Opinion Article: Autism Terminology and Clinical Practice

Autism Spectrum Disorder Versus Autism Spectrum Disorders: Terminology, Concepts, and Clinical Practice

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Autism spectrum disorder (ASD) is a behaviorally defined complex neurodevelopmental disorder. The diagnosis of ASD is based on observations and assessments of behavior using Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (1) or International Classification of Diseases, 11th Edition (ICD-11) criteria (2). Though the DSM and ICD are quite useful in determining whether a given individual’s behavior is consistent with a given diagnosis, it does not speak to the etiology or impact of co-occurring conditions on the behavioral phenotype or presentation. Genetic syndromes, defined mutations, and de novo copy number variations are reported to account for almost 10% to 20% of cases within ASD (3). While the revisions to the diagnostic criteria introduced a few years ago into DSM-5 (1) updated ASD from the conceptual and practical perspectives, some persistent confusion regarding terminology and the diagnosis of the condition in individuals with intellectual disability remains. The simplified diagnosis of ASD, which merged previous diagnoses into a single disorder, has led to its use in plural (autism spectrum disorders) for different purposes.

Oberman LM and Kaufmann WE (2020) Autism Spectrum Disorder Versus Autism Spectrum Disorders: Terminology, Concepts, and Clinical Practice. Front. Psychiatry 11:484. doi: 10.3389/fpsyt.2020.00484

Toilet Training in FXS

Toilet Training in Fragile X Syndrome.

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Summary: Toilet training issues can be burdensome and a significant problem for families with children affected by Fragile X Syndrome (FXS). This groundbreaking study utilized FORWARD data on 633 individuals with FXS to fill the gap for much needed information on when children with FXS learn bladder and bowel toileting skills. By characterizing toileting milestones in children with FXS, this study helps to shed light on the factors causing delays in toilet training.

Language, behavioral irritability and autism spectrum diagnoses (ASD) presented as the main factors in predicting bowel and bladder training delays. ASD diagnosis and gender had a strong impact on age of toilet training. Males and individuals with a co-diagnosis of ASD showed a significant delay in learning toilet training skills. By 5 years of age, almost 100% of females achieve bladder toilet training versus 70% of females with a co-diagnosis of ASD. In comparison, about 50% of males with FXS alone achieved bladder training by age 5 and over 90% achieved toilet training by age 10, while 35% of males with a co-diagnosis of ASD achieved bowel toilet training by age 5 and about 60% by age 10. Across all the groups in a multi-variate analysis, more impaired language/communication was the single most important predictor of the length of toileting delay.

Why this is important: This important study will allow practitioners to inform families about the typical toilet training process and what to expect with toilet training efforts in a thoughtful, informed and encouraging manner. These findings will help providers develop and evaluate specifically targeted toilet training approaches based on gender, ASD diagnosis and other clinical features identified in this study.

What are the next steps: The data presented in this report will serve as an important reference for evaluating the effectiveness of new toileting interventions in future research.

Age is shown on the horizontal line at the bottom of the graph. This is plotted against the proportion of individuals toilet trained at a given age (eg. 0.6 would mean 6 of 10 or 60% of individuals are trained).

Berry-Kravis, E. (2019). Toilet Training in Fragile X Syndrome. Journal of Developmental & Behavioral Pediatrics. 40(9), 751-761.

Preventive care services in FXS

Preventive care services and health behaviors in children with fragile X syndrome.

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Published in Disability and Health Journal, researchers from the Centers for Disease Control and Prevention and other organizations presented FORWARD data on preventive services received by children and young adults with FXS. This research can help clinicians identify preventive care services that patients with FXS may need.

Key findings:

  • Only one in four children and young adults with FXS met the physical activity guidance from the United States Department of Health and Human Service (DHHS). DHHS recommends children 6–17 years of age get one hour of physical activity every day, while adults need about 2.5 hours per week.
  • Slightly more than half of the children and young adults with FXS met the CDC recommendation for an annual influenza vaccination.
  • Almost three out of four children and young adults with FXS met dental care guidance from the American Academy of Pediatric Dentistry (AAPD). The AAPD recommends children have their first dental exam at the time of their first tooth eruption, or by one year of age, followed by regular exams every 6 months for children and adults.
  • About nine out of ten children and young adults with FXS received the immunizations recommended by CDC between birth and 18 years of age.

Gilbertson K, et al. (2019). Preventive care services and health behaviors in children with fragile X syndrome. Disabil Health J. 12, 564-573

Drug Interventions for IAAS in FXS

Pharmacologic Interventions for Irritability, Aggression, Agitation and Self-Injurious Behavior in Fragile X Syndrome: An Initial Cross-Sectional Analysis.

