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Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment Walter E

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Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment Walter E Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment Walter E. Kaufmann, MD,a, b Sharon A. Kidd, PhD, MPH,c Howard F. Andrews, PhD,d Dejan B. Budimirovic, MD, e Amy Esler, PhD, LP, f Barbara Haas-Givler, MEd, BCBA, g Tracy Stackhouse, MA, OTR,h Catharine Riley, PhD, MPH,i Georgina Peacock, MD, MPH, i Stephanie L. Sherman, PhD, j W. Ted Brown, MD, PhD,k Elizabeth Berry-Kravis, MD, PhDl abstract BACKGROUND AND OBJECTIVE: Individuals with fragile X syndrome (FXS) are frequently codiagnosed with autism spectrum disorder (ASD). Most of our current knowledge about ASD in FXS comes from family surveys and small studies. The objective of this study was to examine the impact of the ASD diagnosis in a large clinic-based FXS population to better inform the care of people with FXS. METHODS: The study employed a data set populated by data from individuals with FXS seen at specialty clinics across the country. The data were collected by clinicians at the patient visit and by parent report for nonclinical and behavioral outcomes from September 7, 2012 through August 31, 2014. Data analyses were performed by using χ2 tests for association, t tests, and multiple logistic regression to examine the association between clinical and other factors with ASD status. RESULTS: Half of the males and nearly 20% of females met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for current ASD. Relative to the FXS-only group, the FXS with ASD (FXS+ASD) group had a higher prevalence of seizures (20.7% vs 7.6%, P < .001), persistence of sleep problems later in childhood, increased behavior problems, especially aggressive/disruptive behavior, and higher use of α-agonists and antipsychotics. Behavioral services, including applied behavior analysis, appeared to be underused in children with FXS+ASD (only 26% and 16% in prekindergarten and school-age periods, respectively) relative to other populations with idiopathic ASD. CONCLUSIONS: These findings confirm among individuals with FXS an association of an ASD diagnosis with important cooccurring conditions and identify gaps between expected and observed treatments among individuals with FXS+ASD. a Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts; bGreenwood Genetic Center, Greenwood, South Carolina; cNational Fragile X Foundation, Washington, District of Columbia; dDepartment of Biostatistics, Columbia University Mailman School of Public Health, New York, New York; eKennedy Krieger Institute, Baltimore, Maryland; fUniversity of Minnesota, Minneapolis, Minnesota; gGeisinger Health System, Lewisburg, Pennsylvania; hDevelopmental FX, Denver, Colorado; iNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia; jDepartment of Human Genetics, Emory University School of Medicine, Atlanta, Georgia; kNew York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York; and Departments of lPediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, Illinois Dr Kaufmann conceptualized and designed the analyses, contributed to data collection and interpreted the data, drafted the initial manuscript, and revised the manuscript; Dr Kidd contributed to design of the analyses, interpreted the data, and drafted and revised the manuscript; Dr Andrews analyzed and contributed to the interpretation of the data and critically reviewed and revised the manuscript; Dr Budimirovic contributed to design of the analyses, contributed to data collection and interpretation of the data, and drafted and revised the manuscript; Dr Esler contributed to data collection and interpretation of the data and critically reviewed and revised the manuscript; Ms Haas-Givler contributed to the conception and design of the analyses, contributed to data collection, and assisted with drafting of the manuscript; Ms Stackhouse contributed to the conception and design of the analyses and assisted with drafting of the manuscript; Dr Riley drafted and revised the manuscript; Dr Peacock critically reviewed and revised the manuscript; Dr Sherman contributed to the conception and design of the analyses and critically Downloaded from www.aappublications.org/news by guest on September 24, 2021 SUPPLEMENT ARTICLE PEDIATRICS Volume 139 , Number s3 , June 2017 :e 20161159 Fragile X syndrome (FXS)1, 2 is the individuals with FXS exhibit poor FXS+ASD also have a higher rate most common known inherited form eye contact, difficulties with peer of seizures than those with FXS of intellectual disability (ID), with relationships, social withdrawal, only. 13, 32 The increased frequency prevalence estimates of ∼1/4000 repetitive behaviors, and need for of neurologic and behavioral to 1/5000 in males and ∼1/6000 to sameness (ie, distress at apparently impairments in subjects with 1/8000 in females.3 –5 FXS is nearly small changes in daily activities). 