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Clinical outcomes and survival of individuals with methylmalonic acidemia, propionic acidemia, classic homocystinuria, and remethylation disorders identified through newborn screening

Reischl-Hajiabadi, A. T.; Schnabel, E.; Gleich, F.; Mengler, K.; Lindner, M.; Burgard, P.; Posset, R.; Lommer-Steinhoff, S.; Grunert, S. C.; Thimm, E.; Freisinger, P.; Hennermann, J. B.; Kramer, J.; Gramer, G.; Lenz, D.; Christ, S.; Horster, F.; Hoffmann, G. F.; Garbade, S. F.; Kolker, S.; Mutze, U.

2023-09-15 pediatrics
10.1101/2023.09.15.23295546 medRxiv
Show abstract

The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, the NBS pilot study in Southwest Germany identifies individuals with methylmalonic acidemia (MMA), propionic acidemia (PA), cystathionine {beta}-synthase (CBS) deficiency, remethylation disorders [e.g. cobalamin (cbl) C and methylenetetrahydrofolate reductase (MTHFR) deficiency], and neonatal cbl deficiency through a combined second-tier algorithm. The long-term health benefits of screened individuals are evaluated in a prospective multicenter observational study. Twenty-seven individuals with IMDs [MMA (N=6), PA (N=13), cblC deficiency (N=5), MTHFR deficiency (N=2) and CBS deficiency (N=1)] and 42 with neonatal cbl deficiency were identified by the NBS pilot study and followed for a median of 3.6 years. Seventeen IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (cbl-nonresponsive MMA, PA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with MMA or PA and all with cblC deficiency presented with permanent, mostly neurological symptoms, while individuals with CBS, MTHFR and neonatal cbl deficiency had a favorable outcome. Utilizing a combined second-tier algorithm we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with CBS deficiency, MTHFR deficiency, neonatal cbl deficiency, and to some extent, cblC deficiency and cbl-responsive MMA. However, its advantage is less evident for individuals with cbl-nonresponsive MMA and PA.

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