evidence, however, that although there are many similarities between individuals with FXS+ASD and those with nonsyndromic ASD, there are differences as well. Moreover, these differences may be clinically important, suggesting fundamentally different problems and courses of treatment. In the remaining sections of this chapter, we briefly summarize some of the benefits and limitations of diagnosing ASD in individuals with FXS.

VALUE OF AN ASD DIAGNOSIS IN FXS

There are many differences between individuals with FXS who do and do not meet criterial for ASD, which suggests that the diagnosis is clinically useful in that it tells us something important about the differential treatment needs of the individuals in question. In children with FXS, those with an ASD diagnosis, relative to those without the diagnosis, have (1) more atypical reactions to overtures from an unfamiliar person (Scherr et al. 2017); (2) have more serious problems in using language to participate successfully in social interaction (Roberts et al. 2007; Estigarribia et al. 2011; Klusek et al. 2014; Lee et al. 2016); and (3) are more likely to exhibit social avoidance behaviors, such as failing to make eye contact or withdrawing from social interaction, as well as showing unusual patterns of physiological arousal in social situations (Roberts et al. 2007; Roberts et al. 2009).

The differences between individuals with FXS with and without ASD extend beyond the symptoms and behaviors that are part of the criteria for an ASD diagnosis (see Table 2.2). First, there are differences in cognitive functioning. In particular, individuals with FXS+ASD have lower IQs, on average, than those with FXS only and, more generally, the lower the IQ the more severe the ASD symptoms (Bailey et al. 2000; Rogers, Wehner and Hagerman 2001; Kaufmann et al. 2004; Philofsky et al. 2004; Hatton et al. 2006; Lewis et al. 2006; Hernandez et al. 2009; Thurman et al. 2015). The relationship between IQ and ASD symptoms is generally stronger and more consistent, however, for the social aspects of ASD than for its restricted interests and repetitive behavior aspects (Lee et al. 2017).

Second, the language challenges of individuals with FXS vary according to whether they have an ASD diagnosis and with the severity of their ASD symptoms. Kover et al. (2012), for example, studied 10to 17-year-old males with FXS and found that individuals with more severe ASD symptoms were less talkative, an association that is consistent with the lack of motivation to engage in social interaction that is a hallmark of ASD in general (Chevallier et al. 2012). In addition, several studies have found individuals with FXS+ASD are especially impaired in receptive language relative to those with FXS only, with fewer differences in expressive language (e.g. Rogers et al. 2001; Philofsky et al. 2004; Lewis et al. 2006). ASD severity is also more closely related to receptive language skill than expressive language skill in males with FXS (McDuffie et al. 2012). Interestingly, there is evidence that receptive language is also more challenging than expressive language for individuals with nonsyndromic ASD (e.g. Kjelgaard and Tager-Flusberg 2001; Ellis Weismer, Lord and Esler 2010; Kover et al. 2013). In a recent study, Martin et al. (2018) found that females with FXS+ASD were more linguistically nonresponsive than females with FXS only, whereas males with FXS+ASD were more likely to produce language that was not contingent on the previous talk than males with FXS only.

Third, Raspa et al. (2018) conducted a study focused on mastery of a variety of skills necessary for independent adult functioning, such as handling money, personal hygiene, reading, and writing, assessed via parent report in a large internet-based survey. These researchers found that on virtually all measures of functional academic and daily living skills, males with FXS+ASD scored more poorly than males with FXS only. Importantly, these differences in skills also predicted the extent to which these men with FXS led independent lives. It is unclear from these findings, however, whether specific ASD symptoms were more important than others or whether other skills that are related to ASD, such as language ability, played a role as well. Nevertheless, the findings demonstrate the potential value of an ASD diagnosis by focusing on the need for training of functional skills.

In concluding this section on the value of the ASD diagnosis, we note that there have been some studies that have examined specific ASD symptoms that distinguish individuals with FXS who meet criteria for ASD from those who not meet criteria. There is some evidence that the differences, at least for older children and adolescents, are more pronounced in the domain of restricted interests and repetitive behaviors than in the social domain (McDuffie et al. 2010). Such findings are important in suggesting that, although the ASD diagnosis identifies real differences among individuals with FXS, the differences may