Children with the rare genetic disorder Prader-Willi syndrome have a high rate of autism spectrum disorders, with features including restricted and repetitive, compulsive and self-injurious behaviors. They also typically present with neonatal feeding difficulties, developmental delay, endocrine dysfunction and obesity. Prader-Willi syndrome is usually caused by the inactivation of a group of genes on chromosome 15. Spontaneous, or de novo, inactivating mutations in one of those genes, MAGEL2, have been identified in four children who have autism and other features of Prader-Willi syndrome. Loss of MAGEL2 function is likely to be responsible for autism predisposition in children with Prader-Willi syndrome.

Autism is a complex disorder of many biological causes that results in characteristic behavioral symptoms. However, recent advances in the genetics of autism point to a constellation of genetic causes that converge on a subset of intracellular signaling pathways, including RAS-MAPK and PI3K/AKT, that may all contribute to autism, even if mutations in these pathways on their own may not be sufficient to cause the disorder.

David Heeger, André Fenton and Robert Froemke of New York University, in collaboration with Marlene Behrmann of Carnegie Mellon University in Pittsburgh, are investigating the possibility that generic, brain-wide circuit malfunctions lie at the root of autism spectrum disorders. They posit that if we understood these malfunctions better, both diagnosis and intervention might be optimized.

Genetic and neuroimaging studies provide strong evidence that the gene CNTNAP2 (also known as CASPR2) is a critical risk factor for autism spectrum disorders. CNTNAP2 encodes a protein on the surface of neurons that is involved in interactions between neurons and glial cells in axons with a myelin sheath.

Duplication of a small region on chromosome 22, resulting in 22q11.2 duplication syndrome, has been associated with autism, but to date there has not been a large-scale cohort study of this association.

Fragile X syndrome, which is closely associated with autism, is a single-gene disorder caused by the lack of a protein that suppresses protein synthesis. A fragile X mouse model has been shown to exhibit increased protein synthesis in the brain.

The causes of social dysfunction in autism, a core symptom of the disorder, remain unknown. Many genetic abnormalities seem to be involved in the disorder. Because behavioral problems are mediated by malfunctions in neural circuits, it is likely that diverse genetic defects converge to cause similar functional abnormalities at the neural circuit level. Therefore, understanding the neural circuit malfunctions may hold the key to understanding social dysfunction in autism.

Similar to the well-known critical period in development for language acquisition, there is likely to be a critical window during childhood for acquiring normal social behavior. An important goal in autism research is to identify this critical period, and possibly to manipulate the length of the window or reopen it in adulthood to help with the acquisition and maintenance of appropriate social behaviors.

The diagnosis of autism spectrum disorders is currently based on behavioral observations. As a result, many children with autism are not diagnosed until after their third birthday. This delay in diagnosis can be detrimental, as earlier interventions can significantly improve cognition, adaptive behavior and symptoms.

Few robust biomarkers have been identified for autism, and there are no medications that treat the social deficits associated with the disorder. Progress has been impeded in part by the challenge of obtaining relevant tissue samples from people with autism and matched controls.