Symptoms Vary Greatly in People with MT-ATP6 Mutations and Better Tests Needed, Study Says

Symptoms vary greatly among people with mitochondrial disease linked to any one of the many mutations evident in the MT-ATP6 gene, a study found, and its researchers call for better tests to diagnose this disease in all its forms and determine the best course of treatment for each patient.

The study, “MT‐ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases,” was published in Human Mutation.

Mitochondria are the cell compartments responsible for the production of energy in the body. Energy is produced in the form of a small molecule, called adenosine triphosphate (ATP), that is used as fuel by cells.

ATP is produced in mitochondria through a signaling cascade known as the mitochondria respiratory chain (MRC), in which five main complexes (CI-CV) work together to produce energy. Mitochondrial disease occurs when genetic mutations affect the activity of one of these main MRC complexes, compromising the production of energy and, consequently, cell function.

Mutations in MT-ATP6, a gene that provides instructions to make a subunit of complex V (CV, also known as ATP synthase), the last complex in the MRC and the one responsible for ATP production, are among the first mutations (or gene variants) linked to mitochondrial disease in humans.

Indeed, it is estimated that mutations affecting CV are present in 10%–20% of all cases of Leigh syndrome, a mitochondrial disease that causes progressive brain damage. Such mutations are also present in a disorder known as neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

However, “due to a lack of clinically available functional assays [tests], validating the definitive pathogenicity [ability to cause disease] of additional MT‐ATP6 variants remains challenging,” the researchers wrote.

Researchers at the University of Pennsylvania, working with colleagues in Germany, reviewed the 218 reported cases of patients with mitochondrial disease and mutations in MT-ATP6, looking for a possible relationship between the variants they carried and their clinical symptoms.

And they detailed a new cases series covering 14 related patients with MT-ATP6 mutations of unknown significance (whose relation to the disease is not well understood).

A total of 34 different disease-causing variants within the MT-ATP6 mutation were identified. Patients with this mutation go through a series of biochemical changes, like reduced ATP production or abnormally high mitochondrial membrane potential (a key component in the process of energy storage), but no single change was found to be common to them all.

“This study provides an important point of reference for patients in whom MT-ATP6 variants are discovered in diagnostic testing, as we now recognize just how variable this disease may be,” Rebecca Ganetzky, MD, an attending physician in the Mitochondrial Medicine Frontier Program at the Children’s Hospital of Philadelphia (CHOP), an assistant professor of pediatrics in the Perelman School of Medicine, and the study’s lead author, said in a news release.

“We need to develop better ways to test for this disease, since the classical clinical syndromic presentations of NARP and Leigh syndrome are not sufficient to capture the problems present in all of these patients,” Ganetzky added.

“Overall, the diversity of biochemical findings in MT-ATP6 disease suggests that the best diagnostic confirmatory approach is a multi-pronged one. In addition, expert curation of MT-ATP6 variants will improve understanding and consistency of allele [different forms of the same gene] pathogenicity assessment that can be deposited in common community resources including ClinVar and MSeqDR,” the researchers wrote.

“Indeed, [National Institutes of Health] NIH-supported expert panel curation is currently underway for MT-ATP6 variants reported to cause pediatric Leigh syndrome,” they added.

In the meantime, researchers and physicians at CHOP continue to look for the best ways of evaluating mitochondrial disease and its varied disorders in people, including tools to better understand the impact some MT-ATP6 variants have on energy production in cells.