Trajectories of Change in the Behavioral and Health Phenotype of Adolescents and Adults with Fragile X Syndrome and Intellectual Disability: Longitudinal Trends Over a Decade

Purpose The behavioral phenotype of fragile X syndrome (FXS) and intellectual disability (ID) proposed by Hagerman et al. (2009) was primarily based on data from male children and teens. The purpose of this study was to promote a better understanding of how this condition manifests in adults. Design/methodology/approach A total of 18 men of FXS were paired with men with Down syndrome on the basis of age and level of ID. A screening checklist was created on the basis of existing scales and the Hagerman et al. (2009) behavioral phenotype and completed by care providers. Findings Five of the 12 features of the phenotype were significantly more present among men with FXS than in men with Down syndrome. Originality/value This study provides partial confirmation for Hagerman et al.’s (2009) behavioral phenotype of FXS among men with moderate ID and identified some traits that warrant further investigation.

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Fragile X: A Family of Disorders

Cognitive and Behavioral Abnormalities of Pediatric Diseases ◽

10.1093/oso/9780195342680.003.0024 ◽

2010 ◽

Author(s):

Ann M. Mastergeorge ◽

Jacky Au

Keyword(s):

Intellectual Disability ◽

Fragile X Syndrome ◽

X Chromosome ◽

Culture Media ◽

Fragile Site ◽

Fragile X ◽

Single Gene ◽

Repeat Sequence ◽

Full Mutation ◽

Tissue Culture Media

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

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Towards Mechanism-Based Treatments for Fragile X Syndrome

Brain Sciences ◽

10.3390/brainsci9080202 ◽

2019 ◽

Vol 9 (8) ◽

pp. 202

Author(s):

Daman Kumari ◽

Inbal Gazy

Keyword(s):

Autism Spectrum Disorder ◽

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Autism Spectrum ◽

Spectrum Disorder

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide [...]

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Single-Nucleotide Mutations in FMR1 Reveal Novel Functions and Regulatory Mechanisms of the Fragile X Syndrome Protein FMRP

Journal of Experimental Neuroscience ◽

10.4137/jen.s25524 ◽

2015 ◽

Vol 9s2 ◽

pp. JEN.S25524 ◽

Cited By ~ 10

Author(s):

Joshua A. Suhl ◽

Stephen T. Warren

Keyword(s):

Intellectual Disability ◽

Fragile X Syndrome ◽

Fragile X ◽

Point Mutations ◽

Regulatory Mechanisms ◽

Cgg Repeat ◽

Novel Variants ◽

Sequencing Studies ◽

The Cost ◽

Syndrome Protein

Fragile X syndrome is a monogenic disorder and a common cause of intellectual disability. Despite nearly 25 years of research on FMR1, the gene underlying the syndrome, very few pathological mutations other than the typical CGG-repeat expansion have been reported. This is in contrast to other X-linked, monogenic, intellectual disability disorders, such as Rett syndrome, where many point mutations have been validated as causative of the disorder. As technology has improved and significantly driven down the cost of sequencing, allowing for whole genes to be sequenced with relative ease, in-depth sequencing studies on FMR1 have recently been performed. These studies have led to the identification of novel variants in FMR1, where some of which have been functionally evaluated and are likely pathogenic. In this review, we discuss recently identified FMR1 variants, the ways these novel variants cause dysfunction, and how they reveal new regulatory mechanisms and functionalities of the gene.

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Delineating Repetitive Behavior Profiles across the Lifespan in Fragile X Syndrome

Brain Sciences ◽

10.3390/brainsci10040239 ◽

2020 ◽

Vol 10 (4) ◽

pp. 239

Author(s):

Debra L. Reisinger ◽

Rebecca C. Shaffer ◽

Nicole Tartaglia ◽

Elizabeth Berry-Kravis ◽

Craig A. Erickson

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Repetitive Behavior ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Motor Behaviors ◽

Sensory Motor ◽

Adolescents And Adults ◽

Males And Females ◽

The Impact

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7–12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.

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