Kim Goodsell: one gene for two diagnoses

The situation

Kim Goodsell spent most of her adult life outdoors. She had been a gymnast in high school, a cyclist, and an Ironman triathlete. In the Rockies she was a climber, a skier, and a mountain runner. She studied pre-med at UC San Diego, then left that path. She and her husband lived an itinerant life, renovating houses and moving between wilderness trips¹.

The heart trouble started in 1995, during a stressful renovation in La Jolla. Two years later she was driving on Highway 1 when she went into ventricular fibrillation. That is a chaotic rhythm in which the heart stops pumping effectively. She came close to dying.

The diagnosis was arrhythmogenic right ventricular cardiomyopathy, or ARVC. It is a rare inherited condition in which the muscle of the right ventricle is gradually replaced by fat and scar tissue. She left the hospital with an implanted defibrillator. She resisted the device at first and later nicknamed it her “internal terrorist”¹.

The second problem arrived in 2002, when she was 44. Her left ankle began turning inward on a mountain run. Within weeks she was struggling to lift her feet near the end of long efforts. Her back and joints began to ache. The symptoms worsened for eight years. In the summer of 2010 she lost the ability to grip a pen or a fork. At the Mayo Clinic in Rochester, Minnesota, a neurologist diagnosed Charcot-Marie-Tooth disease. That is a group of inherited disorders that damage the peripheral nerves running to the limbs¹².

She asked her physicians whether the two conditions could be connected. She was told they were not. By Eric Topol’s later estimate, the odds of having both ARVC and Charcot-Marie-Tooth were about four in ten million. He compared it to the chance of being hit by an asteroid³. Her cardiologist’s report to the neurologist had not even mentioned the ARVC. She recalled that to him “it meant nothing”¹.

What she gathered and how

She began reading the day she left the Mayo Clinic. Staying at a friend’s house on Lake Michigan, she sat on the balcony for about eight hours a day with PubMed, the public index of the biomedical literature. She used Google to decode terms she did not know. Her pre-med coursework was 30 years old, and she said the papers at first read “like Chinese.” Over hundreds of hours she learned the vocabulary. In her words, she got a feeling for what was being said¹².

She was working toward one thing, what she called a unifying field theory for why she had both conditions³. She went through every gene linked to Charcot-Marie-Tooth, more than 40 of them. One stood out. LMNA encodes the lamins, a family of rope-like proteins that mesh into a network lining the inside of the cell nucleus and give it structure. Mutations in LMNA cause a group of disorders known as laminopathies. These affect the nerves, muscles, fat tissue, and heart.

Reading through them, she recognized her own history. That included bone and joint problems that had never been folded into either diagnosis. “Everything was encapsulated,” she said. “It was like an umbrella over all of my phenotypes”¹³.

She wrote her reasoning up as a 36-page white paper and took it back to Mayo. Her cardiologist, Martha Grogan, was impressed by the work but doubted it would change anything. In November 2010 she saw a medical geneticist. By Goodsell’s account he was cool to the idea and told her the odds of being right were slim. He recommended a seven-gene ARVC panel that insurance would cover. Sequencing LMNA alone would cost about $3,000 out of pocket. Goodsell insisted and paid for it herself, and the LMNA test was ordered¹²³⁴.

What it showed

The result came back in May 2011. Her LMNA gene carried a single-letter change at position 1,044, a G replaced by a T, on one of her two copies. That position is almost never altered across species. That is one signal that a change there is likely to matter. The laboratory report read: “All evidence suggests that the mutation found in this patient might be disease-causing”¹⁵. She was, she said, running up and down the beach with excitement¹.

Independent support followed within months. A British research group studying 108 ARVC patients reported LMNA mutations in some of them. They wrote that, to their knowledge, it was the first report of ARVC caused by mutations in LMNA⁵. Michael Ackerman is a Mayo geneticist specializing in inherited heart conditions. He called LMNA the leading contender for a unifying explanation of her case and said the evidence was pretty good. Among more than a thousand patients, he said, she was the only one who had done the detective work and told her physicians which test to order¹.

In 2016 her Mayo physicians and she published the case in the Journal of Cardiovascular Electrophysiology as “LMNA-Mediated Arrhythmogenic Right Ventricular Cardiomyopathy and Charcot-Marie-Tooth Type 2B1: A Patient-Discovered Unifying Diagnosis.” The abstract describes a patient who discovered her own pathogenic LMNA mutation. That mutation explained her ARVC and Charcot-Marie-Tooth phenotypes as well as her musculoskeletal abnormalities. The paper concludes that suspicion for LMNA-mediated cardiomyopathy should arise in patients with non-cardiac signs of laminopathy⁶.