Behavioral dysregulation, or the impairment of behavioral processes, is common in FXS. A regularly cited group of behaviors in individuals with FXS, particularly males, is irritability, agitation, aggression and self-injurious (IAAS) behaviors. These behaviors can put a strain on both the individual and their caregiver’s quality of life and there is little information about how to manage these behaviors with medication. This publication in the Journal of Autism and Developmental Disorders presented information from a FORWARD dataset involving 415 individuals with IAAS behaviors. The study describes the psychopharmacologic management of IAAS and examines the characteristics of individuals that are treated with drug therapy for IASS.

Findings showed that among the individuals with FXS that were exhibiting IAAS, those receiving drug treatment were more likely to be older males with significant intellectual disability. The individuals receiving drug treatment were also more likely to have comorbid autism, anxiety, hyperarousal and social impairment. The medications most used in this population are antipsychotic medications, particularly Aripiprazole and Risperidone. Both Aripiprazole and Risperidone are FDA-approved for treating irritability associated with ASD. Individuals were also prescribed drugs outside of antipsychotic medications, including Selective serotonin reuptake inhibitors (SSRIs), stimulants, non-SSRI antidepressants, alpha-agonists, mood-stabilizers, and anxiolytics.  Most individuals (63%) did not experience side effects from their drug treatment.

Eckert EM, et al. (2019). Pharmacologic interventions for irritability, aggression, agitation and self-injurious behavior in fragile X syndrome: an initial cross-sectional analysis. J Autism Dev Disord. 49, 4595-4602

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ASD Diagnosis in FXS

Improving the Diagnosis of Autism Spectrum Disorder in Fragile X Syndrome by Adapting the Social Communication Questionnaire and the Social Responsiveness Scale-2.

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This paper published in the Journal of Autism and Developmental Disorders addresses the difficulty of diagnosing ASD in FXS. Although individuals with FXS are commonly diagnosed with ASD, it is a challenging diagnosis because intellectual disability and co-occurring mental health conditions can be interpreted as autistic features. Two commonly used standard measures, the Social Communication Questionnaire (SCQ) and the Social Responsiveness Scale (SRS), were examined as potential tools for improving ASD diagnosis and characterization in FXS. Researchers scientifically analyzed the SCQ and SRS and compared it to the standard DSM5 method used across clinicians to diagnose ASD in FXS. To improve diagnostic accuracy of ASD, various methodological revisions were applied to the SCQ and SRS in order to improve sensitivity and specificity of the measures.

Although the revised SCQ and SRS have an improved sensitivity/specificity balance and may be better suited for identifying ASD in males with lower cognitive function and irritability/aggression, the diagnostic accuracy of these measures is still below optimal levels, reflecting to some extent the inherent difficulty of diagnosing ASD in intellectual disability. This research suggests there are differences between the diagnosis of FXS and FXS+ASD. More work needs to be done to examine additional modifications, beyond deletion of non-informative items, that can further improve the diagnostic potential of the SCQ and SRS in FXS.

Kidd SA, et al. (2019). Improving the Diagnosis of Autism Spectrum Disorder in Fragile X Syndrome by Adapting the Social Communication Questionnaire and the Social Responsiveness Scale-2. J Autism Dev Disord. 2019, 1-20. doi: 10.1007/s10803-019-04148-0


FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome.

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Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers.


FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who are 0 to 24 years of age, although individuals of any age can participate.


The registry includes >2300 registrants (data collected September 7, 2009 to August 31, 2014). The longitudinal database includes data on 713 individuals diagnosed with FXS (data collected September 7, 2012 to August 31, 2014). Longitudinal data continue to be collected on enrolled patients along with baseline data on new patients.


FORWARD represents the largest resource of clinical and demographic data for the FXS population in the United States. These data can be used to advance our understanding of FXS: the impact of cooccurring conditions, the impact on the day-to-day lives of individuals living with FXS and their families, and short-term and long-term outcomes.

Sherman SL, et al. Fragile X Online Registry With Accessible Research Database (FORWARD): Experience from the Fragile X Clinical and Research Consortium to study the natural history fragile X syndrome. Pediatrics 2017;139 (Suppl 3):S183-S193

Autism in FXS

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

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Many individuals with fragile X syndrome (FXS) also have a diagnosis of autism spectrum disorder. This new article takes a closer look at the effects of this dual diagnosis. Previously, the only information available to clinicians and researchers about autism among people with FXS was from small family studies and surveys. Thanks to FORWARD data, this paper presents new findings on co-occurring medical and behavioral conditions from a large number of people who have both FXS and autism.

This research suggests that half of males and almost 20% of females with FXS met the clinical criteria for a diagnosis of autism. This research also found that people with both FXS and autism were more likely than those with FXS alone to have seizures, sleep problems and aggressive behavior. In addition, individuals with autism and FXS had significantly higher use of medications to treat aggression (alpha-agonists and antipsychotics) than individuals with FXS alone. The paper reports that behavioral health services appear to be used less often in individuals with FXS and autism compared to individuals diagnosed with autism alone.

