Once Torkamani and Raskind started identifying more people with ADCY5 mutations, they could finally gauge the full breadth of symptoms caused by those faults. And they have used that knowledge to find even more cases: There are now more than 50, about 10 of which have the same mutation as Lilly. The team will soon detail a newly defined set of defining criteria in the journal Neurology, with the hope that patients can be diagnosed based on symptoms alone, without needing a genetic test.
This makes Lilly’s condition, now rebranded as ADCY5-related dyskinesia, very different from other genetic disorders, like Huntington’s disease or cystic fibrosis. In those cases, scientists toiled for years to find the genes behind well-characterized and diagnosable conditions.
“It was done in an almost haphazard way, but this is something we can expect to see more of,” says Torkamani. “You’ll see people get an initial diagnosis based on genome sequencing. Then, the patients themselves proactively establish a network and identify additional individuals with the same mutations. If it wasn’t for [the Grossmans] and their willingness to take this beyond just a diagnosis, to get the word out and identify new subjects, I don’t think we would have been nearly as successful as we have been.”
But what happens after diagnosis? Once you know the gene responsible for a new disorder, what then? Topol says that studies like IDIOM will eventually lead to three possible outcomes. In the best of these, a genetic diagnosis suggests treatments that lead to an outright cure (as in the now-famous case of Nicholas Vollker). Few cases will be corrected so easily, even with a new suite of powerful genome-editing technologies. “That category is going to be rare for a long time,” says Topol.
In the worst scenario, families still won’t get a diagnosis despite having their genomes deciphered. That’s the case for around 40 percent of families who have taken part in the IDIOM study so far, and there are many reasons for that. Their disorder might not be a genetic disease at all. The scientists might get a long list of candidate genes that are impossible to narrow down. The genes in question may rest in parts of the genome that are poorly characterized. “But those cases will fill in over time,” says Topol. “The sequence data won’t go away and it will get colored in by hundreds and thousands of other sequences.”
Lilly exemplifies the third and most likely scenario, in which genome sequencing hints at ways of controlling symptoms but provides neither cures nor easy solutions. Lilly, for example, started improving after taking Diamox but the drug’s effects soon wore off. When I spoke to the Grossmans in March 2013, the tremors had returned, albeit less severely than before.
Her doctors tried her on a variety of other possible drugs, to varying effect, but in the summer of 2014, Lilly was back to days of continual sleeplessness. Delirious with exhaustion and worry, the Grossmans checked her into hospital, where their doctor, Jennifer Friedman from the University of California, San Diego, prescribed her Valium. That night, she slept for four hours. “The nurse came in and apologized saying my night must be horrible,” Gay recalls. “And I was like: You have no idea! Four hours is heaven!”