New Screening Approach Helps Doctors Diagnose Rare Diseases

While a small number of IEMs are diagnosed through newborn screening, the majority are diagnosed only after a child becomes ill. Because these diseases are rare, it can take months or even years to establish the correct diagnosis. Many of these diseases have overlapping symptoms, so even if a doctor suspects an IEM, it is often difficult to pinpoint the problem.

“We hope our new technique will increase the speed with which we can pinpoint the defective gene in patients evaluated in our clinics at Children’s Health,” said Ralph DeBerardinis, professor at Center Research Institute and professor of Pediatrics at UT Southwestern, and chief of the Division of Pediatric Genetics and Metabolism. “Pinpointing the mutation allows us to provide useful information to the family about the disease and its risk to other family members. In some cases, the information either points to an existing therapy or helps us to devise new ones.”

DeBerardinis and his colleagues report on the approach in a study published in Cell Reports. The researchers describe how they identified the gene responsible for a rare inborn error of metabolism that caused abnormal brain development, seizures, and severe metabolic acidosis.

To find the gene, the researchers used a combination of DNA sequencing and an analysis of metabolites in the blood. The researchers compared the level of each metabolite found in the patients to healthy subjects using a technique called “untargeted metabolomic profiling.” They said the technique allowed them to detect 20 times as many metabolites in the blood as would a conventional metabolic screen and provided a granular view of the metabolic alterations in the patient.

Researchers then used advanced DNA sequencing techniques to look for mutations among the nearly 20,000 human genes. Next, they combined the list of metabolic alterations and the list of mutated genes to determine which mutation could explain the metabolic differences present in the patient.

“Performing metabolomics in parallel with DNA studies makes it possible to pinpoint disease-causing mutations much faster than the DNA studies alone,” said Dr. Min Ni, lead author of the study and Assistant Professor at CRI and of Pediatrics at UT Southwestern. “In this case, it helped us determine that the patient had a genetic defect in one enzyme known as LIPT1. We were able to confirm our new screening technique worked by using cultured cells from the patient and a mouse model to show that the mutation we identified in the patient caused the metabolic disturbances and prevented normal development.”

DeBerardinis credits the unique setup of the GMDP for the discovery. “With support from Children’s Health and UT Southwestern, we’ve tripled the size of our clinical group and built a research program to handle human genomics and metabolomics data. Our scientists and doctors work side by side to evaluate patients, learn about their diseases, find new mutations, and think creatively about developing better treatments. Seeing patients in the clinic keeps our research focused and ensures we are asking the right questions. In the past five years, we have identified new disease genes, provided accurate diagnostic information to families, and, in a few cases, helped patients find better treatments tailored to their mutations. We are very excited about what we will learn in the next few years.”

Photo: Ralph DeBerardinis, professor at Center Research Institute at UT Southwestern