Like most medical students, I struggled to memorize the Krebs cycle, the complex energy-producing process that takes place in the body's mitochondria. Rote learning of Sir Hans Krebs' eponymous cascade of reactions persists and has been cited as a waste of time in modern medical education. However, it looks like that specialized knowledge about mitochondrial structure and function may finally come in handy in the clinic.
Advances in genetics have contributed to improved diagnostic accuracy of a diverse spectrum of mitochondrial disorders. Respiratory chain, nuclear gene, and mitochondrial proteome mutations can lead to multisystem or organ-specific dysfunction.
A new potential treatment for mitochondrial disorders, elamipretide, has received orphan drug designation from the US Food and Drug Administration (FDA) and is in clinical trials sponsored by Stealth Biotherapeutics. [Dr Wilner has consulted for Stealth Biotherapeutics.] Recently I had the opportunity to interview Hilary Vernon, MD, PhD, associate professor of genetic medicine at Johns Hopkins University, Baltimore, Maryland, and an expert on mitochondrial disorders. Dr Vernon discussed her research on elamipretide as a treatment for Barth syndrome, a rare form of mitochondrial disease.
What is your experience in treating mitochondrial disorders? How did you get interested in this particular area?
I am the director of the Mitochondrial Medicine Center at Johns Hopkins Hospital. I work with individuals from infancy through adulthood who have mitochondrial conditions. I became interested in this particular area when I was early in my pediatrics/genetics residency at Johns Hopkins and saw the toll that mitochondrial disorders took on patients' lives and the limited effective therapies. At that point, I decided to focus on patient care and research in this area.
Mitochondrial disease is often initially unrecognized by clinicians. Could you offer a few tips that would increase the likelihood that a physician would diagnose a patient with this spectrum of disorders?
Mitochondrial disorders can be difficult to recognize because of their inherent multisystem nature and variable presentations (even between affected members of the same family). However, there are several considerations that should raise a clinician's suspicion for a mitochondrial condition. Ascertaining a family history of disease inheritance through the maternal line can raise the suspicion for a mitochondrial DNA disorder. Identification of a combination of medical issues in different organ systems that are seemingly unrelated in an individual (ie, optic atrophy and muscle weakness or diabetes and hearing loss) can also raise suspicion for a mitochondrial condition.
Which mitochondrial disorders are of interest to neurologists?
Due to the nature of mitochondria as the major energy producers of the cells, high-energy-requiring tissues such as the brain and the muscles are often affected. Perhaps the best known mitochondrial diseases to neurologists are MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) as well as MERFF (myoclonic epilepsy with ragged red fibers). There is a nice body of literature on the effects of arginine and citrulline in modifying stroke-like episodes in MELAS, and this is a therapy that is in current practice.
Although not FDA approved, biotin and coenzyme Q-10 are often used to treat mitochondrial disease. What is the rationale for these treatments?
Mitochondria are complex organelles whose structure and function are encoded in hundreds of genes originating from both the nucleus of the cell and the mitochondria themselves. Mitochondria have many key roles in cellular function, including energy production through the respiratory chain, coordination of apoptosis, nitrogen metabolism, fatty acid oxidation, and much more.
Various cofactors and vitamins can be employed to improve mitochondrial function for different reasons. For example, if a specific enzyme is dysfunctional, supplying the cofactor for that enzyme may improve its function (ie, pyruvate dehydrogenase and thiamine). Antioxidants have also been considered to help reduce the oxidant load that could potentially cause ongoing damage to the mitochondrial membrane resulting from respiratory chain dysfunction (ie, coenzyme Q-10).
Gene therapy is now available that can repair nuclear DNA. One example is Zolgensma (onasemnogene abeparvovec-xioi) for pediatric patients with spinal muscular atrophy. This treatment can potentially prevent the occurrence of symptoms in presymptomatic patients, effectively curing the disease. Because mitochondria have their own genes that are distinct from nuclear DNA, is a similar approach with gene therapy possible for mitochondrial disease?
It is important to remember that the highest number of individual mitochondrial disorders result from mutations in genes located in the nuclear DNA. For example, the TAZ gene that is abnormal in Barth syndrome is a nuclear gene located on the X chromosome. These genes are amenable to the "regular" approaches to gene therapy.
Targeting mitochondrial DNA for gene therapy requires a different set of approaches because the gene delivery has to overcome the barrier of the mitochondrial membranes. However, research is ongoing to overcome these obstacles.
What is Barth syndrome?
