Mitochondrial diseases affect the mitochondria, which are responsible for the body’s energy. These diseases are often fatal, and typically affect children, although adults are diagnosed as well.
Depending on which genes are affected, the disease can affect different organs, the muscles, or other systems.
Recent news reports of families in legal battles for treatment show how complex these diseases are.
A teenager in England died recently while trying to secure an experimental mitochondrial disease treatment, according to BBC News. Sudiksha Thirumalesh, 19, was hoping for nucleoside therapy—which improves or stabilizes disease across key outcomes including survival, ambulation, and requirement for mechanical ventilation, according to the journal Mitochondrion—by traveling to Canada to receive it.
However, BBC reports that a judge ruled Thirumalesh “could not make the decision for herself because she did not have the mental capacity.” She died on September 12 before the Court of Protection could hear her case.
Mitochondrial diseases are complex, currently incurable, and can be life-threatening. Jaya Ganesh, MD, an associate professor at the Department of Genetics and Genomic Sciences and director of the Mitochondrial Diseases program at the Icahn School of Medicine at Mount Sinai, explains that mitochondrial diseases affect the mitochondria, which are “the subcellular organelles important for energy production, ATP synthesis…and other functions, like regulating calcium, regulating the aging process, and managing certain reactive oxygen species.” There are multiple types of mitochondrial diseases.
When the mitochondria fail, they can no longer convert food or oxygen into energy, resulting in cell injury and death. As this process repeats throughout the body, organs can fail, and the body stops functioning.
The nervous system, the brain, the heart, the liver, the kidneys, and the muscles are often impacted—depending on the gene affected. “When the body’s energy production is compromised, invariably you see these organ systems bearing the brunt of it,” Dr. Ganesh notes.
The diseases can affect “any organ system, any age, and any manifestation. There is so much variability in presentation: Where [in the body], how severe, and how the mutated mitochondrial DNA is distributed,” Dr. Ganesh adds. One patient might experience low muscle tone or visual problems, while another experiences seizures.
The Lily Foundation, the UK’s leading mitochondrial disease charity, says that a “substantial number of children with mitochondrial disorders do not reach adulthood.” In adults, mitochondrial disease can cause significant morbidity and mortality, although causes of death are often unknown, according to JIMD Reports.
In Thirumalesh’s case, her hearing, sight, muscle strength, and organs were affected, necessitating a ventilator and dialysis, according to the University Hospitals Birmingham.
As the BBC reports, Thirumalesh wanted to raise money for nucleoside therapy but died during her legal battle to secure it. Her brother, Varshan Thirumalesh, told BBC Radio 4, “She was really struggling for the past year and two months, and she wanted to seek experimental therapy abroad.”
The University Hospitals Birmingham NHS Foundation Trust, which was involved in her care, said that she needed end-of-life care rather than treatment; thus, she was barred from traveling and receiving the treatment.
Thirumalesh’s case echoes that of an infant named Charlie Gard, who died from encephalomyopathic mitochondrial DNA depletion syndrome (MDDS). The baby’s parents sought nucleoside bypass therapy, which was offered to him by an American hospital despite it not ever being used to treat Charlie’s condition.
What followed was a lengthy and public battle for his treatment, which certain doctors did not think would be effective. The baby died in 2017 after his life support was withdrawn.
A closer look at mitochondrial diseases
Mitochondrial diseases are caused by mutations to mitochondrial DNA (mtDNA) gene or a mutation in a nuclear gene (nDNA). There are many kinds of mitochondrial diseases, and more than 250 pathogenic mutations to mtDNA have been reported.
Dr. Ganesh says mitochondrial diseases are genetically inherited. “In 99.9% of cases, the mitochondrial DNA is inherited through the mother. We don’t say 100% because case reports have shown the father's mitochondrial DNA has passed through,” she explains. The Proceedings of the National Academy of Sciences found that “although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring.”
Dr. Ganesh also says a mother may carry mutations she doesn't know about, thereby passing it to the infant. Additionally, spontaneous mutations—changes to the mitochondrial DNA—can occur in the baby.
Some patients with mitochondrial disease may not show symptoms, although, in mitochondrial diseases that affect children, symptoms often present when they are toddlers.
No cure currently exists for mitochondrial diseases, but there have been a number of supportive treatments explored in the past few years, with clinicians calling it a “lively field.”
There are several therapies being investigated, Dr. Ganesh notes—including supplemental vitamins and cofactors, which are used to reduce manifestations of the disease.
Additional therapies include treatments designed to stabilize the mitochondrial membrane integrity, organ transplants (which Dr. Ganesh says works well in select cases), gene therapy, mitochondrial replacement therapy, or MRT (which is not legal in the US).
MRT is an in vitro fertilization (IVF) approach that removes “an intended mother's nDNA from her oocyte or zygote, which contains mutated mtDNA, and transferring it into a female provider's oocyte or zygote, which contains nonpathogenic mtDNA and from which the nDNA has been removed,” according to the National Library of Medicine.
However, slowly, the treatment landscape is gaining momentum, with more therapies on the market for specific mitochondrial diseases.
To test a patient for mitochondrial disease, you’ll need to run blood and urine analysis to check for amino acids, acylcarnitines, lactate, pyruvate, and urine organic acids, as well as DNA testing and a muscle biopsy, according to the United Mitochondrial Disease Foundation.