He wrote an email to a prominent scientist about his chronic fatigue, and his case led to a revolutionary discovery: “It’s not psychological.”

journey of amanda twinham to understand His decades of exhaustion It all starts with diagnosis breast cancer 28 years old. Twinam underwent a mastectomy before undergoing chemotherapy. The drugs made her sick and caused seizures, and she eventually saw a rheumatologist.

That doctor found markers of an autoimmune disease in Twinham’s blood. However, None of the proposed diagnoses are entirely consistent.. “Fatigue was my main and sometimes only disease,” said Tweenham, who suffered from suspected mononucleosis in high school, which left her exhausted for months. “But no one knew what to do.”

In 2015, after further testing, Twinam, now 44, was found Carriers of the hereditary cancer disease Li-Fraumeni syndrome. Shortly after she was diagnosed with her second breast cancer, Twinam underwent another mastectomy. But Twinum knew something else was wrong.

After entering the quarantine area, It became increasingly difficult for him to stand and walk. The Albany, New York, attorney reduced her job to part-time because she couldn’t keep up with her legal cases while raising her young daughter.

“I’m a person with less and less functionality, and I don’t have much of an explanation for that, and it drives me crazy,” she said. “The doctors didn’t know what to do with me.” So Twinam began a years-long journey to understand his ongoing fatigue, neuropathy, muscle weakness and other issues.

Their tenacious efforts led to a new scientific discovery from the National Institutes of Health and a promising new research direction. This could ultimately help many other people with conditions that cause chronic fatigue, which may include long-term COVID-19.

“We’re very excited to be able to test drugs” that treat the problems Twinan identified, he said. Paul Hwang, researcher at the National Institutes of Health who directed this work.

Warning signs indicate Twinam suffers from an unrecognized chronic disease They started after he was accused of having mononucleosis in high school. He said he believed he never fully recovered. BIG TIP: Twinam didn’t experience an endorphin rush after working out in college. Instead, she told friends she “felt like garbage.”

Between two bouts with breast cancer, Twinam decided to return to pursue a master’s degree in public health. She wanted to understand herself by learning about biostatistics. “When I got a 100 on my biology midterm, I was actually more excited than I was when I passed law school,” she said.

In 2016, he was interested in an article written by Hwang about Li-Fraumeni syndrome. The article describes problems with mitochondria, the famous powerhouses of cell biology, the small tube-like structures within cells that produce the energy we need to survive.

Huang’s lab found that in people with the syndrome, mitochondria produce too much energy, which cancer cells gobble up as they metastasize. Twinum wondered whether his particular version of Li-Fraumeni syndrome might cause the opposite problem: too little energy?

Twinam sets out to deliver a message to Hwang that turns out to be crucial: “I read with interest your recent article on inhibiting mitochondrial respiration in a mouse model of Li-Fraumeni syndrome.”

“I had zero expectations,” Twinum said. “I’m sending an email to this extravagant scientific researcher, but he won’t give me the time of day.”

Huang is in charge of the laboratory at the National Heart, Lung, and Blood Institute, He responded the next day.He wrote: “Yes I agree with you, (his Li-Fraumeni syndrome) may have altered his metabolism and contributed to his fatigue symptoms. “

Wong was wrong: Ternan’s energy problems were not related to Li-Fraumeni syndrome. But it took Huang and his colleagues years of lab work, including the creation of genetically modified “Amanda mice,” to understand it.

“Amanda showed up and challenged us,” Huang said during an interview in his office. “So we dig.”

In 2017, Hwang brought Twinam to Bethesda. During a series of tests, a strange result emerged. After a brief workout, Twinam’s calf muscles took a long time to replenish energy-carrying molecules. In other patients with Li-Fraumeni syndrome, the molecule regenerated in an average of 35 seconds. At Twinam, it took 80 seconds.

“We’ve never seen it fall that far behind,” Huang said.

