Progress Report 2008: Disorders That Appear in Childhood
The 2008 Progress Report on Brain Research

February, 2008

In 2007, scientists identified some of the genetic bases of autism spectrum disorders and attention-deficit/hyperactivity disorder—two of the most common developmental disorders. Researchers also began to lay the foundations for finding a potential cure for Rett syndrome, the most physically disabling of the autism spectrum disorders, with which mostly girls are diagnosed because few boys survive past age 2, as well as fragile X syndrome, the most common inherited form of mental retardation, which occurs primarily in boys.

The Genetics of Autism

Although studies in twins have shown that autism spectrum disorders are highly heritable, researchers have not been able to identify strong autism gene candidates so far. Moreover, the majority of people with autism have no family history of the disease, suggesting that inherited risk factors are quite complex. But in 2007, a team of scientists led by Jonathan Sebat of Cold Spring Harbor Laboratory was able to gain some new insights into the genetics of these disorders.

In a paper published in Science in April, Sebat and colleagues reported that gene mutations called copy number variations, not present in either parent, appear to create a greater risk for autism than had been thought previously.1 These mutations typically involve deletions of tiny gene segments that arise spontaneously, rather than being inherited.

Sebat’s team looked for copy number variations in 264 families, including 118 “simplex” families with a single child with autism, 47 “multiplex” families with multiple affected siblings, and 99 control families with no diagnoses of autism.

The investigators found that, among children with autism spectrum disorders who had no siblings with a disorder, 10 percent had gene-segment deletions, compared with 2.6 percent of children with autism spectrum disorders from multiplex families and 1 percent of the controls. These deletions occurred at many different sites in the genome. These data support the notion that spontaneously arising mutations in many genes are involved, and may in part explain why findings from previous genetic studies were inconsistent.

The fact that many genes may be involved in a disorder also suggests something fundamental about autism: perhaps the common features of autism (impaired social interaction, difficulty with communication, and restricted interests and behaviors) owe their “commonality” not to common genes but to a common biological pathway involving a large and diverse set of genes.

The findings also have implications for the clinic. By screening children with autism spectrum disorders for spontaneous mutations, clinicians may be able to inform the parents about their risk of having a second child with an autism spectrum disorder—which is thought to be lower if a spontaneous mutation is present.

Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder is characterized by several features: it is very common (affecting 3 to 7 percent of children), it is highly heritable, and it tends to ease in affected children as they get older. And a 2007 study may have homed in on one gene associated with the improvement in older children.

In a study published in August in Archives of General Psychiatry, Philip Shaw and colleagues at the National Institute of Mental Health investigated the effects of one of the most important known genetic risk factors for the disorder.2 The researchers studied a gene that is one of the rarer forms of the receptor for the neurotransmitter dopamine, called D4. Unlike other dopamine receptors, this receptor has a 7-repeat variant in a part of the gene called axon 3. This genetic variant accounts for about 30 percent of inherited cases of the disorder, making it by far the strongest candidate gene.

The researchers collected DNA, clinical data, and brain magnetic resonance images for 105 children with attention-deficit/hyperactivity disorder (ADHD) and 103 children without the disorder. An analysis of the data showed that, among children with attention-deficit/hyperactivity disorder, possession of the 7-repeat gene was associated with both better clinical outcome and higher intelligence compared with children who did not have the 7-repeat gene. These findings were highly specific: no similar association with either a clinical outcome or a distinctive trajectory of cortical development was found with two other known genetic risk factors for ADHD.

Cortical thinning from ADHD - Spotlight

Children with  attention- deficit/hyperactivity disorder have a thinner cortex than those without, but brain scans (in which the numbers note the child’s age) show that, in the 30 percent of cases where ADHD is associated with a certain rare genetic variant, this gap is resolved by about age 16. (Philip Shaw/ NIH)

The investigators also found that children who had the 7-repeat variant of this gene showed a distinctive pattern of cortical development: the thickness of the cortex in areas important for the control of attention was initially thin, but then it thickened, converging with the development path of the healthy children by about age 16.

In a previous study, the same group of researchers reported that this pattern of cortical development was associated with better clinical outcomes in attention-deficit/hyperactivity disorder. The 2007 study linked genetics with both clinical outcome and cortical development, and it raises the hope that in the future, such genetic information could guide treatment efforts by clinicians.

Rett Syndrome Progress

Rett syndrome, caused by mutations in the gene methyl-CpG-binding protein 2 (MeCP2), affects primarily girls. Symptoms develop in early childhood, resulting in impairments in speech, normal movement, and hand use. Disordered breathing patterns and Parkinson’s-like tremors are common.

