April is National Autism Awareness Month, a time to raise awareness and recognize Autism Spectrum Disorder (ASD) and the families living with autism. Working with families pursuing fertility treatments, we commonly receive questions from our patients regarding whether autism is genetic, what causes it and whether there is any way to prevent it. Our genetic counselor in Shanghai, Olive Zhu, MS, had the pleasure of speaking with an expert in the field, Dr. Arthur L. Beaudet. Dr. Beaudet is a professor of molecular and human genetics at Baylor College of Medicine. He has shared with us his insight into some common questions about ASD.
By Olive Shihui Zhu, MS; Genetic Counselor, ORM China
What is Autism?
Autism, or ASD, is a condition that disturbs behavior, social interactions, and language. This can exhibit as lack of eye contact, delayed speech, and repetitive behavior. We refer to it as “ASD” because there is a wide spectrum of severity. Dr. Beaudet emphasizes, “These two ends of the spectrum are absolutely different from each other, they have very little to do with each other, and I think it sometimes causes confusion.” Children on the severe end of the spectrum often have low IQ and no speech, as well as other clinical features such as a heart defect or other anomalies. Children on the milder end of the spectrum look just like other children and would be considered high-functioning with normal speech and a variable IQ. For the purposes of this article, these two groups are referred to as ‘mild ASD’ and ‘severe ASD’.
ASD affects around 1/170 individuals and has a characteristic bias for males at a ratio of ~4:1. The male to female ratio is even higher in patients with mild ASD, with reported ratios of 6-23 males for every one female. Dr. Beaudet believes that this striking male to female ratio is the best lead in trying to identify what causes ASD in this group of individuals.
What causes Autism?
Like many complex conditions, ASD is believed to be caused by a combination of genetic and environmental factors. By following genetic testing recommendations from the American College of Medical Genetics, a genetic cause can be identified in 30-40% of individuals with ASD. These causes include Fragile X syndrome, changes in the number or structure of chromosomes, and single-gene disorders caused by genetic mutations. Genetic causes are most frequently identified in individuals on the more severe end of the spectrum, leaving many individuals with mild ASD having no answer.
ASD may also be caused by new mutations arising spontaneously; there have been over 500 ASD-related genes identified to date. Since men tend to accumulate new mutations in their sperm as they age, we also see an exponential increase of reproductive risk for ASD proportional to paternal age. This means that the older men are when they have children, the more risk there is for their child to have ASD. The age of male partners undergoing IVF tends to be higher than that of men who are not using IVF to conceive.
Many patients ask us whether fertility treatments such as in vitro fertilization (IVF) directly contribute to an increase in the risk of having a child with ASD. At this time there is no firm evidence to suggest that this is the case. IVF is associated with an increased chance of a twin pregnancy, and multiple pregnancies, in turn, are associated with an increased risk for complications such as premature birth, and Dr. Beaudet acknowledged that twin births are a risk factor for ASD. Some patients choose to have a single embryo transfer to minimize the risk of multiple pregnancies and the associated complications; however, the number of embryos to transfer in IVF is a complex decision influenced by multiple factors.
New Hypotheses
Dr. Beaudet shared with us a new hypothesis for what causes ASD. His team hypothesizes that mild ASD may be caused by carnitine deficiency in the brain. This hypothesis may explain the cause of ASD for up to 10-20% of cases on the milder end of the spectrum, who would have tested normal on the genetic tests recommended by ACMG. Carnitine is a micronutrient found in milk and protein. Our bodies are also usually able to generate carnitine from other nutrients if we don’t consume enough of it in our diet. Dr. Beaudet’s team has identified a gene involved in the biosynthesis of carnitine that might be a risk factor for ASD. They have also identified a gene on the X chromosome that is involved in the transport of carnitine to the brain. This could explain why girls are protected against ASD (since females usually have two copies of the X chromosome and males only have one copy) and why there is such a large male bias for mild ASD. As Dr. Beaudet explains, “The general belief is that no one gene accounts for more than 1% of autism and we’re arguing against that hypothesis or rule that people tend to go by.” If this hypothesis holds true, it may provide answers to many more families living with ASD. Possibly the most exciting implication of this hypothesis is that, if confirmed, carnitine supplementation in infancy and during the weaning period may prevent or reverse adverse effects to the brain and avoid symptoms of mild ASD in these 10-20% of cases.
Is there a cure for ASD?
The short answer to this is no, but there are many treatments and support services available that do improve overall function. Behavioral, speech, occupational, and physical therapies are all recommended by the American Academy of Pediatrics to help children with ASD to reach their full potential. Support from schools and governments may vary depending on location and families may find it useful to explore resources in their local area as well as online support groups (two well-accredited organizations are listed at the end of this article). Dr. Beaudet shares that there are often ASD support groups locally in large cities and, although it is not a cure or treatment, he has seen many families benefit from interacting with these support groups and meeting other families going through the same situation.
Can IVF be used to prevent ASD?
Preimplantation genetic diagnosis (PGD) is a technology that can be performed in conjunction with IVF to avoid passing a particular genetic condition on to the next generation. We know that when parents have one child with ASD, their risk of having a second child with ASD is 3-10% (depending on the sex of the child). However, PGD is currently not available to screen for ASD unless the specific genetic cause is known, as may be the case in Fragile X syndrome or chromosomal microdeletions. In Dr. Beaudet’s opinion, PGD might be available in the future for severe ASD as we are getting closer to identifying a genetic cause in about half of affected individuals; however, there is still much more to learn in the milder half of the spectrum.
If you have questions regarding the risk of ASD personally or for loved ones, please refer to your local medical genetics center. The National Autistic Society and the Autism Society are also great places to look for resources and support: www.autism.org.uk, www.autism-society.org
References
Beaudet, A. L. (2017). Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis. BioEssays, 39(8).
Fombonne, E. (2003). The prevalence of autism. Jama, 289(1), 87-89.
Johnson, C. P., & Myers, S. M. (2007). Identification and evaluation of children with autism spectrum disorders. Pediatrics, 120(5), 1183-1215.
Loomes, R., Hull, L., & Mandy, W. P. L. (2017). What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. Journal of the American Academy of Child & Adolescent Psychiatry, 56(6), 466-474.
Miles, J. H., & Hillman, R. E. (2000). Value of a clinical morphology examination in autism. American Journal of Medical Genetics Part A, 91(4), 245-253.
Vasudevan, P. C. (2006). Oxford desk reference: clinical genetics.