Confused, Huang sent Twinam’s brother and father to Maryland because they were both carriers of the Li-Fraumeni gene. But in energy production tests, both showed rapid energy recovery, unlike Amanda. Neither of them complained of severe fatigue.

Amanda is an exception.

Huang now has compelling evidence that Ternan’s energy problems—both at the cellular level and in the human body—are caused by something other than Li-Fraumeni. But what?

Around the same time, in 2017, Huang received another serendipitous letter. NIH researcher Brian Vallett I heard that Huang studied energy production inside mitochondria.

Wallett is interested because he is conducting an in-depth study of a small number of hospitalized patients at an NIH research hospital who are diagnosed with chronic fatigue syndrome, also known as myalgic encephalomyelitis or myalgic encephalomyelitis. ME/CFS –Chronic Fatigue Syndrome – (I was a patient in this study, and Huang used my data in his study.)

This contact aroused Huang’s curiosity: What if this patient with the unusual cancer syndrome also suffers from a condition such as ME/CFS that causes chronic fatigue?

yellow A thorough biochemical study begins. He found Twinam’s skin cells appeared to produce excessive amounts of a protein called WASF3. Huang and colleagues zoom in on Twinam’s mitochondria They saw something surprising: Like a stick stuck in a bicycle spoke, excess protein actually clogs the gears of energy production.

“It’s really surprising,” Huang said.

Mitochondria produce energy through respiration, a process that converts oxygen and glucose into energy-carrying molecules. At the center of this chemical chain reaction is an 800-pound biochemical gorilla known as the Super Complex.

Is Twinam protein doing too much? The super complex is severely clogged. “That makes the whole thing so bad,” Huang said. “It’s actually falling apart.”

Extensive laboratory work confirmed and extended this finding. In cell culture dishes, increasing WASF3 reduces cellular energy production. Reducing it produces more energy. Mice that produced too much protein pooped quickly, such as Twinam, who walked on the treadmill in half the time of normal mice.

One last chance opportunity expanded Hwang’s research from a single patient to an entire patient population: He obtained muscle tissue from Walitt’s ME/CFS patients.

Nine of the 14 volunteers had similar levels of WASF3 to Twinam, and on average, levels of this protein were higher in this group than in healthy volunteers. Although the sample size is small, the findings suggest that energy deficiency is prevalent in ME/CFS.

Research driven by Twinam culminated in August when Hwang and colleagues published a paper in the journal PNAS. Scientists working in the small field of ME/CFS are excited about the discovery, which suggests a possible and much-needed treatment strategy.

“This is done very elegantly,” said Mady Hornig, who also studies ME/CFS as a physician researcher at Columbia University’s Mailman School of Public Health. “It’s not common for us to do all of these . . . steps, to have physicians who are really relentless in understanding individual circumstances and applying a scientific perspective.”

ME/CFS is common—as many as 2.5 million Americans have the disease, according to a 2015 Institute of Medicine report—but it’s also often misunderstood.

Research funding has been scarce. Diagnosis is often delayed or does not occur at all. Studies show that up to half of people with chronic fatigue syndrome qualify for this diagnosis. There is no blood test to identify the disease and no Food and Drug Administration-approved treatment, let alone a cure. Up to a quarter of people with ME/CFS are bedridden.

For Huang, developing treatments for the disease is now “what keeps me going.” His small lab of four scientists planned to conduct a clinical trial with a drug that had just become available to treat another disease.

“Amazing discoveries in medicine are sometimes based on a single patient,” he said.

As for Twinham, who has been feeling unwell for decades without a proper diagnosis, she believes her story has finally been legitimized and published in a major scientific journal.

“There’s a difference between cancer and chronic fatigue syndrome,” he said, and his rheumatologist finally added the diagnosis to his record. “When you have cancer, everyone believes you. You joke about having a “cancer card” that makes you stop doing things. No one hands out CFS cards. In closing I can say: “It’s not psychological“. “Now we have a scientific explanation. “

Washington Post Special Report