[In May of 2020, we first reported on the discovery of a new type of CMT potentially treatable with a drug used to treat diabetes. Here, we bring you an updated version of how that discovery took place, as well as “A Diagnosis Worthy of a Tattoo,” in which CMT patient and champion fundraiser Vittorio Ricci describes how he was finally diagnosed after six years and several trips to the CMTA Center of Excellence headed by Dr. Michael Shy.]
A Diagnosis Worthy of a Tattoo
by Vittorio Ricci
When I found out that my type of previously unknown CMT had been identified, I was very excited—partly because I was finally going to know the truth after six years of being in the dark—and partly because I’d been planning on getting my first tattoo to commemorate the occasion.
In the past, I visited Dr. Shy’s CMT Center for Excellence in Iowa to track the progression of my disease in order to determine its severity and to undergo more genetic testing. The scientists there had been sequencing my genome and comparing it to all the other patients in the Inherited Neuropathy Consortium registry in an attempt to find the mutation that caused the neuropathy.
My third trip to the clinic in the summer of 2018 had a different purpose: The mutation had been discovered on Chromosome 15 in a region titled SORD1. Intrigued by the diabolical-sounding name, I flew out to Iowa for my first-ever skin biopsy to confirm the diagnosis. It was also the first time I almost passed out during an exam (due to dehydration), so suffice to say it was quite a rollercoaster experience. The biopsy confirmed that one section of DNA base pairs was missing in my SORD1 region.
The results of the study were officially published in May in Nature Genetics. The article details the methodology of the study and explains how the mutation inhibits enzyme function and eventually leads to the breakdown of peripheral neurons, which was fascinating to the bioengineering student in me.
Having participated in the study, I read the article with the notion that I already knew what it contained. I had been privy to the progress of the study and how the mutation leads to neuropathy. I was just excited to see it officially published. Toward the end of the article, I was surprised to read about potential treatments. There are drugs currently in clinical trials that could jump-start the afflicted enzymes, effectively preventing further damage.
I don’t think I’ve completely wrapped my head around the diagnosis and prognosis for a potential treatment. One thing I’ve learned over the years is that big events can take a while to set in. I’ve spent the past six years reading, listening and speaking about big goals—getting a diagnosis, finding a treatment. It seems surreal to learn the full truth of my condition after so many years of questioning. It’s just another example of the great things the CMTA community has accomplished and of the many more to come.
Another great thing to come? My tattoo—the DNA code that includes the SORD1 mutation on my lower leg.
Vittorio, 22, is a rising senior at Northeastern University. He is currently interning at Alnylam Pharmaceuticals. Vittorio and his family, which includes Boston Branch Co-Leader Jill Ricci, have raised well over a quarter of a million dollars for CMT research since 2012.
University of Miami researchers led by Dr. Stephan Züchner have discovered a new type of CMT that may be treatable with the same drugs used to reduce elevated sorbitol in people with diabetes.
The initial discovery was made by Andrea Cortese, MD, and Adriana Rebelo, PhD, who worked with a large group of CMT2 families convened by the Inherited Neuropathy Consortium, with support from the National Institutes of Health, the CMTA and many others.
The newly discovered type is caused by a mutated SORD (sorbitol dehydrogenase) gene that raises sorbitol levels so high they cause nerve damage. Researchers found that treating fruit flies with a diabetes drug (aldose reductase inhibitors) reduced their high levels of sorbitol to near normal.
An estimated 3,000–5,000 people in the United States—and more than 60,000 worldwide—may have this type of CMT, making it the most common recessive form of the disease. Dr. Züchner and his colleagues are looking to screen undiagnosed CMT patients to identify as many patients as possible in preparation for clinical trials.
“We’re very optimistic about the therapy going forward,” Dr. Züchner said, noting that the drug basically cured CMT in fruit flies. “This is a remarkable discovery only possible due to large scale genomic data aggregation from volunteering CMT patients,” he added.
Dr. Züchner, MD, PhD, is a professor of human genetics and neurology and chair of the Dr. John T. Macdonald Foundation Department of Human Genetics at the University of Miami Miller School of Medicine. He is also a member of the CMTA’s STAR Advisory Board. He and his team—Rebelo, associate scientist at the Hussman Institute for Human Genomics, and Cortese, a visiting scholar from University College of London— discovered the SORD mutation “hidden” from the gene analysis software that most researchers use. Using a different strategy, the researchers found the relevant variations hidden behind a “pseudogene.” Pseudogenes mirror the DNA sequence of their active counterparts, but have no function.
After identifying the gene, the team identified 45 individuals from 38 families who had the specific mutation. With gene and patients identified, the next step was finding the necessary animal model.
Serendipity intervened in the person of R. Grace Zhai, PhD, senior associate dean for basic science research and associate professor in the Department of Molecular and Cellular Pharmacology at the Miller School. Her lab is right across the street from Dr. Züchner’s and the two of them ran into each other over lunch. When he told her about his team’s discovery, she said he could introduce the gene mutation into her fruit fly model.
Dr. Zhai and colleagues were able to genetically manipulate flies to raise sorbitol levels, causing precisely the same kind of damage observed in people. The fruit flies with neuronal damage behaved differently, but when treated, showed an “amazing reversal” of their altered movements, Dr. Zhai said, adding, “This is truly remarkable. In my career I work on neurodegenerative diseases, and I’ve never seen such complete suppression of the phenotype. We are very excited about this.”
After modeling CMT in fruit flies, the next step was to test the theory using skin cell fibroblasts from CMT patients. The team found that just as in the fruit fly model, when relevant genes were inactivated, they saw accumulation of the sorbitol and a reversal with the addition of the medication.
According to Dr. Züchner, SORD neuropathy will represent one of the first examples of a treatable hereditary neuropathy. The experience with SORD neuropathy reinforces the power of international collaborations, which can accelerate the journey from gene identification to effective treatment, he said.
“This story is really unique. Because we can measure the sorbitol, we will be able to determine effectiveness of treatments and even can determine pathogenicity of DNA variants,” Dr. Züchner said. Measuring sorbitol levels in a blood sample could flag people at risk and could also help physicians monitor their response to treatment over time.
The core study team included INC members Dr. Michael Shy, MD, from the University of Iowa, and David Hermann, MBBCh, from the University of Rochester, both of whom are also on the CMTA STAR Advisory Board, and Dr. Rosemary R. Shy from the University of Iowa. Dr. Mario Saporta, MD, assistant professor of neurology at the Miller School, also participated in the study. He built and runs the premier CMT clinic in Florida and is a member of the CMTA STAR Advisory Board. “Without the support of the Inherited Neuropathy Consortium and the CMTA, this work would not have been possible,” Dr. Züchner said.
If you are interested in being screened for this new type and want to be contacted in the near future, please click here to fill out a Patients as Partners in Research profile. The criteria for screening are: 1) you have received a diagnosis of CMT, but genetic testing did not reveal with certainty the responsible gene; 2) your parents never had CMT symptoms.