One stop shop for a scholarly review of state-of-the-art research on autism in children

This article reviews the recent research that has been done on autism in 6 main areas.

Recent years have seen exciting progress in key areas of research on autism spectrum disorders (ASD): from possible genetic causes, to effective treatments for common symptoms and clinical problems, to promoting success for young people with ASD entering college. Updates on these and other advances in ASD research are presented in the March special issue of Harvard Review of Psychiatry.

"Autism is one of the most challenging disorders to treat and the public health concerns associated with the disorder are numerous due to its burden on the individual, on the family and on society," write guest editors Drs Jean A. Frazier of University of Massachusetts Medical School and Christopher J. McDougle of Harvard Medical School. The special issue provides a timely update on research into the causes, important clinical issues, and evidence-based treatments for ASD.

Updates on ASD Research in Six Key Areas

Leading experts provide state-of-the-art reviews on six topics: the genetics of ASD; the use of psychoactive drugs; symptoms of special clinical problems, including obesity, gastrointestinal problems, and sensory issues; and transitioning to college.

Genetics. Over the last few years, there have been "unprecedented advances" in understanding the genetic causes of ASD. Hundreds of genes conferring varying degrees of ASD risk have been identified to date. Many of these genes also appear to be risk factors for related neurodevelopmental disorders and psychiatric problems. While many unanswered questions remain, it may soon be possible to make specific genetic diagnoses in children with ASD.

Psychoactive medications. Despite limited evidence, psychotropic drugs are widely used to manage behavior problems and mental health disorders in children with ASD. For medication classes -- including antidepressants and stimulants -- effectiveness may differ for youth versus adults with ASD. New treatments affecting specific neurotransmitters and the hormone oxytocin are under development, and may help in targeting the "core symptoms" of ASD.

Obesity. Obesity is a common problem with a major impact on the health of children with ASD. Some ASD-related genes may also promote obesity; the same is true for antipsychotic drugs used to help manage behavior problems. Other contributing factors may include sleep disorders and barriers to getting enough exercise. Childhood obesity and related health issues may be a "significant threat" to the health and quality of life of children with ASD.

Gastrointestinal issues. Children with ASD also have high rates of gastrointestinal symptoms and disorders. Some genes linked to ASD may also play a role in gastrointestinal disturbances, with a possible link to immune system dysfunction. There's also emerging evidence of a potential "gut-brain" connection, with gastrointestinal dysfunction contributing to the development or severity of ASD symptoms.

Sensory symptoms. Children with ASD have various abnormalities of sensory function, including both over- and under-responsivity as well as "sensory seeking behavior." Although the neurobiology of these sensory symptoms remains unclear, some researchers suggest they are related to known abnormalities of brain structure and function. Recent studies show that sensory symptoms are related to other ASD-related symptoms and behaviors; more research is needed to demonstrate the effectiveness of "sensory integration therapy" and other occupational therapy approaches.

Preparing for college. The final article highlights the need for new approaches to meeting the needs of "high-functioning" ASD patients entering college. Students "on the spectrum" transitioning to college are at risk of both academic and social problems, and may benefit from accommodation and supports. Based on a growing body of research, a set of recommendations for developing more effective transition plans for children with ASD are proposed.

Along with the editors of Harvard Review of Psychiatry, Drs Frazier and McDougal hope their special issue will provide a useful update for clinicians caring for the growing numbers of individuals and families living with ASD. They conclude, "Clearly, more research is needed on every level for the field to help support and treat individuals on the spectrum so that they can optimize their developmental trajectory and as adults become integral members of our work force."

The journal can be found online at:http://journals.lww.com/hrpjournal/Pages/default.aspx

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http://journals.lww.com/hrpjournal/pages/currenttoc.aspx

Females may have advantage to not developing autism

This study suggests that females may have an advantage in resisting genetic pressures to develop autism symptoms.

A protective effect in females may help explain one of the biggest mysteries of autism: Why boys are five times more likely to develop the developmental brain disorder than girls.

A new, preliminary study suggests that developing females are much better able than males to fight off genetic pressure to develop symptoms of autism.

The findings aren't definitive and don't point to a treatment or cure. Still, "first steps like this are important" and could lead to greater understanding of autism, said study lead author Elise Robinson, an instructor in the department of medicine at Harvard Medical School in Boston.

An estimated 1 in 88 children in the United States has an "autism spectrum disorder." The condition, which can range from mild to severe, is characterized by impaired communication and social interaction. Prevalence of autism is increasing in the United States, although it's not clear if that's largely because there's more awareness of the disorder.

According to the U.S. Centers for Disease Control and Prevention, boys are almost five times more likely than girls to have a form of the disorder -- 1 in 54 boys compared to 1 in 252 girls.

There are many theories about why this autism "gender gap" exists. One idea is that males are threatened in the womb by exposure to testosterone, the male hormone. Another theory holds that females might be somehow inherently better protected against the threat of the condition.

This may fit in with the idea that males are weaker in the womb than females. Boys are generally more prone to develop neurological disorders than girls, noted Dr. Andrew Zimmerman, director of clinical trials at the Lurie Center for Autism at Massachusetts General Hospital.

"We poor males are vulnerable," he said. "Girls have two X chromosomes, so if there's a problem on one, they have a spare." On the other hand, males have one X chromosome and "a Y chromosome that has very few genes," added Zimmerman, who was not involved in the study.