6, 14, 15 FXS+ASD appears to result in more always due to an expanded CGG Depending on the gold standard severe educational and vocational repeat sequence (>200 repeats), research criteria used for the problems, 7 as well as more significant termed a “full mutation, ” in the 5′ diagnosis of autism or ASD, studies therapeutic challenges, than those untranslated region of the FMR1 on males with FXS have reported that present in subjects with FXS only, gene located at Xq27.3. Smaller CGG 30% to 54% met diagnostic criteria although data describing these repeat expansions in the range of 55 for autism by direct assessment16 – 18 outcomes are limited. to 200 (termed the “premutation”) and 46% by parent report. 19 In are associated with other clinical addition, 30% to 43% of males met The main obstacle for determining presentations, reviewed elsewhere.6, 7 diagnostic criteria for ASD20 or medical and neurobehavioral The majority of males who carry the pervasive developmental disorder– cooccurring conditions exacerbated full mutation have mild to moderate not otherwise specified.18 For by ASD in FXS, and their impact ID. One-third to one-half of all females, 16% to 20% met diagnostic on interventions and outcomes, is females with the full mutation have criteria for autism17 or were assigned that most studies of ASD in FXS are normal intellectual function because by parent report. 19 –22 Several studies based on small clinical research of cellular mosaicism resulting have attempted to delineate unique samples or family surveys. Small from X-chromosome inactivation features of ASD in FXS; their findings cohorts may not be generalizable to patterns. 8, 9 A high proportion of show relatively more prominent the entire population and although males and females with FXS display social withdrawal, higher levels of family surveys may produce behavioral abnormalities.6 As with anxiety, and less intense simple and accurate accounts of medical most aspects of the FXS phenotype, complex repetitive and restricted data, this type of information behavioral manifestations in FXS are behaviors as measured by ASD always needs to be confirmed in quite variable and include attention diagnostic instruments. 6, 13 a clinical setting. The Fragile X deficits, hyperactivity/impulsivity, Online Registry With Accessible hyperarousal, anxiety, self-injurious ASD is a lifelong disorder that Research Database (FORWARD), a behavior, and autism spectrum impacts multiple aspects of the registry and longitudinal database, disorder (ASD).6 individual’s functioning. Comparisons provides a large sample size with between subjects with FXS with ASD clinical data for this rare disorder ASD is a developmental behaviorally (FXS+ASD) and subjects with FXS to examine the impact of ASD in defined disorder with multiple without ASD (FXS only) reveal that FXS (see Sherman et al in this etiologies. Among the genetic causes, the former group is more affected supplement). In this study, we used FXS is the most common known in many cognitive 9, 20, 23, 24 FORWARD to study the impact of inherited single-gene disorder, and behavioral areas.6, 7, 13 – 15, 25 an ASD diagnosis in children and accounting for an estimated 1% to Examples of areas that are more adolescents/young adults with 6% of all cases of ASD. 10, 11 ASD is problematic in those with FXS+ASD FXS in 4 key areas: (1) neurologic characterized by an impairment in than in those with FXS only include cooccurring conditions known social interaction and communication less developed language skills, to be associated with idiopathic and the presence of restricted and particularly receptive skills 21, 23, 26, 27; ASD, including seizures and sleep repetitive patterns of behavior, lower nonverbal cognition and IQ disorders; (2) behavioral cooccurring interests, or activities.12 Other scores28, 29; lower adaptive skills 21; conditions; (3) psychopharmacologic cooccurring behavioral abnormalities and, in small cohorts, more severe interventions targeting behavior; are often associated with these overall behavioral problems (eg, and (4) nonpharmacologic core symptoms (eg, anxiety). 13 The attention problems, hyperactivity interventions. Based on past relationship between FXS and ASD is and impulsivity, anxiety, aggressive literature and clinical impressions, complex and evolving, influenced in and self-injurious behaviors).7, 30, 31 we hypothesized that (1) the part by revised definitions of ASD12 Idiopathic ASD is associated with association of an ASD codiagnosis and by a better understanding of a higher rate of epilepsy
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