Barth syndrome is a very rare genetic X-linked disorder that usually only affects males. The genetic defect leads to an abnormal composition of cardiolipin on the inner mitochondrial membrane. Cardiolipin is an important phospholipid involved in many mitochondrial functions, including organization of inner mitochondrial membrane cristae, involvement in apoptosis, and organization of the respiratory chain (which is responsible for producing ATP via the process of oxidative phosphorylation), and many of these functions are abnormal in Barth syndrome. Individuals with Barth syndrome typically have early-onset cardiomyopathy, myopathy, intermittent neutropenia, fatigue, poor early growth, among other health concerns.
A disorder like that must have a devastating effect on children and their families. It's tough for their doctors, too.
Early in my post-residency career, I followed several patients with Barth syndrome and was quickly welcomed into the Barth syndrome community by the families and the Barth Syndrome Foundation. From there, I founded the only interdisciplinary Barth syndrome clinic in the US and began to focus a significant amount of my clinical and laboratory research on this condition.
In your Barth syndrome study, the patients had multisystem defects. What was the primary problem that brought them to medical attention?
Most commonly, these individuals come to medical attention because of cardiomyopathy, but a minority of patients do come to attention due to repeated infections and neutropenia. Patients were identified for study participation through the Barth Syndrome Foundation or because they were already patients of my study team.
How did you confirm the diagnosis of Barth syndrome?
All participants were known to have Barth syndrome prior to study entry, and all had confirmatory genetic testing showing a pathogenic mutation in the TAZ gene.
What was your rationale for treating Barth syndrome patients with elamipretide?
By binding to cardiolipin in the inner mitochondrial membrane, elamipretide is believed to stabilize cristae architecture and electron transport chain structure during oxidative stress. I thought it would be great if this could help to stabilize the abnormal cardiolipin components on the inner mitochondrial membrane in Barth syndrome.
What were your initial results from the recent TAZPOWER trial?
We observed improvements in several areas across the study population in the open-label extension part of the study. This includes a significant improvement in exercise performance (as measured by the 6-minute walk test, with an average improvement of 95.9 meters at 36 weeks) and a significant improvement in muscle strength. We also observed a potential improvement in cardiac stroke volume. Most of the adverse events were local injection-site reactions and were mild to moderate in nature.
Do you have any follow-up research planned?
The TAZPOWER trial has an ongoing open-label extension with the same endpoints as the placebo-controlled portion evaluated on an ongoing basis. In addition, in my laboratory, we are using induced pluripotent stem cells to learn more about how cardiolipin abnormalities affect different cell types in an effort to understand the tissue specificity of disease. This will help us to understand whether different aspects of Barth syndrome would necessitate individual management or clinical monitoring strategies.
Does elamipretide have potential therapeutic value in other mitochondrial disorders besides Barth syndrome?
Mitochondrial inner membrane dysfunction is increasingly recognized as a major aspect of the pathology of a wide range of mitochondrial conditions. Therefore, based on the role of stabilizing mitochondrial membrane components, elamipretide has a potential role in many disorders of the mitochondria.
Do mitochondria become less efficient when there is a systemic disease that is not mitochondria-specific? For example, when patients are septic and hypotensive, are their mitochondria working well? Could a mitochondrial medication be potentially useful in this common scenario? What about traumatic brain injury? Please speculate!
Yes, this is what we would call "secondary mitochondrial dysfunction" (meant to differentiate from "primary mitochondrial disease," which is caused by defects in genes that encode for mitochondrial structure and function). Approaches intended to protect the mitochondria from further damage, such as antioxidants or strategies that can bypass the mitochondria for ATP production, could overlap as treatment for primary mitochondrial disease and secondary mitochondrial dysfunction.
Mitochondrial transplant from a healthy donor using in vitro fertilization is another proposed treatment for genetic mitochondrial disease. Could this technique be used by patients with Barth syndrome or primary mitochondrial myopathy?
This is something that is much discussed as a newer consideration for families who are affected by disorders of the mitochondrial DNA, but not something I have experience with firsthand.
Are there any centers of excellence for the care of patients with mitochondrial disease?
Yes. The United Mitochondrial Disease Foundation and the Mitochondrial Medicine Society collaborated to develop the Mito Care Network, with 19 sites identified as Mitochondrial Medicine Centers across the US.
Many thanks, Dr Vernon. Thanks for enlightening us about mitochondrial disease. I'm glad I memorized the Krebs cycle after all!
Andrew Wilner is an associate professor of neurology at the University of Tennessee Health Science Center in Memphis, a health journalist, and an avid SCUBA diver. His latest book is The Locum Life: A Physician's Guide to Locum Tenens.
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Cite this: Maybe Memorizing the Krebs Cycle Was Worthwhile After All - Medscape - Feb 06, 2020.