Progress Report 2008, Chapter 1, Image 3, Rett Syndrome - Content

Mutations in the protein MeCP2 cause Rett syndrome.  Mice bred with these mutations show elevated levels of a stress-control hormone called corticotrophin releasing hormone (CrH) in the hypothalamus, which is likely to contribute to the stress and anxiety that are a Rett feature. (Courtesy of Adrian Bird)

Females with Rett syndrome have one mutated and one normal MeCP2 gene. Therefore, female mice with a stopped gene on one X chromosome are the best genetic model for this disorder. These mice develop Rett-like symptoms, such as tremors and problems with mobility and gait, between 4 and 12 months of age, and they then remain chronically symptomatic for an apparently normal life span.

Although neurons show fewer branches than normal, there is no evidence for nerve cell death in either the mouse model or Rett patients (unlike neurodegenerative disorders such as Parkinson’s, Huntington’s, or Alzheimer’s disease). Because the faulty neurons remain alive, researchers at the Wellcome Trust Centre for Cell Biology at Edinburgh University in Scotland wondered whether restoring normal MeCP2 protein could rescue the nerves’ function and “cure” the mice.

In a study published in February in Science, Adrian Bird and colleagues tested this hypothesis by introducing a “stop-cassette” into the mouse MeCP2 gene, which prevented it from making MeCP2 protein.3 The stopped gene could be reactivated at will by injecting the mouse with the drug Tamoxifen, which set in motion a sequence of molecular events culminating in deletion of the stop-cassette, thereby reactivating the MeCP2 gene to produce the protein.

The scientists waited until full-blown symptoms had developed in female mice before administering Tamoxifen. Strikingly, restoration of the MeCP2 gene to produce MeCP2 protein eradicated tremors and normalized breathing, mobility, and gait in mice that were sometimes only days away from death. In addition, female mice also recovered electrophysiological function, as measured by the ability of nerve cells to respond to stimulation.

Investigators also tried Tamoxifen in male mice after symptoms had developed. Again, most or all symptoms disappeared in male mice with a restored MeCP2 gene, and these mice survived for an apparently normal life span.

These findings imply that the symptoms of Rett syndrome are potentially reversible, which may inspire similar research in related autism spectrum disorders.

Important Enzyme in Fragile X

A research group led by Nobel laureate Susumu Tonegawa at the Massachusetts Institute of Technology obtained similarly encouraging results regarding fragile X syndrome, the most common inherited form of mental retardation, which occurs primarily in males. Their research was published in the July Proceedings of the National Academy of Sciences.4

In the study, mice with a model of fragile X syndrome exhibited symptoms similar to those in human patients: hyperactivity, repetitive movements, attention deficits, and difficulty with learning and memory tasks.

The experimental animals also had structural abnormalities that were similar to those found in humans. These males have a high number of dendritic spines in neurons in their brains, but each spine is longer and thinner than normal and transmits weaker electric signals than those in non-affected individuals. Dendritic spines are small protrusions on the branch-like dendrites of neurons that receive chemical signals from other neurons and communicate them to the main cell body.

The scientists hypothesized that inhibiting a certain enzyme in the brain could be an effective way to counter these structural changes, as well as the debilitating symptoms of fragile X syndrome. The enzyme, called p21-activated kinase, affects the number, size, and shape of connections between neurons in the brain.

The researchers found that halting the enzyme’s activity reversed the structural abnormality of neuronal connections in mice. Moreover, inhibiting the enzyme restored electrical communication between neurons in the brains of the mice, correcting their behavioral abnormalities in the process.

Because the expression of the gene that inhibits p21-activated kinase occurs after birth, it is possible that chemical compounds that inhibit the enzyme’s activity could one day be used to prevent or reverse mental impairments in young children with fragile X syndrome.


1. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, and Wigler M. Strong association of de novo copy number mutations with autism. Science 2007 20;316(5823):445–449.

2. Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D, Sharp W, Evans A, Giedd JN, Castellanos FX, and Rapoport JL. Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Archives of General Psychiatry 2007 64(8):921–931.

3. Guy J, Gan J, Selfridge J, Cobb S, and Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 2007 23;315(5815):1143–1147.

4. Hayashi ML, Rao BS, Seo JS, Choi HS, Dolan BM, Choi SY, Chattarji S, and Tonegawa S. Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. Proceedings of the National Academy of Sciences USA 2007 104(27):11489–11494.

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