April 30, 2020
Michio Hirano, MD, and Emanuele Barca, MD, PhD
Michio Hirano, MD, and Emanuele Barca, MD, PhD

For the first time, researchers have described the spectrum of mitochondrial diseases (MtDs) in North America. A new study in Neurology Genetics uses data from the North American Mitochondrial Disease Consortium (NAMDC) Registry to evaluate the clinical, biochemical, and genetic features of patients with MtDs. NAMDC is part of the NIH-funded Rare Diseases Clinical Research Network.

Among the most diverse of human disorders, MtDs are often difficult to diagnose and treat. While some are confined to the nervous system, most involve multiple systems throughout the body (multisystemic syndrome). Patients often experience a wide range of symptoms with varying severity. Given this extraordinary clinical spectrum, how can we better understand and treat MtDs?

Researchers found the key to solving this challenge in the NAMDC Registry. Led by Michio Hirano, MD, Principal Investigator of NAMDC, and lead author Emanuele Barca, MD, PhD, of Columbia University, the team analyzed data from over 600 registry participants. Their paper offers the first wide-ranging look at the MtD population, including demographic, clinical, biochemical, and genetic characteristics.

Overall, the team’s analysis confirms the robust diversity of MtDs at every level. Researchers identified 24 different clinical entities among the participants, most of whom were diagnosed with multisystemic syndrome. The data also highlight the vast genetic variability of patients with MtDs. Several participants were found to have unique gene mutations, illustrating the ultra-rare nature of many MtD genotypes.

A diagram showing genes mutated in the mitochondrial syndromes studied, demonstrating the vast genetic variability of patients with mitochondrial diseases.
© 2020 Barca, Long, Cooley, et al. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This diagram shows genes mutated in the mitochondrial syndromes studied, demonstrating the vast genetic variability of patients with mitochondrial diseases.

“Similar to studies of MtD cohorts in other countries, molecular diagnostics have revealed underlying genetic causes for 54 percent of patients in the NAMDC Registry, indicating the need for further genetic characterization of nearly half of the registrants,” the authors say. “A surprising finding was the skewed racial composition of the participants, with the vast majority (greater than 85 percent) Caucasian, and less than three percent African American. In contrast, 2010 US Census data identified 72 percent Caucasian and approximately 13 percent African American US citizens.”

This data from the NAMDC Registry has allowed researchers to paint a more complete picture of MtDs. By providing the first comprehensive description of these rare diseases, the study is an essential resource for future discoveries.

“Analyzing the registry pointed out gaps in our knowledge of MtDs to guide current NAMDC projects,” the authors say. Future plans include next-generation sequencing of genetically undefined MtD patients and functional mitochondrial tests, which will help substantiate new causative molecular genetic variants. In addition, they want to determine if the uneven racial distribution of the NAMDC registrants reflects recruiting bias or biological factors that may contribute to disease susceptibility of some populations.

“Moving forward, the NAMDC Registry will surely enhance our understanding of MtDs and hopefully lead to better clinical diagnosis and treatments of these challenging, rare, and often devastating disorders,” Hirano and Barca say.

Read the full study in Neurology Genetics.

Learn more about the NAMDC patient registry.