Tables 1 & 2: Seizures and Sleep Problems Associated With FXS+ASD and FXS Only, by Age Groups and All Ages, in Subjects Enrolled From September 7, 2012 through August 31, 2014, FORWARD Database.

Kaufmann WE, et al. Autism spectrum disorder in fragile X syndrome: characterization using FORWARD. Pediatrics 2017;139 (Suppl 3):S194-S206.

The Future of FXS

The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary.

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Fragile X syndrome (FXS) is the most common known inherited cause of intellectual disability (ID). Males and females with FXS exhibit a wide range of intellectual ability and may experience various degrees of emotional, behavioral, sensory, learning, and social difficulties. In 1991, the gene responsible for FXS was identified on the X chromosome at q27.3 and named fragile x mental retardation 1 ( FMR1 ) gene.1 FXS and fragile X–associated disorders (FXD) are caused by a trinucleotide repeat (CGG) expansion mutation in the promoter region (exon 1) of FMR1 . Affected individuals with the full FXS mutation have >200 repeats. When the full mutation is present, FMR1 methylation occurs during gestation, which causes silencing of gene transcription.2 This in turn leads to a reduction or absence of fragile X mental retardation protein (FMRP), which is needed for brain development and function. Most males with FXS have ID. A small number of males have less impaired function due to methylation patterns or mosaicism. In females, FMRP levels depend on the X activation ratio, or the percent of cells expressing the normal allele on the active X chromosome,3 resulting in a range of normal intellectual ability to moderate ID. Over the past 2 decades, scientists have made significant advancements in identifying and describing genetic, molecular, and cellular underpinnings of FXS, allowing for a more precise diagnosis of this condition. The present challenge is to move from accurate diagnosis to public health action for FXS, requiring better understanding of the natural history of FXS, …

Riley C, Mailick M, Berry-Kravis E, Bolen J. The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary. Pediatrics. 2017;139(Suppl 3):S147‐S152. doi:10.1542/peds.2016-1159B

Predictors of Attendance at FX Clinics

Attendance at Fragile X Specialty Clinics: Facilitators and Barriers.

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The objectives were to describe the demographic characteristics of children with Fragile X syndrome (FXS) and to determine predictors of attendance at Fragile X (FX) clinics. Findings from the Community Support Network (CSN) and Our Fragile X World (OFXW) samples showed that children who attended FX Clinics were mostly male, high-school aged or younger, and white, non-Hispanic. Using logistic regression models, awareness about FX Clinic services, guardian education, and income (CSN), and child age, family income, and total number of co-occurring conditions (OFXW) were predictors of clinic attendance. Demographic and child characteristics accounted for a large portion of the explained variance. Importantly, symptom severity and parent knowledge about services were independent predictors beyond the demographic characteristics of families.

Kidd SA, Raspa M, Clark R, Usrey-Roos H, Wheeler AC, Liu JA, et al. Attendance at fragile X specialty clinics: facilitators and barriers. Am J Intellect Dev Disabil. (2017) 122:457–75. doi: 10.1352/1944-7558-122.6.457

Importance of FX Specialty Clinics

Importance of a specialty clinic for individuals with fragile X syndrome.


Advances in human genetics have identified a significant number of genetic disorders associated with intellectual disability. As a result, appropriate clinical management of these affected individuals and their family members have become critical in addressing medical needs to improve quality of life. We examine the importance of a Fragile X Clinic for individuals with fragile X syndrome (FXS) and their family members by conducting a retrospective chart review of 123 new patients with FXS evaluated at the Fragile X Clinic at Emory University. After the initial diagnosis of a proband with FXS with cascade testing, there were 345 family members identified with a mutation (70% with premutations; 30% with full mutations). In terms of the impact of the clinic visit, males had a substantial number of new diagnoses in all behavioral disorders (P < 0.001), with anxiety (62%) being the most common. For female probands, the most frequent diagnosis was also anxiety (87%). Prior to the clinic visit, very few patients were prescribed psychotropic medications. After the clinic visit, the most frequently prescribed psychotropic medications for males were stimulants (41%; P < 0.001) and SSRIs (40%; P < 0.001). For females, only stimulants (33%; P = 0.03) and SSRIs (44%; P = 0.008) were statistically significantly prescribed. Our results revealed that there is a gap in care to address the co-morbid behavioral issues, psychopharmacologic medication management, and genetic counseling needs regarding FXS. A multidisciplinary setting and approach, such as that offered by a Fragile X Clinic, is one method of treating the complex needs of patients with FXS.

Visootsak J, Kidd SA, Anderson T, Bassell JL, Sherman SL, Berry-Kravis EM. 2016. Importance of a specialty clinic for individuals with fragile X syndrome. Am J Med Genet Part A 170A:3144–3149.

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