Scientists at the Children’s Medical Center Research Institute at UT Southwestern (CRI); are using a new approach to pinpoint the causes of rare genetic diseases; in children and identify treatment options faster; than with traditional methods. The new approach combines DNA sequencing; and a chemical analysis called metabolomics; to identify mutant genes that cause defective metabolic pathways in patients.
CRI’s Genetic and Metabolic Disease Program
“Pinpointing the mutation allows us to provide useful information; to the family about the disease and its risk to other family members. So, in some cases, the information either points to an existing therapy; or helps us to devise new ones;” Dr. DeBerardinis added. So, diseases with a genetic basis account for a large number of illnesses and mortality in children and result in about 25% of pediatric hospital admissions.
So, the largest subset of these genetic diseases are; known as inborn errors of metabolism (IEMs). However, although individually these diseases are rare; collectively they affect a disproportionate number of children, he said. IEMs are caused by defects in genes that help the body metabolize or break down the sugars, proteins, and fats in food. Defective metabolism can lead to chemical imbalances that can cause death or permanent disability in children, unless identified and treated at a young age.
IEMs diagnosed through newborn screening
Encouragingly, many IEMs are treatable through dietary modifications and medical therapy once the genetic basis of the disease has been identified. A handful of IEMs are diagnosed through newborn screening, but the majority are diagnosed only after a child becomes ill. Because these diseases are so rare, it can take months or even years to establish the correct diagnosis, and the process often involves invasive procedures like muscle or liver biopsies.
“IEMs are traditionally hard to identify,” Dr. DeBerardinis said. “Many of these diseases have overlapping symptoms, so even if you suspect an IEM, it is often difficult to pinpoint the problem. There are over 400 known IEMs and several thousand genes involved in human metabolism. Identifying the mutated gene in a child with an IEM — particularly a new or recently discovered disease — is like hunting for a needle in a haystack.”In the study, published in Cell Reports, researchers identified the gene responsible for a rare IEM causing abnormal brain development, seizures, and severe metabolic acidosis.
So, to find the gene, they used a combination of DNA sequencing and metabolomics, a technique that can detect hundreds of small chemical compounds in the blood. However, researchers compared the level of each metabolite found in the patients to healthy subjects using a technique called untargeted metabolomic profiling. This technique allowed researchers to detect 20 times as many metabolites in the blood as would a conventional metabolic screen. This approach provided researchers with a granular view of the metabolic alterations in the patient.