Combining DNA sequencing with a type of chemical analysis that provides information about the metabolic pathways underlying diseases is helpful for diagnosing rare pediatric conditions, according to a case report published April 30 in Cell Reports.
Researchers at the Children's Medical Center Research Institute at the University of Texas (UT) Southwestern Medical Center reported on the usefulness of DNA testing and a chemical analysis called metabolomics for identifying mutant genes behind defective metabolic pathways in children with rare diseases.
Lead author Min Ni, PhD, and colleagues shared their experience with DNA sequencing and metabolomics in diagnosing the underlying genetic cause of disease in an 8-year-old girl with abnormal development, seizures, and lactic acidemia (Cell Rep, Vol. 27:5, pp. 1376-1386).
These symptoms occur with many inborn errors of metabolism (IEMs) and didn't suggest a specific defect, but with metabolomics and whole exome sequencing, the researchers identified lipoyltransferase-1 (LIPT1) mutations as the underlying cause of the patient's symptoms.
About one-fourth of hospital admissions of children are related to genetic diseases, including inborn errors of metabolism, which cause problems in metabolizing sugars, proteins, and fats in food, the researchers noted.
Inborn errors of metabolism are detected through simple blood and urine tests, and testing in newborn screening programs is feasible. But given that more than 400 IEMs have been described and several thousand genes are involved in metabolism, making the exact diagnosis is a big challenge.
Metabolomics enables the detection of hundreds of small chemical compounds in the blood. In fact, compared with conventional metabolic screening, the use of untargeted metabolomic profiling enabled the researchers to detect 20 times as many metabolites in the blood, UT Southwestern said in a statement.
"Many IEMs are treatable if the underlying metabolic anomaly is known," Ni and colleagues wrote in Cell Reports. "Accurate counseling and treatment require identifying the mode of inheritance, ideally by pinpointing the mutant gene."
In the case of LIPT1 deficiency, there is no definitive treatment available, but the researchers suggested it is helpful to know the underlying cause of disease and provide genetic counseling.
Also, because other cases have been reported, it may be possible to assess the disease and predict outcomes, they added.
"We believe the disorder is underdiagnosed based on the high frequency of unexplained syndromes involving lactic acidosis," Ni et al concluded.