For most of her 13-year life, Hannah Manning was a mystery to her doctors. At age 2, she had her first seizure. At 4, she was diagnosed with autism. She developed cognitive deficits, muscle weakness, exercise intolerance, swallowing difficulties, a speech impediment, balance and coordination problems and gastroparesis, a condition that slows the stomach’s ability to empty the food inside.
Hannah’s mother, Christina Wyatt Manning, of Baldwinsville, N.Y., was baffled after several genetic tests came back normal. Finally, in December 2014, Christina and her wife, Kristin Manning, got the explanation they had long been seeking. The answer emerged after doctors ran a new type of DNA test, called next-generation sequencing, to identify abnormalities that may cause disease. The test showed that Hannah had a gene mutation that causes spinocerebellar ataxia autosomal recessive 9, or SCAR9, an ultra-rare, recessively inherited neurological disorder. Hannah’s doctors believe she is the only person in the United States with the disease and perhaps one of only two dozen in the world.
Next-generation sequencing technology became commercially available only recently, after the first test was given approval by the Food and Drug Administration in 2013. But scientists and clinicians say it has already identified multiple cases similar to Hannah’s, where a patient’s puzzling symptoms turned out to be signs of a rare disease.
As this technology gets cheaper and faster, experts say more patients will get tested and find they have rare diseases. They will have the satisfaction of finding out what is causing their symptoms but then will often face a frustrating question: What do you do when diagnosed with a rare disease that has been studied little and has no known treatment, and few other patients to turn to for support?
“We found a needle in a haystack with this diagnosis,” Christina Manning says. Since then, she has been researching her daughter’s condition nonstop and blogging on her website in hopes of finding researchers, medical specialists and patients who know anything about SCAR9.
One physician and researcher she connected with is Michael Kruer, a pediatric neurologist at Phoenix Children’s Hospital who specializes in genetic diseases and has studied hereditary ataxias, the group of disorders to which SCAR9 belongs.
“Rare diseases are literally coming out of the woodwork,” Kruer says. “We’re starting to realize that, collectively, these rare diseases are more common than we ever thought.” For SCAR9, Kruer says, “We don’t exactly know what the true prevalence of this disease is.” While about two dozen patients around the world have been identified, there may be more who haven’t been diagnosed yet.
In the United States, a rare disease is defined as one that affects fewer than 200,000 people. Because rare diseases affect such small populations and because they are so diverse, it is difficult to conduct the clinical trials that might lead to cures. The Orphan Drug Act of 1983 provided incentives for drug companies to develop treatments for rare diseases. That improved matters somewhat: Before 1983, only 38 drugs for rare diseases had been developed, while 400 have been approved since the law went into effect. But 2015 saw considerable progress, with 21 out of 45 new drugs approvals for rare or “orphan” diseases.
Still, for most rare diseases, patients have few options.
Joan Pellegrino, a geneticist at SUNY Upstate Medical University in Syracuse, first met Hannah in September 2014. Pellegrino typically sees patients after they have been to several other specialists who have been unable to identify the etiology, or root cause, of their illness.
Hannah had taken several genetic tests over the years, so Pellegrino and her team suggested whole-exome sequencing, which searches all the protein-coding genes in a person’s genome for mutations responsible for disease. The exome represents only about 1 percent of a person’s genome, or genetic code, but it contains around 85 percent of known disease-related variants.
These new DNA tests are often not covered by insurance. Whole-genome sequencing ranges from about $1,500 to $3,000, while whole-exome sequencing can be about half that.
The results of Hannah’s test were illuminating. “She would have never been diagnosed with this clinically. Nobody would have ever proposed SCAR9 as a diagnosis because she didn’t have an abnormal MRI,” a scan that in patients with SCAR9 often shows brain atrophy, or loss in brain volume, Pellegrino says.
The test results were a mixed blessing. The Mannings finally had an answer for what was wrong with Hannah. But the family soon realized there was no community of SCAR9 patients and no drugs to slow the progression of the disease.
In SCAR9, the body doesn’t make enough of a vitamin-like substance called coenzyme Q10, which allows mitochondria to produce energy needed for cell growth and maintenance. Kruer says there’s some evidence to suggest that coenzyme Q10 supplements may help mitigate symptoms, but there’s not enough research to know for sure.
Hudson Freeze, director of the Human Genetics Program at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Calif., says many patients such as Hannah probably have gone undiagnosed or misdiagnosed because the technology didn’t exist to identify their conditions until recently. “Doctors have had to rely for a long time on symptoms to figure out what’s wrong with patients,” he says. “Now, with the availability of these techniques, almost everybody is going to get their DNA sequenced.”
That can sometimes be problematic. Because these tests may reveal hundreds or thousands of irregularities in a person’s genome, Freeze says, it can be difficult to know which ones are disease-causing. “Some mutations are pretty much a slam-dunk. Other ones are just a prediction of what we think might be causing a disease,” Freeze says. And some mutations might not even be pathogenic, or likely to cause disease — and no one knows yet which is which.
In Hannah’s cases, a mutation in the ADCK3 gene resulted in SCAR9. ADCK3 was a slam-dunk because it’s a “validated” gene, one that has been shown to actually cause SCAR9. But Freeze says of the nearly 7,000 rare diseases that have been identified, about 3,000 do not yet have a known genetic cause.
With the new DNA sequencing technology, though, most of the remaining disease-causing genes might be identified by 2020, according to some genetic experts.
“There’s so much in genetics that’s available now that wasn’t available even 10 years ago,” Pellegrino says. “Now that we’re doing this on so many more patients, it might be that more patients with rare diseases will be picked up.”
Next-generation sequencing is broadening the list of traits associated with certain diseases, Pellegrino says. Many of Hannah’s symptoms do not match those of other patients with SCAR9, so her doctors think hers may be the only known case in the world with this type of SCAR9.
Next-generation sequencing is far from the end of the road for rare-disease patients and their families, though. “A genetic diagnosis doesn’t necessarily give you a specific prognosis in the long term,” Freeze says.
For Bo Bigelow and his wife, Kate McCrann, of Falmouth, Maine, the results from a whole-exome sequencing test in March 2014 didn’t even provide a conclusive diagnosis for their 6-year-old daughter Tess, who has global developmental delay, visual processing disorder and hypertonia, which makes muscles difficult to move.
Years of genetic testing turned up nothing, but the whole-exome sequencing test showed that Tess has a mutation in a gene called USP7. Researchers at Baylor College of Medicine in Houston published a study in September showing that, in seven children, the mutation seems to cause developmental delays, including autism. Bigelow and McCrann are awaiting lab results to know for sure whether the mutation is causing Tess’s symptoms.
Bigelow says the sequencing test was nonetheless helpful. Since it was done, he has been able to connect with parents of children with other rare diseases, which has provided a sense of community.
Both families are hopeful that treatment options will eventually be found. But time is of the essence: Hannah’s condition is degenerative, and the patients with the same mutation as Tess seem to worsen as they age, too.
“Trying to find a cure for this disease has been such a lonely thing,” Manning says. Until then, the Mannings, like Bigelow and his wife, are taking things one day at a time. “Quality, not quantity of life: That’s our goal. We want to do everything to make Hannah happy,” Manning says.