By Dejan B. Budimirovic, M.D.
This summary was extracted in part from the Autism Spectrum Disorder in Fragile X Syndrome consensus document and from original text by Dr. Dejan Budimirovic of the Kennedy-Krieger Institute FX Clinic in Baltimore.
About consensus documents: The professionals who are part of the National Fragile X Foundation Fragile X Clinical & Research Consortium (FXCRC) and who are committed to the well-being of the Fragile X community, along with the parents on the Consortium’s executive council, diligently update the Fragile X treatment guidelines and recommendations (aka, consensus documents) that were first drafted in 2011.
Overlaps & Gaps Between the Two Conditions
Families and some providers are often confused by the relationship between Fragile X syndrome (FXS) and autism spectrum disorder (ASD). It is important to note that it is more common for a child to be diagnosed with ASD and then to receive an additional diagnosis of FXS. This document attempts to clarify overlaps and gaps between the two conditions. Understanding these distinctions can be particularly helpful when deciding upon the most appropriate medical, therapeutic, counseling, and education interventions, and will increase the potential for both short-term and long-term benefits.
What is known about autism and its relationship with FXS?
ASD is a developmental disorder primarily characterized by a selective impairment in social interaction. Namely, people with ASD have differences in how they understand and react to people and social situations, which result from differences in how their brains process socially relevant information.
Symptoms of ASD appear in early childhood. It is a lifelong disorder, though symptoms change over time. At this time, there is no medical test, such as a blood test or brain scan, that can diagnose ASD. Yet in some cases the cause of ASD is known, such as FXS—the most common-known single-gene disorder that accounts for about 2 to 3 percent of all ASD cases. Specifically, FXS is a genetically defined condition that can be diagnosed by a DNA blood test, unlike ASD, which is behaviorally defined. Thus FXS is one cause out of many, for a person to manifest the clinical symptoms that define ASD.
Why are autistic features common in FXS?
Our current ASD knowledge indicates that it is a developmental brain disorder, beginning shortly after birth or even earlier. Its most characteristic feature is the presence of abnormal patterns of neural “wiring,” or connectivity. Because multiple genetic and environmental factors have been linked to ASD, there are probably multiple ways in which neural connectivity and other processes can be disrupted, leading to a common outcome or set of clinical features that result in a diagnosis of ASD. In regard to the neural connectivity, many proteins that have similar jobs as FMRP (the protein made from the Fragile X gene, FMR1, which is absent or reduced in people with FXS) and also proteins that interact with FMRP have been found to be associated with ASD. Thus, it is likely that ASD is frequently present in FXS because the lack of FMRP in FXS adds to the risk of developing the types of abnormal wiring and related brain abnormalities that lead to autism symptoms.
FXS as Part of the Autism Cloud
It may be useful to see ASD as a cloud that represents a final common diagnostic category, illustrative of abnormal patterns of brain wiring resulting from a blend of multiple diverse genetic and other etiologies.
The cloud contains a common set of behavioral characteristics that are core features of ASD. Individuals with FXS who meet criteria for the current definition of ASD represent a spot in the cloud where one may meet criteria for ASD, but also tend to have an FXS-related type of autism with higher rates of social anxiety, intellectual disabilities, hyperarousal, repetitive behaviors, and other FXS-related differences, than those with ASD of an unknown cause.
Yet, sometimes it is unclear whether or not someone should receive a diagnosis of ASD. The level of overlap between the FXS behavioral phenotype (symptoms) and ASD determines whether a person with FXS makes it into the ASD cloud. Some individuals may have enough ASD features to be near the cloud, but not at the threshold needed for an actual diagnosis. Those with FXS who are in the ASD cloud likely have genetic factors that add to FMRP deficiency, which pushes them toward meeting ASD criteria.
What are some recommendations for treatment of individuals with FXS who meet criteria for autism?
Challenging behaviors such as attention problems, disruptive behavior, anxiety, and aggressive and self-injurious behaviors, can significantly impact an individual’s academic and adaptive functioning, limiting their participation in the community.
In addition to behavioral therapy (the mainstay of treatment), medication can sometimes be helpful to support therapeutic services and to allow a child to learn in the least restrictive environment. For children with FXS, regardless of whether they meet criteria for ASD, interventions that target communication and socialization skills are appropriate. However, the crucial point for teachers, therapists, and others involved in the support of individuals with FXS, is to utilize existing knowledge of behavior and learning styles typical of FXS in an individualized manner (i.e., in FXS we would not force eye contact, different from the applied behavioral analysis-based treatment of individuals with ASD of unknown cause).
This approach will help to better customize educational, behavioral, and other strategies to the needs of each individual. Further molecular, educational, behavioral, and non-pharmacological therapeutic intervention studies are needed to refine our understanding of the similarities and differences between individuals with only FXS and individuals with FXS and ASD. Clinical trials of both standard pharmaceutical medications and promising new treatments targeted to underlying brain mechanisms are also needed to explore whether individuals with FXS who meet or do not meet the criteria for ASD respond differently to treatment.
Overall, the future not only holds hope but also the realistic potential for meaningful clinical and functional progress in individuals with FXS and ASD.
For more on FXS & Autism:
- Fragile X & Autism
- Autism Spectrum Disorder in Fragile X Syndrome: An NFXF Webinar with Dr. Walter Kaufmann
- FXCRC Consensus Document: Autism Spectrum Disorder in Fragile X Syndrome — PDF
- The Fragile X Syndrome–Autism Comorbidity: What Do We Really Know? — PDF
- The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments — PDF
- Q&A With Dr. Hagerman: Exploring the Fragile X Syndrome / Autism Link
[Last updated: March 25, 2019]
About the Author
Dejan B. Budimirovic, M.D.
Dr. Budimirovic earned his undergraduate degree from a pre-medical nursing program and his medical degree from Belgrade University, where he graduated magna cum laude. He then completed residencies at Belgrade, Harvard, and New York University School of Medicine, respectively. He is an attending child neuropsychiatrist, main sub-Investigator, and the medical co-director of the Fragile X Clinic at Kennedy Krieger Institute, Johns Hopkins Medical Institutions. Under his leadership, the Clinic has been critical in establishing the Institute’s Clinical Trials Unit. He is also an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine.
Dr. Budimirovic is board certified by the American Board of Psychiatry and Neurology in adult, child, and adolescent psychiatry. He is an active member of the Fragile X Clinical and Research Consortium and its Clinical and Clinical Trials Committees, respectively.