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Abstract 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.

Glutaric aciduria type 1 (GA1) is an autosomal recessive disease frequently leading to dystonia. Deep brain stimulation (DBS), intrathecal baclofen (ITB), and intraventricular baclofen (IVB) are the current interventional treatment options for refractory dystonia. We performed a scoping review, individual patient data (IPD) analysis, and clinical trials review to summarize the existing literature on these interventions in this population, characterize outcomes, and suggest directions for future investigation. PubMed, Embase, and Scopus were searched following PRISMA guidelines. IPD were extracted from studies providing IPD for GA1 patients. ClinicalTrials.gov was reviewed. Of 139 articles, 7 studies with 10 patients were included. In study-level data, 2/4 (50.0%) DBS studies found no improvement in dystonia and 3/3 (100%) on baclofen found decreased dystonia and enteral medication regimen. In the IPD analysis, four studies with 5 patients (2 IVB, 2 DBS, 1 ITB) were included. The average percent reduction in dystonia was 29.9% ± 32.5% (median:18%, IQR:18%-29.2%). Function improved in 4 (80.0%) patients. All patients with reported changes in enteral dystonia-related medication regimen (3/3, 100%) reported reduction in medication usage. No patients (0%) had perioperative complications. Mean follow-up length was 14.8 ± 12.2 months. No interventional clinical trials were found. ITB, IVB, and DBS represent present neuromodulatory approaches for the treatment of GA1. ITB and IVB reduce dystonia, while DBS has a heterogeneous effect. ITB and IVB improved function and reduced enteral medication regimens. These findings must be viewed with caution considering limited data and a serious risk of bias. Further large-scale studies are necessary to determine indications for ITB, IVB, and DBS and elucidate treatment algorithms., (© 2023 SSIEM.)

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., Competing Interests: The authors declare no potential conflict of interest., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)