Cobalamin‐Related Remethylation Disorders: Pregnancy Outcomes and Prenatal Treatment‐New Cases and a Literature Study

Vollständiger Abstract

Worum geht es in dieser Arbeit?

ABSTRACT Cobalamin‐related remethylation disorders (cbl‐RD) are rare, heterogenous conditions with a wide phenotypic spectrum, including prenatal and early infantile manifestations. Data on pregnancy outcomes in affected women and the efficacy and safety of prenatal treatment of affected fetuses remain limited. Here we report (1) five women with cbl‐RDs (3 cblC/epi‐cblC, 1 cblD, 1 cblE) who had in total nine pregnancies and (2) eight fetuses with cbl‐RD (7 cblC, 1 cblF) diagnosed and treated prenatally. All affected mothers were treated with hydroxocobalamin (OHCbl) during pregnancy and two also received betaine and carnitine. Complications included three preterm deliveries and nephrotic‐range proteinuria in one previously undiagnosed mother with cblE. All offspring had favourable outcomes. In pregnancies with affected fetuses, OHCbl was administered to the mother between gestational weeks 5 and 32 at varying doses. Prenatally treated cblC cases exhibited attenuated phenotypes without microcephaly, epilepsy, or severe multisystemic disease. Notably, three of five infants harbouring severe MMACHC variants, who received high‐dose pre‐ and postnatal OHCbl, exhibited normal neurodevelopment and no maculopathy up to age 2–3 years, though variability in genotype, treatment regimens, and duration of follow‐up limit generalizability. A literature review identified nine additional pregnancies in women with cbl‐RD and seven prenatally treated fetuses, with follow‐up available for three. Collectively, our main findings support the safety of maternal and fetal OHCbl treatment during pregnancy. We recommend that when combined with preconception counselling, early standardized diagnosis, optimal monitoring and postnatal care, prenatal OHCbl therapy can improve pregnancy outcomes and mitigate neurodevelopmental and ophthalmic complications in cbl‐RD.