Newborn screening: A disease‐changing intervention for glutaric aciduria type 1

Nikolas Boy, Katharina Mengler, Eva Thimm, Katharina A. Schiergens, Thorsten Marquardt, Natalie Weinhold, Iris Marquardt, Anibh M. Das, Peter Freisinger, Sarah C. Grünert, Judith Vossbeck, Robert Steinfeld, Matthias R. Baumgartner, Skadi Beblo, Andrea Dieckmann, Andrea Näke, Martin Lindner, Jana Heringer, Georg F. Hoffmann, Chris Mühlhausen, Esther M. Maier, Regina Ensenauer, Sven F. Garbade, Stefan Kölker

Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programmes has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. This prospective, observational, multi-centre study includes 87 patients identified by NBS, four patients missed by NBS and three women with GA1 identified by positive NBS results of their unaffected children. The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany between 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but is lower (84%) for patients with low excretor phenotype. Neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, while the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than non-interventional variables: Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), while delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a non-neurologic manifestation not predicted by any variable included in this study. NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy while kidney dysfunction does not appear to be impacted by recommended therapy. This article is protected by copyright. All rights reserved.