New Monogenic Disease Identified in Five Individuals

By Mike Howie

In a collaborative effort led in part by the Indiana Biosciences Research Institute (IBRI) and Columbia University, researchers have discovered a new monogenic disease. Dubbed “DHPS Deficiency” and caused by mutations in the gene encoding deoxyhypusine synthase (DHPS), the disease affects an enzyme essential to the production of hypusine, which is used by the body to make proteins. The researchers published their work in the American Journal of Human Genetics in January 2019.

To date, DHPS Deficiency has been identified in five individuals from four unrelated families in North America. Two are siblings — the oldest and youngest of three. The older of the two had been experiencing seizures and other health problems since birth, and the family’s medical team suspected an undiagnosed genetic condition. In 2016, Dr. Orrin Devinsky of New York University, their epileptologist, referred them to Dr. Wendy Chung of Columbia University, a medical geneticist whose lab works to understand unexplained genetic diseases.

The First DHPS Gene Mutation in a Human

Dr. Chung’s lab performed exome sequencing on DNA from both affected children to search for a possible cause of the seizures. They discovered mutations in the DHPS gene — the first found in humans. To understand if the mutations could be causing the clinical symptoms in the children, Dr. Chung enlisted the help of Dr. Teresa Mastracci of the IBRI, who first met Dr. Chung when she was a postdoctoral fellow at Columbia University, where Dr. Chung has her lab. Dr. Mastracci’s lab studies the DHPS gene as it relates to diabetes.

Dr. Leah Padgett, a postdoctoral fellow who works in Dr. Mastracci’s lab, performed some of the in vitro studies that confirmed the mutations discovered in Dr. Chung’s lab caused problems with the DHPS enzyme. In combination with work from a collaborating lab at the National Institutes of Health (NIH), the researchers concluded that the mutations caused the enzyme to dysfunction, which ultimately may explain the clinical symptoms in the affected individuals.

In addition to seizures, DHPS Deficiency leads to neurodevelopmental delay and altered growth and gait. Currently, it is unclear how these symptoms will evolve or if they will resolve as the individuals age. Follow-up studies are in progress to gain a deeper biological understanding of this disease.

"Most questions about DHPS Deficiency are still unanswered."

Unknown Origin and Prevalence

Researchers don’t know how many people around the world could be affected by this disease. They’re beginning to search outside North America, but the five affected individuals could be the extent of the disease’s prevalence. Interestingly, the affected individuals share some common ancestry: all of the families reported at least one parent of Irish and/or English heritage, which gives researchers a starting point to investigate the incidence of DHPS Deficiency.

While DHPS Deficiency is currently categorized as a rare or orphan disease, it may be biologically related to other diseases. One possible related disease is Snyder-Robinson Syndrome, which affects a protein that’s in a parallel pathway to DHPS and results in delayed development and other symptoms. Similarly, a group of researchers in Michigan recently identified a mutation that overexpresses an enzyme that’s upstream of DHPS and results in a neurological phenotype. These diseases currently affect fewer than 20 people, but their similar pathways could mean that they’re related. Working together, researchers studying the three diseases hope to find common mechanisms that would help explain them all.

Early Stages of Research

Most questions about DHPS Deficiency are still unanswered. Dr. Mastracci’s lab is just beginning to study basic characterization of the disease in animal models, performing metabolic tests and even examining how the animals develop in utero. They’re also using lymphoblast cell lines from the patients and their families to study the basic functions and growth of the cells.

In the end, researchers hope to reach two goals: find a way to test for the disease, and develop a method to treat it. If DHPS Deficiency can be identified during pregnancy or early in life, doctors could help prepare parents or possibly intervene. And if they can develop a way to treat the disease, they can dramatically improve the quality of life for the affected individuals.

“Ultimately all of us are working to help the children with this disease,” Dr. Mastracci said. “We hope we’ll be able to identify some way to lessen the clinical presentation or, ideally, provide a treatment that altogether eliminates the symptoms of the disease.”

To learn more about DHPS Deficiency and stay up to date with the latest research, visit