Some of the genetic diseases that can cause autism spectrum disorder (ASD) and intellectual disability (ID) are so rare that even physicians who specialize in treating them can't be certain they have seen every possible symptom.
That's a problem for those clinicians, and it also makes it difficult to design interventions in hopes of improving the lives of people who live with the diseases.
But a new nationwide effort, the Developmental Synaptopathies Consortium (DSC), which includes Rush and other top medical centers, is seeking to change that. The DSC will link families and specialists scattered across the country in a study that could provide solid pictures of three rare diseases that, among other devastating effects, can cause ASD and ID.
The DSC will carry out the five-year study at 10 medical centers, enlisting a total of 330 children ages 3 to 21 to develop a "natural history" of the progression of the diseases — tuberous sclerosis complex, Phelan-McDermid Syndrome and PTEN Hamartoma Tumor Syndrome. These three rare genetic diseases all disrupt the formation of synapses in the brain.
Rush Pediatric Neurologist Dr. Elizabeth Berry-Kravis and Clinical Psychologist Latha Soorya,PhD, will be co-investigators in the study at Rush.. The National Institutes of Health has pledged $6 million to the consortium through its Rare Diseases Clinical Research Network (RDCRN), and will also participate as a member. Dr. Mustafa Sahin, at Boston Children's Hospital, will serve as the consortium's director.
The study will ask, "What would a group of 330 patients look like as the years go by? We will be able to see the trajectory of these diseases," says Berry-Kravis.
As drugs to combat the conditions become available — and some are already in the pipeline — a new question will be added, "Would the cohort look different with a drug [that addresses the disease]? The long-term hope is to come up with a treatment," . Berry-Kravis says.
ASD has many causes, only some of which are known at this point, but genetics is key. Hundreds of genes in the human body can mutate in ways that can contribute to ASD, a condition that presents in varying degrees of severity. ASD's two defining characteristics are difficulties with social interaction, a tendency to engage in repetitive behaviors and restricted interests. Research has shown that environmental factors probably also contribute.
A major distraction in autism research came in 1998, when the British medical journal The Lancet published a study that appeared to establish certain vaccines as a cause of autism. That paper was later found to be deeply flawed and possibly fraudulent, withdrawn by The Lancet, and repudiated by 10 of its 13 authors, but belief in a link between vaccines and autism has persisted in the public mind.
ASD affects about 1 in 68 children, according to the latest figures from the Centers for Disease Control and Prevention. The previous figure had been 1 in 88 children. Autism is not becoming more common, though, Soorya says. The latest statistical increase came from better diagnosis in previously under-diagnosed ethnic groups, she says.
About 40 percent of people with ASD have average to above-average intelligence, while others have severe disabilities and are not able to live independently. ASD is five times more common in boys than in girls.
"The general theory is that autism is often related to a person's genetic background," says Berry-Kravis. "With neurobiology and genetics, a lot depends on how much proneness you inherit." Single-gene defects can cause autism, but "multiple-gene inheritance" is also common. "For example If you inherit three [damaged] autism risk genes, you may be a little socially awkward, perhaps have some problems with language and communication. With five problem genes, you may have autism. The effect can be additive," she says.
For example, the Shank3 gene is important to the development of the human nervous system, and Shank3 mutations, like the ones that cause Phelan-McDermid Syndrome, have a high correlation with ASD. Hundreds of people have been diagnosed with Phelan-McDermid Syndrome, but researchers suspect many more may actually have the disease, Soorya says. The consortium approach will raise awareness and provide medical homes for patients to see clinicians knowledgeable about the condition.
"That natural history is the primary goal of this network. We want to know the best way to assess and treat these kids over time," says Soorya.
But treatment is also a long-term goal. Once researchers establish the characteristics and trajectory of Phelan-McDermid Syndrome, for example, in a substantial population, that information will help them understand changes that might occur in patients during trials of new medications targeted to the brain mechanisms impacted by the disease.
Disturbances in the mTor-related signaling pathways are known to occur in all three of the diseases the consortium will address. The three diseases "may not all have the same full repertoire of affected pathways, but this is one pathway common to all three conditions," Berry-Kravis says. Researchers know that the drug rapamycin inhibits activity in the mTor pathway, and early trials in humans with tuberous sclerosis complex are already under way, she says.
"One way to understand it is this: Study the disease [in the affected population], see the symptoms, and go back and ask, 'What is the abnormal gene doing to cause the problem?'" Then correct the dysfunctional activity with a drug to see if the treatment relieves the symptoms, Berry-Kravis says.
Soorya adds, "We'll learn from the biology what is impaired, and build interventions." Not all those interventions will necessarily be pharmacological, Soorya says; her background is in behavioral approaches to treating autism. Indeed, at Rush's Autism Assessment, Research, Treatment and Services Center (AARTS Center) specialists offer comprehensive assessment and treatment of children, adolescents and adults with autism spectrum disorder. "We'll help people define the disorder, and develop clinical practice standards with these kids." Combinations of pharmacological and training or learning interventions are likely to be the best approach to treating these diseases in the future.
Enrollment in the study is expected to begin in spring of 2015 — 90 patients with Phelan-McDermid Syndrome, 100 with tuberous sclerosis, and 140 with PTEN mutations. In addition to Rush, NIH and Boston Children's Hospital, the consortium will include Cincinnati Children's Hospital Medical Center, Cleveland Clinic, Icahn School of Medicine at Mount Sinai Hospital in New York, Stanford University in Palo Alto, Cal., University of Alabama at Birmingham, University of California at Los Angeles, and the University of Texas at Houston.
The NIH announced last month that Rush will also participate in a second RDCRN consortium, this one to focus on Rett Syndrome, a mostly non-inherited genetic disease caused by spontaneous mutations in a gene called MECP2, that impair formation and function of synapses and cause problems with motor control and intellectual functioning in girls.
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