Matthew and Joshua, born five years apart, led normal, healthy lives into young adulthood. Matthew was a quiet, observant and smart kid, who was placed in the gifted and talented program in middle school. Joshua was more outgoing and also more mischievous. He sometimes got into trouble for behavior problems.
The first signs of disease
Matthew began to worry his parents, Barbara and Michael, during his junior year of college. He started drinking heavily and fell behind on his course work. Then, when he was 24, he began to have vision problems. He saw double and became unable to track moving objects. His doctors in Connecticut struggled to understand the cause. At one point, they suggested it might be a brain tumor.
While the family waited for a definitive answer, Matthew had a psychotic break. He was living at home at the time, and would have fits where he broke things and punched the walls.
“He would scream, ‘Get this thing out of my head,’” Michael remembers.
Joshua was also at home then, taking time off between high school and college. He was very caring and supportive of Matthew as his condition deteriorated. He made the decision to attend a nearby university so that he could be available to help Matthew, if needed.
More About Mitochondrial Disease
But that spring and summer, as Joshua prepared for college, he too began to exhibit worrisome signs of a change. He also started seeing double. He grew more withdrawn and stopped going out with friends. Joshua became less attentive to his hygiene, avoiding showering or changing his sheets.
“He was not participating in life,” remembers Barbara.
In September, soon after Joshua started college, Matthew went to a party in Joshua’s dorm. During the party, Joshua had an extreme adverse reaction to something he smoked. He couldn’t stand up, and he couldn’t speak. Matthew called Michael and Barbara, who took Joshua to the hospital. Blood tests showed that Joshua’s magnesium and potassium levels were near zero, which is dangerous. It was five days before he was able to talk again, but doctors couldn’t figure out the cause.
Looking for an answer
Barbara found a neurologist who worked with Joshua over the next two years to understand what was causing his decline. The doctor was the first to suspect the problem might be mitochondrial disease.
Mitochondrial disease is a condition in which mitochondria — which serve as biological batteries to produce energy in cells — don’t function correctly. Depending on which cells have poorly functioning mitochondria, the disease can cause a wide range of health problems, including fatigue, weakness, exercise intolerance, developmental disabilities, seizures, strokes, vision or hearing loss, growth and feeding difficulties, hormone imbalances, and serious problems with heart, liver or kidney function.
The doctor guessed that both Joshua and Matthew had a clinical form of mitochondrial disease known as Leigh syndrome, which more typically presents with symptoms in early childhood. Leigh syndrome causes progressive neurological deterioration and has many different genetic causes.
Even without a firm diagnosis, the neurologist began to treat both men for the condition, which was affecting Matthew and Joshua differently. For Matthew, the effects were primarily psychological. Joshua’s symptoms were more physiologic. The left side of his body tightened, and he would sometimes get stuck, unable to move.
More About Exome Sequencing
The tentative clinical diagnosis would be genetically confirmed eight years later when another doctor ordered whole exome sequencing for Joshua, a test in which lab personnel use high-tech machines to read and analyze the genetic code of all 20,000 genes. Once the defects were identified in Joshua, further DNA analysis of the affected DNA strands were conducted for Matthew, Michael and Barbara.
Michael and Barbara were found to each be single mutation carriers in the nuclear gene SURF1, while both Joshua and Matthew inherited both of their mutated SURF1 gene copies to cause them to be affected with Leigh syndrome. As SURF1 is needed in cells to properly form complex IV of the mitochondrial electron transport chain, affected patients without functional SURF1 develop severe complex IV deficiency and energy failure. Remarkably, Matthew and Joshua are the oldest known people affected with SURF1 disease.
Treatment breakthroughs in Philadelphia
That diagnosis eventually opened the door to their participation in clinical trials. After years of searching for possible research studies, Joshua was accepted into a study in 2016 at Children’s Hospital of Philadelphia (CHOP) led by Marni Falk, MD, Executive Director of Mitochondrial Medicine, a Frontier Program at CHOP.
The REATA Pharmaceuticals sponsored phase II clinical trial was testing the safety and preliminary effectiveness of a new drug, RTA 408, in adult patients with mitochondrial disease. In periodic visits to CHOP, Joshua would work out on an exercise bike while connected to an EKG monitor and other sensors. His blood was drawn every 10 minutes while he exercised and again after a period of rest.
While they began the trials separately, Joshua and Matthew are committed to fighting their disease together, and accompany each other on all trips to Philadelphia. Matthew first participated in a separate glycemic index nutritional research study at CHOP while Joshua underwent his tests. That study was led by Shana McCormack, MD, an attending physician in CHOP Endocrinology with special expertise in endocrine problems in mitochondrial diseases. He was accepted into the REATA Pharmaceuticals RTA 408 study at CHOP in 2017.
In the process of being evaluated for participation in the studies, and as part of the frequent visits to CHOP required for both studies, both men were seen by members of the Mitochondrial Medicine team. They now receive regular clinical care through the CHOP Mitochondrial Medicine Frontier Program by Zarazuela Zolkipli-Cunningham, MBChB, MRCP, an attending physician with special expertise in neuromuscular problems. She has become an important part of their multidisciplinary care team.
“Dr. Zolkipli-Cunningham was able to connect with Matt and Josh,” says Barbara. “She listened to them and they listened to her. When she didn’t get a response to a question, she would rephrase it to draw out an answer. She impressed on them that they needed to eat a healthy diet and to exercise.”
“Both boys have abilities,” says Michael. “They can get things done when they want to.”
“CHOP is helping them want to. Dr. Zolkipli-Cunningham has motivated them.”
Dr. McCormack got Matthew working out daily on a recumbent stationary bicycle, and Joshua with less regularity. Dr. Zolkipli-Cunningham worked with them on taking their medications, which include supplemental vitamins and cofactors that are critical to support their health.
When Joshua let her know that he was having trouble swallowing the pills, she did a swallow test that revealed a difficulty that hadn’t been noticed before. She changed the medication for both men to a liquid form, which they now take three times a day.
Hope for the future
With close adherence to their medication plan and better eating and exercise habits, Matthew and Joshua are feeling better, and their parents notice that they are more alert and more focused. Matthew loves to attend Yale sports events, especially basketball games. Most weeks, he writes an extended blog about his experiences, which he shares with family and friends. Joshua has a passion for books and science fiction movies. He’s most comfortable at home, but is also very sociable and takes great pleasure in making people laugh at his jokes.
Joshua appreciates what Dr. Zolkipli-Cunningham has done for him. “She gave me hope,” he says. “She showed me there’s a light at the end of the tunnel, with the research they are doing.”
For Barbara and Michael, CHOP has brought hope, too. “After 20 years, we feel like we had found the right doctors,” says Barbara. “We are in the right place. When we ask questions, we get answers from real knowledge, based on international research. Without CHOP we wouldn’t feel so comfortable about Matt and Josh’s future.”
“The doctors at CHOP know about this disease, and they are doing research to learn more. Matt and Josh will have the benefit of new treatments as they are found.”