Wednesday, July 3, 2019

Discovery of Mutated Gene Leads to Cure for Lymphatic Disorder

Daniel was only 10 years old when he was first rushed to the hospital for shortness of breath, swelling in his abdomen and exercise intolerance. “This came on suddenly” said his mother. The doctors at the Virginia hospital ended up having to drain lymphatic fluid around Daniel’s heart. After, he was transferred to Children’s Hospital of Philadelphia (CHOP) for further evaluation and care by the lymphatics team. The lymphatics team at CHOP treated Daniel with minimally invasive strategies and surgical interventions, but the fluid persistently returned. Over a two year period, Daniel’s condition worsened.

Hakonarson, a pediatric pulmonologist at CHOP, consulted with the lymphatics team. His genomics team then performed whole-exome sequencing (WES) on Daniel’s DNA. The purpose of whole-exome sequencing is to find a genetic cause of a patient’s signs and symptoms. This form of genetic testing only considers the portion of DNA that is used to create proteins. 

 Courtesy of EpilepsyU
The sequencing revealed a mutation in Daniel’s ARAF gene. Researchers studied the function of the ARAF mutation by inserting it into the embryos of zebrafish. Subsequently, the zebrafish developed abnormal lymphatic channels. The next step was to try using an MEK inhibitor, known to effect biological pathways affected by the ARAF gene. MEK inhibitors are commonly used to treat melanoma and some tumors. 
Credit:  Mirko Rosenau/shutterstock.com

Based on Harkonson’s research with the zebrafish, he was able to collaborate with other doctors at CHOP and gain permission from the FDA to use an MEK inhibitor, trametinib, on Daniel. A couple of months into the experimental treatment, Daniel’s breathing improved. A month after that improvement, Daniel had a reduced amount of fluid retention and was able to start breathing on his own. The doctors used an MRI to confirm his lymphatic vessels were being remodeled.

Daniel, now 14 years old, has resumed numerous of his favorite physical activities. Harkonson and Dori say this experimental technique is “the first real evidence for complete remodeling of an entire organ system by a drug.” Based on Harkonsons work, not just with Daniel’s case, has allowed CHOP to expand an existing program that allows research for possible involvement in genetic mutations.


My reaction to this article is both excited and interested. I am excited for Daniel and the results of Harkonson’s research. I am interested to see what research and studies come from a successful experience like this one. It is amazing how much doctors and researchers can learn by studying our DNA. Read the full article at ScienceDaily.

1 comment:

  1. This research pulled me in and is extremely remarkable. The insertion of the gene mutation into the zebrafish is the part that is fascinating to me because researchers were able to use all other elements as a control group while the abnormal lymphatic channels. In addition, the development of WES is a big medical tool that could lead to solving thousands of diseases. The technology was able to pinpoint Daniel's specific gene mutation which was impossible just a few years ago. In my opinion, this type of technology is important and must be used to its full ability now that it is available, regardless of the ethical problems.

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