Open AccessThe low excretor phenotype of glutaric acidemia type I is a source of false negative newborn screening results and challenging diagnoses
Author(s) -
Guenzel Adam J.,
Hall Patricia L.,
Scott Anna I.,
Lam Christina,
Chang Irene J.,
Thies Jenny,
Ferreira Carlos R.,
Pichurin Pavel,
Laxen William,
Raymond Kimiyo,
Gavrilov Dimitar K.,
Oglesbee Devin,
Rinaldo Piero,
Matern Dietrich,
Tortorelli Silvia
Publication year - 2021
Publication title -
jimd reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.412
H-Index - 25
ISSN - 2192-8312
DOI - 10.1002/jmd2.12217
Subject(s) - newborn screening , medicine , urine , dried blood , glutaric acid , pediatrics , disease , phenotype , clinical phenotype , chemistry , gene , biochemistry , organic chemistry , chromatography
Background Glutaric acidemia type I (GA1) is an organic acidemia that is often unrecognized in the newborn period until patients suffer an acute encephalopathic crisis, which can be mistaken for nonaccidental trauma. Presymptomatic identification of GA1 patients is possible by newborn screening (NBS). However, the biochemical “low‐excretor” (LE) phenotype with nearly normal levels of disease metabolites can be overlooked, which may result in untreated disease and irreversible neurological sequelae. The LE phenotype is also a potential source of false negative (FN) NBS results that merits further investigation. Methods Samples from six LE GA1 patients were analyzed by biochemical and molecular methods and newborn screen outcomes were retrospectively investigated. Results Five LE GA1 patients were identified that had normal NBS results and three of these presented clinically with GA1 symptoms. One additional symptomatic patient was identified who did not undergo screening. Semiquantitative urine organic acid analysis was consistent with a GA1 diagnosis in two (33%) of the six patients, while plasma glutarylcarnitine was elevated in four (67%) of the six and urine glutarylcarnitine was elevated in four (80%) of five patients. Five GCDH variants were identified in these patients; three of which have not been previously linked to the biochemical LE phenotype. Conclusions The data presented here raise awareness of potential FN NBS results for LE GA1 patients. The LE phenotype is not protective against adverse clinical outcomes, and the possibility of FN NBS results calls for high vigilance amongst clinicians, even in the setting of a normal NBS result.