Identification of PRODH mutations in Korean neonates with type I hyperprolinemia

Hyperprolinemia is a rare inherited metabolic disorder characterized by a high proline level in blood and/or urine and various neuropsychiatric symptoms. Type I hyperprolinemia is caused by a proline oxidase deficiency, which is encoded by the PRODH gene on chromosome 22q11. Herein, we present a study of Korean patients with type I hyperprolinemia who were diagnosed during newborn screening by tandem mass spectrometry and confirmed by molecular analysis.

Four neonates were referred to our hospital for workup of high proline levels in newborn screening test. We analyzed the biochemical findings and the PRODH gene was amplified by long-range PCR to confirm molecular genetic abnormalities.

All patients had high plasma proline levels, ranging from 742 to 1192 μmol/L (reference range, 77.4 - 244.6 μmol/L). In molecular analysis, 4 disease-associated mutant alleles were identified: c.1414G>A (p.A472T), c.1279G>A (p.V427M), c.1357C>T (p.R453C) and c.1562A>G (p.Q521R). All mutations were missense and c.1279G>A included the majority of mutant alleles. No relationships between type of mutation and clinical outcomes were observed.

We found that distinct molecular alterations of the PRODH gene result in abnormal proline levels. Newborn screening and molecular analysis are necessary to identify patients before clinical expression of metabolic disease.