What she did with it

The diagnosis did not come with a cure. Laminopathies have no specific treatment, and her defibrillator remained. What changed was that she now had a mechanism to study. She went on to read about the molecular pathways downstream of lamin A/C. She also read how those pathways interact with desmosomal proteins, the cell-to-cell anchors classically implicated in ARVC. She wrote what she described as a whole dissertation on it³.

She built her own regimen from that reading. Ed Yong’s profile describes a diet of organic fruit, vegetables, nuts, and seeds with processed foods removed. She also drank ginger tea, which she believed would thin her blood. That was based on reports of clotting problems in laminopathy patients. She kept up a demanding exercise routine and a long daily practice of stretching and self-massage. She reported that her nervous system symptoms had improved and that her defibrillator had not fired in months¹².

She spoke at the Future of Genomic Medicine conference in San Diego in March 2014. There she said she had also removed gluten, free glutamates, and nightshade vegetables. She described regaining function in her left hand and walking without support. Topol, her cardiologist at Scripps, said she had not only diagnosed her disease but set up her own treatment plan³⁷.

These are her reports of her own experience. A single person cannot separate what the diet did from what the exercise, the time, or the removal of uncertainty did. She was clear about the last of these. “Even if you have a terrible prognosis,” she said, “the act of knowing assuages anxiety”¹. In the years since, she has spoken at the Hereditary Neuropathy Foundation’s CMT Summit. With her husband, she co-founded a company designing mobility aids⁸.

What others can take from it

Goodsell has said that she almost takes offense when her work is called exceptional¹. The habits behind it are ordinary ones that anyone with a chronic condition can copy.

Start from your own record. Her insight came from a careful reading of symptoms that already sat in her file: a heart condition, a neuropathy, a curved spine, misaligned hips, contracted muscles. No single specialist had seen all of them together. She did, because she was the only person who had lived with all of them.

Ask whether separate findings share one cause. Two rare diagnoses in one person are so unlikely by chance that the coincidence itself is evidence. Her question was what single mechanism explains everything. That is the same question a good clinical geneticist asks, and it is available to anyone willing to do the reading.

Match the test to the hypothesis. The insurance-covered ARVC panel would not have included LMNA, so it would have looked in the wrong place. A test is only as useful as the question it answers. She paid for the narrow test that could confirm or refute her specific prediction.

Write it down before you ask. The 36-page white paper meant that skeptical physicians had something concrete to evaluate rather than a hunch to dismiss. One of them later said having her on the case was like having another research fellow¹.

Keep your claims proportionate. Her mutation was reported as likely disease-causing, not certain. Independent publications and the peer-reviewed case report are what moved it from a personal conviction to a documented diagnosis. What she changed afterward she describes as her own plan and her own results. Reporting it that way is part of what makes her account credible.

Footnotes

1. Ed Yong. How an Extreme Athlete Uncovered Her Own Genetic Flaw. National Geographic (Phenomena), republished from Mosaic, 2014. https://www.nationalgeographic.com/science/phenomena/2014/08/19/how-an-extreme-athlete-uncovered-her-own-genetic-flaw/ ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴

2. Ed Yong. DIY diagnosis: how an extreme athlete uncovered her genetic flaw. New Statesman, republished from Mosaic, 2014. https://www.newstatesman.com/long-reads/2014/08/diy-diagnosis-how-extreme-athlete-uncovered-her-genetic-flaw ↩ ↩² ↩³ ↩⁴

3. Ron Zimmerman. Patient Cracks Her Own Mysterious Dual Diagnosis. Medscape Medical News, 2014. https://www.medscape.com/viewarticle/822136 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶

4. Hereditary Neuropathy Foundation. A Rare Disease Patient That Does It All! CureCMT, 2014. https://curecmt.org/cmt-update/rare-disease-patient/ ↩

5. Ed Yong. DIY Diagnosis: How an Extreme Athlete Uncovered Her Genetic Flaw. Pacific Standard, republished from Mosaic, 2014. https://psmag.com/social-justice/diy-diagnosis-extreme-athlete-uncovered-genetic-flaw-88763/ ↩ ↩²

6. Jackson J. Liang, Martha Grogan, Michael J. Ackerman, Kim Goodsell. LMNA-Mediated Arrhythmogenic Right Ventricular Cardiomyopathy and Charcot-Marie-Tooth Type 2B1: A Patient-Discovered Unifying Diagnosis. Journal of Cardiovascular Electrophysiology 27(7):868-871, 2016. https://doi.org/10.1111/jce.12984 ↩

7. Scripps Health. Scripps Patient Profiled in Science Website and Huffington Post. Scripps Health News, 2014. https://www.scripps.org/news_items/4910-scripps-patient-who-cracked-genetic-disease-link-profiled-by-science-website ↩

8. Hereditary Neuropathy Foundation. Summit Speaker Spotlight: Kim Goodsell, The Patient Of The Future. CureCMT, 2016. https://curecmt.org/cmt-summit/summit-speaker-spotlight-kim-goodsell-patient-future/ ↩