2015年2月26日
“Several people have said this is like Lorenzo’s Oil part two. To be compared in the same breath, I mean it’s just incredibly humbling, because that was never my intention. I just wanted to diagnose my son.” Six years ago, Stephen Damiani's baby son Massimo begun to suffer from a mystery illness. Stephen held the unwavering belief that aligning the genomes of himself, his wife Sally as well as his son, would find the unique genetic variation causing Massimo‘s illness.
In his first year, Massimo hit all of the typical milestones of a healthy baby. He rolled and began crawling at the expected time. He was thriving and happy, but then on the eve of his first birthday in July 2009 he exhibited unsettling signs that something wasn’t right. He had trouble pulling to stand and, when he was sitting on the floor, he would lose his balance.
A series of diagnostic tests identified abnormalities in his brain and spine consistent with a neurological condition called leukodystrophy – which is a group of life-threatening conditions that affect the formation of myelin around nerve fibers in the brain. There are roughly 40 known variants of the condition, but sadly fifty percent of leukodystrophies remain genetically unclassified offering little hope of treatment, an unknown future and an almost certain tragic outcome. After 472 days of exhaustive and often invasive testing, Massimo fell into this terrible category.
Stephen and his wife Sally pursued the option of having Massimo’s genome sequenced, then eventually their own for comparison. At the time, this was no small feat, being the first familial genome trio sequenced for clinical diagnosis. The sequencing was not the greatest challenge, however – it was finding someone willing to analyze and make sense of the staggering amount of data. A chance encounter with Dr. Ryan Taft, a genetic scientist at University of Queensland, would prove to be the vital link in accessing the science of this new frontier.
After several months of analysis during the fall of 2011, Ryan found variations in the DARS gene. The DARS gene had not been previously associated with human disease, but Ryan thought it was responsible for Massimo’s illness. The finding was initially met with silence and raised an inconvenient truth:
n = 1
They only had one child in the sample. In order to prove that they had finally found the gene causing Massimo’s illness, they had to show supporting results in one or more other studies. They needed to find another Massimo.
In 2009 Massimo had been enrolled in the Myelin Disorders Bioregistry Project, a research project established by Dr. Adeline Vanderver at the Children’s National Medical Center in Washington, DC. With colleagues from the Netherlands, she searched through the bioregistry to find other children similar to Massimo who might be able to validate the finding.
DNA specimens were sent to Ryan for sequencing and analysis. In early September 2012, two of the six patients were confirmed as having variations in the DARS gene validating the initial finding. A new disease had been discovered and was named Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL).
One answer leads to more than anyone expected
Within two years of first sequencing Massimo and his family, Ryan and a global team of medical and genetic experts were able to begin making a life-changing difference not only for Massimo but also for other children.
In fairly short order, the team diagnosed several previously undiagnosed diseases, some of which were completely novel diseases. According to Ryan, “We went from helping one sick child to helping many children, now with a newly identified disorder. And other disorders that nobody could identify before – new disease genes. We thought, ‘This really seems to be working, and we’re finding answers for the first time for many of these families.’”
The team took on ‘the hardest of the hard’ – children who had already undergone a diagnostic odyssey of tests. By building a web interface and creating a pipeline of computational algorithms that allowed them to see the data easily, they were able to share information with clinicians in real-time, across the globe.
“It took an entire community,” says Ryan. Others involved included clinicians at the Royal Children’s Hospital, Melbourne, and VU University Medical Center, Amsterdam, and Sean Grimmond, Chair of Medical Genomics at the Institute of Cancer Sciences, University of Glasgow. Eventually, other relationships were formed with Baylor College of Medicine and The Hospital for Sick Children, Montreal.
Ryan acknowledges, “Everything that’s come after Massimo has been a massive team effort. While I may be the one speaking about him, there’s 50 or 70 people standing with me that have made the work possible.”
Moment(s) of truth
Stephen and Ryan had the opportunity to meet the two girls who validated Massimo’s diagnosis in 2012 and speak at the Children’s Hospital Los Angeles to share the story of how they achieved the diagnosis. What quickly became apparent was the broad spectrum of the condition.
At the conclusion of their presentation, Stephen made a Skype call to Australia to introduce them to Massimo’s neurologist. Dr Rick Leventer initially asked a question through Stephen, who responded by saying, “Why don’t you ask them yourself?” and turned the camera to one of the girls who waved and said hello. “It is fair to say he was astonished at the difference in their development compared to Massimo,” says Stephen.
As infants, the two girls had initially been misdiagnosed with a condition called Acute Disseminated Encephalomyelitis (ADEM), and given a pulse protocol of high-dose intravenous corticosteroids on a monthly basis. Doctors explained that, after the girls received the steroid treatment, they always had a period of improvement, not just stabilization.
“Perhaps this early intervention with steroids had allowed the girls to develop more myelin at a critical stage in the formation of their nervous systems, possibly accounting for their vastly different presentation to Massimo,” suggests Stephen.
Massimo started a twelve month trial of this experimental pulse protocol. Over the course of his treatment Massimo’s medical team observed significant and sustained behavioral and physical improvements. He was far less irritable, more engaged, and attempted both receptive and expressive communication. His fine motor skills improved and lower-limb spasticity reduced dramatically. The time between injections to relax his calves and hamstrings increased from two to six months. However, the observations remained subjective.
In October 2014, Massimo underwent a follow-up MRI scan. Not only had progression of the disease halted, there were two regions of his brain showing improvements. What’s more, he’s now pulling himself up to stand. And, this past fall, he said his first word, which was, "Mum."
What’s Next?
After finding 22 patients with Massimo’s disorder and identifying five new diseases, what’s next for Ryan and team? In the midst of the endeavor, Ryan left academia to join Illumina and the company’s Clinical Services team.
“The reason I made the jump from academia to industry is that there’s a huge challenge of how we get the technology all the way over the line. I believe we have a moral imperative to get this technology into the clinic as quickly as humanly possible. We have to do everything we can to ensure that the quality of the genomes we’re sequencing are as accurate as possible – to the variants we call, to having delivery mechanism for patients and clinicians to look at that data, through to cost savings.”
Ryan points out that many of these children may not have been misdiagnosed if whole genome sequencing was a first-line screening test.
“We’re really trying to ensure that Illumina absolutely becomes first-in-class when it comes to medical whole genome sequencing and can serve as a paradigm for what we hope the world will do.”
