New England Journal of Medicine (NEJM) Announces Results of A Unique Study of Hirschsprung Disease Affecting Infants


An article in BioSpace reports new information published online by the NEJM concerning Hirschsprung disease.

The disease involves the absence of nerves in parts of the intestines prior to birth. Researchers have now found that it is possible to predict the presence of Hirschsprung disease from genetic properties.

About Hirschsprung (HSCR)

The senior author of the study is Aravinda Chakravarti, Ph.D. of NYU Langone. Dr. Chakravarti explains that HSCR is a complex disease brought about by, among other things, genetic and environmental factors.

Over eighty percent of HSCR events are found to be inherited. The disease affects one in five thousand births. Although HSCR usually occurs in very young children, it has been known to occur at a later stage in life. Its symptoms vary with age.

HSCR causes blockages due to the absence of nerves in the intestine that trigger the muscle contractions that allow the stool to pass through the intestine.

The infant is unable to pass stools during the first 48 hours of its life. In addition to ongoing problems with constipation, as the child matures, other symptoms may include vomiting, abdominal pain or swelling, diarrhea, poor feeding, malnutrition, and slow growth.

At some point, corrective surgery to the intestine may be required. However, post surgery, the initial symptoms are resolved in only about fifty percent of patients. Others will continually face the possibility of intestinal infections or perforations.

Two Types of HSCR

According to the National Institution of Health (NIH), there are two main types of HSCR. They are categorized in accordance with the area of the intestine that lacks the nerve cells and known as short-segment and long-segment disease.

HSCR is found to be either an isolated disease or it may be part of other disorders. The isolated form of the disorder is associated with several mutated genes which means that there are permanent alterations in the DNA sequence that comprise the genes.

Results of the Study

The senior author of the study is Aravinda Chakravarti, PhD of NYU Langone. Dr. Chakravarti explained that the study is unique as it included all classes of genetic changes in a full set of human genetic material in 190 patients, whether or not they were associated with HSCR.

The researchers were able to read many of the genes involved in the disease and the cellular mechanisms they alter. Understanding the genetics of HSCR will not only help to define the drugs that will be effective against molecular targets but also be of considerable value in the personalized treatment of patients.

The patient selection was diverse in that some patients were from families with several affected family members; some were the only affected family member, and a few patients had HSCR combined with other HSCR classifications.

In this way the team was able to compile a list of genetic variants that conforms with the risk stratification in groups of HSCR patients.

About Past and Present Studies

For many years scientists had focused on disease risk based on changes in genes or sequences of DNA letters. The DNA letters issue instructions for producing proteins in cells that have many different functions.

At a later date, the scientists discovered a regulatory DNA code that gives genes an on and off signal as well as the number of proteins to be produced.

Results also indicate that about 50% of the risk of acquiring the disease is due to abnormal variations of the regulatory DNA code. The code is responsible for four HSCR genes.

In addition, the scientists were able to connect an increased risk of acquiring the disorder to rare modifications in the structure of twenty-four genes.

Another revelation was that risk was associated with the rare occurrence of either additional or missing parts of chromosomes that are packed with genes and DNA so that they fit into a cell.

After gathering this information, it was determined that it was the regulatory DNA errors that accounted for much of the risk of acquiring HSCR. That is because the DNA errors are more prevalent than rare modifications in the structure of the genes or the chromosome changes. This holds true in spite of the greater potency of the latter two classes of changes.

Dr. Aravinda Chakravarti’s lab studies Hirschsprung disease and is conducting a large, ongoing genetic study of the disease.

Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia (AML) six years ago. During this period of partial remission, Rose researched investigational drugs to be prepared in the event of a relapse. Her husband died February 12, 2021 with a rare and unexplained occurrence of liver cancer possibly unrelated to AML.

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