NEJM: Never-before-reported mitochondrial disease found in identical twins

In a group of identical twins, researchers led by researchers at Massachusetts General Hospital (MGH) and Children's Hospital of Philadelphia (CHOP) identified a previously unreported mitochondrial disease
.

Diseases that affect mitochondria often interfere with mitochondrial function, but in both patients, mitochondria were abnormally active
.
Mitochondria are special regions of cells that contain their own DNA and can convert the food we eat into the energy
needed to sustain life.

So, as reported in the New England Journal of Medicine, the siblings are still underweight
despite eating far more calories than needed.

"This is a very unusual mitochondrial phenotype
.
Senior author Vamsi K.
Mootha, M.
D.
, professor of systems biology and medicine at MGH, said, "There are more than 300 rare inherited mitochondrial diseases, almost all of which are associated with
mitochondrial disruption.
"

Genome sequencing revealed mutations in an enzyme called mitochondrial ATP synthase, which cells need to make the energy-storing molecule ATP
.

Experiments have shown that this mutation creates "leaking" mitochondria that expend energy — a process known as mitochondrial decoupling
.

"We came up with a new name, mitochondrial uncoupling syndrome, which manifests as hypermetabolism and mitochondrial uncoupling," Mootha said
.
"These cases are important
for the fields of rare disease genetics, mitochondrial biology and metabolism.
"

The authors note that additional studies of mitochondrial uncoupling syndrome may provide insights
into differences in energy metabolism in the general population.

"These twins represent the first mitochondrial decoupling disorder in which we can find a genetic cause," said Rebecca D.
Ganetzky, M.
D.
, attending physician in the CHOP mitochondrial medicine program and co-author of the study
.

"By discovering that pathogenic variants in ATP synthase itself can lead to mitochondrial uncoupling, these twins may be the first patients
to be confirmed to have mitochondria-conjugated diseases.
"

Other co-authors include Andrew L.
Markhard, B.
A.
, Irene Yee, B.
A.
, Sheila Clever, M.
S.
, Alan Cahill, Ph.
D.
, Hardik Shah, MS, Zenon Grabarek, Ph.
D.
, and Tsz-Leung To, Ph.
D.

This work is supported
by the National Institutes of Health and other agencies.

Journal Reference:

1. Rebecca D.
   Ganetzky, Andrew L.
   Markhard, Irene Yee, Sheila Clever, Alan Cahill, Hardik Shah, Zenon Grabarek, Tsz-Leung To, Vamsi K.
   Mootha.
   Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation.
   New England Journal of Medicine, 2022; 387 (15): 1395 DOI: 10.
   1056/NEJMoa2202949