In the new study, published online Feb. 18 in Proceedings of the National Academy of Sciences, researchers aimed to figure out how females fared who were born into families that appeared to have a higher genetic risk of autism symptoms. The study authors looked at more than 3,800 pairs of non-identical twins from Great Britain and more than 6,000 pairs of non-identical twins from Sweden. They then tried to figure out how a family risk of autism symptoms (not diagnosed autism itself) affected the twins.

They found evidence that it takes greater family risk -- meaning a higher genetic load -- for a girl to develop autism symptoms. In other words, girls appeared to be more resilient against the threat of autism symptoms compared to boys.

"There's more pressure on them to get it, and once they get it, it's more obvious than in their relatives," said Zimmerman.

Genetics researchers should spend more time studying families with autistic girls in order to better understand the disorder, the research team concluded. This gender-specific research might also help identify ways to prevent autism, they said.

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Tipping Point in Autism: What is Whole-Exome Sequencing? How it Identifies Inherited Mutations in Autism

If your child has undergone testing before without diagnosis, consider re-visiting testing. JR

Whole-Exome Sequencing Identifies Inherited Mutations in Autism

Jan. 23, 2013 — While autism clearly runs in some families, few inherited genetic causes have been found. A major reason is that these causes are so varied that it's hard to find enough people with a given mutation to establish a clear pattern. Researchers at Boston Children's Hospital have pinpointed several inherited mutations -- among the first to be identified -- through an unusual approach: using whole-exome sequencing to study large Middle Eastern families with autism.

The study, published in the January 23 issue of the journal Neuron, also found evidence for some of the same mutations in U.S. families. It shows that a number of genes implicated in severe genetic syndromes can have milder mutations that primarily cause autism, and could broaden the number of genetic tests available to families.

Researchers Tim Yu, MD, PhD, Maria Chahrour, PhD, and senior investigator Christopher Walsh, MD, PhD, of Boston Children's Hospital, began with three large Middle Eastern families that had two or more children with autism spectrum disorders (ASDs), looking for recessive mutations -- those requiring a "double hit" for the child to have an ASD.

"Families from the U.S. are not ideal for finding inherited genetic mutations, since family sizes are often small," says Walsh, chief of Genetics at Boston Children's and an investigator of the Howard Hughes Medical Institute.
In all three families, the parents were first cousins, a common tradition in the Middle East and one that greatly facilitates the identification of inherited mutations. The researchers first used genetic mapping techniques to narrow their search to specific chromosomal locations, then sequenced the protein-coding genes in those areas (known as whole-exome sequencing).

That turned up recessive mutations in three genes not previously known to be involved in autism, but rather in severe genetic syndromes:

• Mutations in AMT, a gene classically associated with a severe metabolic syndrome known as nonketotic hyperglycinemia, marked by severe seizures and death during infancy.
• Mutations in PEX7. Typical PEX7 mutations cause rhizomelic chondrodysplasia punctata, a severe syndrome causing metabolic and bone abnormalities, cataracts, severe epilepsy and early death.
• Mutations in SYNE1, a gene associated with brain malformation, severe motor and muscle problems, and possibly bipolar psychiatric disease.

The severe syndromes linked to these genes often include autistic behavior or intellectual disability, but not as the primary symptom. Interestingly, the milder mutations discovered in these families seemed to cause disease that is more brain-specific.
"This is the first time these genes have been associated with autism," says Chahrour, who shares first authorship of the study with Yu. "The AMT and PEX7 mutations weren't picked up by standard tests for metabolic disorders, but when you're able to sequence the entire exome, you can find them."
These findings inspired the team to look for other metabolic and other genetic syndromes affecting cognition and behavior with milder forms showing up simply as autism. They screened 163 Middle Eastern families with autism for mutations in 70 genes associated with these syndromes, using a whole-exome approach but analyzing only the 70 genes of interest.
This approach turned up several additional families with ASD mutations, including:

• An additional family with a recessive mutation in AMT
• Two families with recessive mutations in VPS13B (known to cause Cohen syndrome, which includes intellectual disability, obesity, vision and joint problems, and small head size)
• A family with a recessive mutation in POMGNT1 (known to cause muscle-eye-brain disease, marked by brain malformation, intellectual disability, muscle and vision problems)
• A family with an X-linked mutation in MECP2 in two boys (MECP2 mutations are known to cause Rett syndrome in girls, but are typically lethal in boys)

"We have textbook descriptions of all these diseases, but in real life, there can be atypical, milder presentations of the same disease," says Yu. "The kids we were studying with autism were alive at age 13. They had double hits for these mutations, but they were much milder mutations. The proteins retained a bit of their function."

The team also examined a cohort of U.S. patients, looking for recessive mutations in six of the genes they identified. They analyzed whole-exome sequence data from 612 families with ASDs, part of a registry known as the Simons Simplex Collection. The analysis suggested that some of the affected children had causative recessive mutations in at least two of the genes identified in the Middle Eastern families, and that larger-scale efforts to examine all 70 genes more fully for recessive mutations may prove fruitful.

"It's not clear yet how many U.S. families have these recessive mutations," says Yu. "Further studies could begin to estimate what fraction of autism cases might fall under this model."

"Together, these two studies firmly establish that recessive mutations contribute importantly to autism, not just in specialized populations but in the population at large," says Yu. "Genome sequencing is going to be a huge advance in identifying more of these mutations, since there are a lot of rare syndromes that are otherwise very difficult to detect."