Featured Research

from universities, journals, and other organizations

One-step test for mitochondrial diseases

Date:
January 28, 2013
Source:
Children's Hospital of Philadelphia
Summary:
A scientific team has expanded next-generation sequencing to create an off-the-shelf tool that does simultaneous whole-exome analysis of both nuclear and mitochondrial DNA. The test will aid genetic diagnosis of these complex disorders.

More powerful gene-sequencing tools have increasingly been uncovering disease secrets in DNA within the cell nucleus. Now a research team is expanding those rapid next-generation sequencing tests to analyze a separate source of DNA -- within the genes inside mitochondria, cellular power plants that, when abnormal, contribute to complex, multisystem diseases.

The study team, headed by a specialist in mitochondrial medicine at The Children's Hospital of Philadelphia (CHOP), adapted next-generation sequencing to simultaneously analyze the whole exome (all the protein-coding DNA) of nuclear genes and the mitochondrial genome. "A first step in developing treatments for a disease is to understand its precise cause," said Marni J. Falk, M.D., the director and attending physician in the Mitochondrial-Genetic Disease Clinic at Children's Hospital. "We have developed a one-step, off-the-shelf tool that analyzes both nuclear and mitochondrial DNA to help evaluate the genetic cause of suspected mitochondrial disease."

Falk and colleagues describe their customized, comprehensive test, which they call the "1:1000 Mito-Plus Whole-Exome" kit, in the journal Discovery Medicine, published Dec. 26, 2012. Her co-corresponding author, biostatistician Xiaowu Gai, Ph.D., now of the Loyola University Stritch School of Medicine, collaborated on developing the test while at Children's Hospital.

While each mitochondrial disease is very rare in the population, hundreds of causes of mitochondrial diseases are known. Some originate in mutations in DNA specific to the mitochondria, tiny structures located outside the cell nucleus, while many other mitochondrial diseases are based in nuclear DNA genes that affect mitochondrial function. The role of mitochondria in human disease has been recognized only since the 1980s, based on pioneering research by Douglas C. Wallace, Ph.D., now at Children's Hospital, and a co-author of the current study.

Many mitochondrial diseases remain poorly understood. One complicating factor is heteroplasmy -- a mixture of mutated and normal mitochondrial genomes within the same cells or tissues. In contrast to conventional gene sequencing, which can detect only heteroplasmic mutations that reach levels of at least 30 to 50 percent, the customized kit has the sensitivity to detect mitochondrial genome mutations present at levels as low as 8 percent. To achieve their results, the study team adapted an existing whole-exome sequencing kit from Agilent Technologies, expanding it to encompass the mitochondrial genome.

The availability of the new kit, said Falk, if used for either clinical or research purposes, may shorten the "diagnostic odyssey" experienced by many patients and families seeking the cause of debilitating and puzzling symptoms. "Many families travel from one specialist to another for years, searching for the cause of their rare disease," she says. Specific treatments are not always available, but identifying their disease cause may be the first step toward discovering treatments.

A second recent study by Falk and colleagues reviews progress in diagnosing mitochondrial disease, through their experience at a single center over a rapidly changing three-year period before whole-exome sequencing was generally available. The retrospective review in Neurotherapeutics, published Dec. 27, 2012, covers 152 child and adult patients evaluated at CHOP's Mitochondrial-Genetics Diagnostic Clinic from 2008 to 2011.

"Before 2005, very few individuals could receive definitive molecular diagnoses for mitochondrial diseases, because of limitations in both knowledge and technology," said Falk. "Since that time, the clinical ability to sequence whole mitochondrial DNA genomes has significantly improved the diagnosis of many mitochondrial disorders."

During the study period covered in the review article, the clinic at CHOP confirmed definite mitochondrial disease in 16 percent of patients and excluded primary mitochondrial disease in 9 percent. While many diagnostic challenges clearly remain, Falk says the advent of massively parallel nuclear exome sequencing is revealing increasingly more of the genes in nuclear DNA that affect mitochondrial function, and the precise genetic disorder in a given patient, even if it is novel or uncommon. She added that molecular genetics is yielding a more nuanced understanding of the cellular pathways underlying symptoms in many mitochondrial disorders. "Those pathways offer potential new targets for treating these disorders," said Falk.

Funding for both studies came from the National Institutes of Health, grant DK082446. The Discovery Medicine study also was funded through a Foerderer Award for Excellence from The Children's Hospital of Philadelphia Research Institute. Co-authors of the Discovery Medicine study included Eric A. Pierce, M.D., Ph.D., and Mark Consugar, M.S., of the Massachusetts Eye and Ear Infirmary; research and development staff from Agilent under the guidance of Emily LeProust, Ph.D.; and other collaborators from CHOP.


Story Source:

The above story is based on materials provided by Children's Hospital of Philadelphia. Note: Materials may be edited for content and length.


Journal References:

  1. Elizabeth McCormick, Emily Place, Marni J. Falk. Molecular Genetic Testing for Mitochondrial Disease: From One Generation to the Next. Neurotherapeutics, 2012; DOI: 10.1007/s13311-012-0174-1
  2. Marni J Falk et al. Mitochondrial Disease Genetic Diagnostics: Optimized Whole-Exome Analysis for All MitoCarta Nuclear Genes and the Mitochondrial Genome. Discovery Medicine, 2013

Cite This Page:

Children's Hospital of Philadelphia. "One-step test for mitochondrial diseases." ScienceDaily. ScienceDaily, 28 January 2013. <www.sciencedaily.com/releases/2013/01/130128163336.htm>.
Children's Hospital of Philadelphia. (2013, January 28). One-step test for mitochondrial diseases. ScienceDaily. Retrieved September 2, 2014 from www.sciencedaily.com/releases/2013/01/130128163336.htm
Children's Hospital of Philadelphia. "One-step test for mitochondrial diseases." ScienceDaily. www.sciencedaily.com/releases/2013/01/130128163336.htm (accessed September 2, 2014).

Share This




More Health & Medicine News

Tuesday, September 2, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Snack Attack: Study Says Action Movies Make You Snack More

Snack Attack: Study Says Action Movies Make You Snack More

Newsy (Sep. 2, 2014) You're more likely to gain weight while watching action flicks than you are watching other types of programming, says a new study published in JAMA. Video provided by Newsy
Powered by NewsLook.com
U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

U.N. Says Ebola Travel Restrictions Will Cause Food Shortage

Newsy (Sep. 2, 2014) The U.N. says the problem is two-fold — quarantine zones and travel restrictions are limiting the movement of both people and food. Video provided by Newsy
Powered by NewsLook.com
Get on Your Bike! London Cycling Popularity Soars Despite Danger

Get on Your Bike! London Cycling Popularity Soars Despite Danger

AFP (Sep. 1, 2014) Wedged between buses, lorries and cars, cycling in London isn't for the faint hearted. Nevertheless the number of people choosing to bike in the British capital has doubled over the past 15 years. Duration: 02:27 Video provided by AFP
Powered by NewsLook.com
Can You Train Your Brain To Eat Healthy?

Can You Train Your Brain To Eat Healthy?

Newsy (Sep. 1, 2014) New research says if you condition yourself to eat healthy foods, eventually you'll crave them instead of junk food. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins