Autism Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder in Boys with the Fragile X Premutation

Abstract

Fragile X syndrome (FXS) is caused by a full mutation expansion (>200 CGG repeats) in the FMR1 gene that results in a deficiency of the fragile X mental retardation protein. Although most individuals with the premutation (55-200 CGG repeats) are considered unaffected by FXS, recent case studies have documented children with the premutation who have cognitive deficits, behavioral problems, and/or autism spectrum disorders. The objective of this study was to compare the prevalence of autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) symptoms in boys with the premutation who presented as probands, in brothers with the premutation who did not present as probands, and in normal brothers of premutation and/or full mutation carriers. Participants included 43 male children: 14 probands who presented to clinic, 13 nonprobands who were identified through cascade testing (routine genetic testing of family members after identification of a proband) and confirmed to have the premutation, and a control group of 16 male siblings of individuals with the fragile X premutation or full mutation who were negative for the FMR1 mutation. Participants came from 1 of 2 collaborative sites: University of California, Davis and La Trobe University in Australia. Parents completed the Conners' Global Index-Parent Version for assessing symptoms of ADHD and the Social Communication Questionnaire (SCQ) for identifying symptoms of ASD. Children who were in the ASD range on the SCQ (n = 13) underwent further evaluation with either the Autism Diagnostic Observation Schedule-Generic (n = 10) or the Autism Diagnostic Interview-Revised (n = 3). A final diagnosis of ASD included clinical assessment utilizing DSM-IV-TR criteria in addition to the standardized assessments. There was a higher rate of ASD in boys with the premutation presenting as probands (p < 0.001) or nonprobands (p < .04) compared with sibling controls without the premutation. In addition, probands had a significant increase in ADHD symptoms compared with controls (p < .0001). Of the probands, 93% had symptoms of ADHD and 79% had ASD. In the nonproband premutation group, 38% had symptoms of ADHD and 8% had ASD. Thirteen percent of sibling controls had symptoms of ADHD and none had ASD. IQ scores were similar in all 3 groups (p = .13), but the use of psychotropic medications was significantly higher in probands with the premutation compared with that in controls (p < .0001). Developmental problems have been observed in premutation carriers, particularly those who present clinically with behavioral difficulties. Although this study is based on a small sample size, it suggests that premutation carriers, even those who do not present clinically, may be at increased risk for an ASD and/or symptoms of ADHD. If the premutation is identified through cascade testing, then further assessment should be carried out for symptoms of ADHD, social deficits, or learning disabilities.

Screening for Expanded Alleles of the FMR1 Gene in Blood Spots from Newborn Males in a Spanish Population

“…6 This higher frequency of premutation alleles has important implications for the prevalence in Spain of developmental and behavioral problems (eg, attention deficit hyperactivity disorder and autism spectrum disorders 22,23 ) that are frequently observed in children who carry premutation alleles, and for fragile X-associated neuroendocrine (fragile X primary ovarian insufficiency) and neurodegenerative (fragile X-associated tremor/ataxia syndrome) disorders among adult carriers. However, the current results speak more broadly of the potential for significant differences in allele frequencies across different populations.…”

Reduced Hippocampal Activation During Recall is Associated with Elevated FMR1 mRNA and Psychiatric Symptoms in Men with the Fragile X Premutation

“…Carriers of premutation expansions (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are at increased risk for social, emotional, and cognitive problems and of developing a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS; Dorn et al 1994;Franke et al 1998;Tassone et al 2000a, b, c;Johnston et al 2001;Hagerman and Hagerman 2002;Borghgraef et al 2004;Moore et al 2004a, b;Cornish et al 2005;Hessl et al 2005;Farzin et al 2006). FXTAS involvement in premutation carriers, when it occurs, typically manifests itself in carriers over the age of 50, though in rare cases it has been reported earlier.…”

Fragile X spectrum disorders

“…Myers et al (2001), in a small study of 14 children with the premutation found a trend towards lower performance IQ (101). Boys with the premutation have higher rates of ADHD symptoms, shyness, social deficits, autism spectrum disorder (98,102) and, less commonly, intellectual disability (ID) compared to controls. Many case reports of premutation involvement and ASD have been published.…”

“…Goodlin-Jones et al (2004), reported four premutation boys and two girls with ASD, and their levels of FMRP were significantly lower than normal (103). In the Farzin et al (2006) study, there were 14 boys with the premutation whose parents sought medical attention for their sons' behavior problems (probands), 13 boys with the premutation diagnosed by cascade testing (nonprobands), and 16 boys who were siblings without the premutation (controls). They found that 93% (13 of 14) of probands, 38% (6 of 13) of the non-probands and 13% (2 of 16) of the controls had ADHD.…”