Nav: Home

In a severe childhood neurodegeneration, novel mechanism found

March 22, 2018

Neurology researchers investigating a rare but devastating neurological regression in infants have discovered the cause: gene mutations that severely disrupt crucial functions in mitochondria, the energy-producing structures within cells. The specific disease mechanism, in which mutations disrupt a critical mitochondrial enzyme, has not previously been implicated in a human disease.

"We uncovered the cause of this mysterious neurodegenerative disease, and now we understand better what happens in the brains of these children," said lead investigator Ingo Helbig, MD, a pediatric neurologist at Children's Hospital of Philadelphia (CHOP). "This new understanding is the very first step toward potentially finding a treatment."

Helbig collaborated with researchers from Germany, Australia and the U.S. in this study, published online today in the American Journal of Human Genetics. The other two co-senior authors were Dr. Franz-Josef Mueller, of the University Hospital Schleswig Holstein, Kiel, Germany; and Dr. Johan L.K. Van Hove, of the University of Colorado.

For Helbig, now an attending physician in the Neurogenetics Program at CHOP and a specialist in genetic epilepsies, the finding builds on an experience early in his medical training when he was involved in the care of an infant girl with severe epilepsy. The child suffered sudden neurological regression after a fever, for no apparent reason. Imaging studies showed the child lost brain volume, mainly in the cerebellum.

The symptoms appeared to mimic those of a progressive neurological disease. Instead, it turned out to be due to energy failure, based in malfunctioning mitochondria, but this became apparent only after nearly a decade of research.

The current study reports on five affected children in four families, including the original patient and her sibling. Both siblings, along with a third patient in the study, died before six years of age. None of the five children were able to walk or speak, and all but one had seizures.

The research team used whole-exome sequencing to pinpoint the causative mutations in the gene PMPCB. Because that gene is highly conserved across yeast and humans, the researchers conducted experiments in a common yeast to investigate the effects of the mutation

The researchers found that mutations in PMPCB interfered with the function of the enzyme mitochondrial processing protease (MPP), which transports proteins into mitochondria to be cut up as part of normal biological processing. Disrupting that process, in turn, blocked the production of iron-sulfur clusters that are crucial to energy metabolism and other cellular functions.

In infants, the diminished activity of MPP causes a deficiency of biological energy. An infection or fever triggers a crisis--a cascade of severe events, including brain atrophy and the neurological regression seen in the patients. The symptoms appear similar to those seen in the well-known mitochondrial disorder Leigh's syndrome.

The biological pathways that MPP is involved in are closely related to the more common neurological disease Friedreich's ataxia, which is also actively studied by researchers at CHOP. In fact, frataxin, the protein altered in Friedreich's ataxia, is one of the main targets of MPP. The conditions however, are very different, and the PMPCB-related disorders identified by Helbig and his collaborators are more severe than Friedreich's ataxia.

The current findings, said Helbig, set the stage for follow-up research in biological implications, for instance, by further investigation in yeast models of the disease. "If we better understand biological pathways and mechanisms," he added, "we may be able to start screening for compounds that may suggest potential treatments for this condition."

See Helbig's research blog, "Beyond the Ion Channel" for his description of the discovery of PMPCB's role in this condition.
-end-
This study had multiple sources of funding support, including the German Research Foundation, the University of Kiel, the Deutsche Forschungsgemeinschaft, the Japan Agency for Medical Research and Development, Miracles for Mito, Summits for Samantha, and the Children's Hospital Colorado Foundation.

F.-Nora Voegtle, et al, "Mutations in PMPCB encoding the catalytic subunit of the mitochondrial presequence protease cause neurodegeneration in early childhood," American Journal of Human Genetics, online March 22, 2018. https://doi.org/10.1016/j.ajhg.2018.02.014

Children's Hospital of Philadelphia: Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 546-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu

Children's Hospital of Philadelphia

Related Mitochondria Articles:

Uncovering the presynaptic distribution and profile of mitochondria
In a recent study published in the Journal of Neuroscience, scientists from the MPFI and the University of Iowa CCOM have provided unprecedented insight into the presynaptic distribution and profile of mitochondria in the developing and mature calyx of Held.
Temple researchers identify new target regulating mitochondria during stress
Like an emergency response team that is called into action to save lives, stress response proteins in the heart are activated during a heart attack to help prevent cell death.
Runaway mitochondria cause telomere damage in cells
Targeted damage to mitochondria produces a 'Chernobyl effect' inside cells, pelting the nucleus with harmful reactive oxygen species and causing chromosomal damage.
Interplay between mitochondria and nucleus may have implications for new treatment
Mitochondria, the 'batteries' that produce our energy, interact with the cell's nucleus in subtle ways previously unseen in humans, according to research published today in the journal Science.
Dissolving protein traffic jam at the entrance of mitochondria
Researchers from Freiburg discovered a novel mechanism that ensures obstacle-free protein traffic into the powerhouse of the cell.
More Mitochondria News and Mitochondria Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...