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Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice
Chloe Santos, … , Andrew J. Copp, Nicholas D.E. Greene
Chloe Santos, … , Andrew J. Copp, Nicholas D.E. Greene
Published December 3, 2019
Citation Information: J Clin Invest. 2020;130(3):1446-1452. https://doi.org/10.1172/JCI132360.
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Concise Communication Development Neuroscience

Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice

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Abstract

Ventriculomegaly and hydrocephalus are associated with loss of function of glycine decarboxylase (Gldc) in mice and in humans suffering from non-ketotic hyperglycinemia (NKH), a neurometabolic disorder characterized by accumulation of excess glycine. Here, we showed that ventriculomegaly in Gldc-deficient mice is preceded by stenosis of the Sylvian aqueduct and malformation or absence of the subcommissural organ and pineal gland. Gldc functions in the glycine cleavage system, a mitochondrial component of folate metabolism, whose malfunction results in accumulation of glycine and diminished supply of glycine-derived 1-carbon units to the folate cycle. We showed that inadequate 1-carbon supply, as opposed to excess glycine, is the cause of hydrocephalus associated with loss of function of the glycine cleavage system. Maternal supplementation with formate prevented both ventriculomegaly, as assessed at prenatal stages, and postnatal development of hydrocephalus in Gldc-deficient mice. Furthermore, ventriculomegaly was rescued by genetic ablation of 5,10-methylene tetrahydrofolate reductase (Mthfr), which results in retention of 1-carbon groups in the folate cycle at the expense of transfer to the methylation cycle. In conclusion, a defect in folate metabolism can lead to prenatal aqueduct stenosis and resultant hydrocephalus. These defects are preventable by maternal supplementation with formate, which acts as a 1-carbon donor.

Authors

Chloe Santos, Yun Jin Pai, M. Raasib Mahmood, Kit-Yi Leung, Dawn Savery, Simon N. Waddington, Andrew J. Copp, Nicholas D.E. Greene

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Figure 1

Gldc deficiency results in ventriculomegaly.

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Gldc deficiency results in ventriculomegaly.
Unlike wild-type (A–E) and...
Unlike wild-type (A–E) and unaffected GldcGT1/GT1 (F–J) fetuses, a subset (7 of 13) of GldcGT1/GT1 fetuses (K–O) were affected by enlargement of the lateral (Lv) and third (III) ventricles at E18.5. The fourth ventricle (IV, arrow in E) does not differ in size between genotypes (compare D with E, I with J, and N with O), nor does the aqueduct (aq) at this posterior axial level. Choroid plexus is detected in lateral, third, and fourth ventricles (arrows in B) of all genotypes. However, the pineal gland (pg) and subcommissural organ (arrowheads in C and H) are absent in GldcGT1/GT1 fetuses displaying ventriculomegaly (M). (P–U) Following bilateral injection into the lateral ventricles of neonatal mice (P, Q, S, and T), dye distributed throughout the ventricular system including the fourth ventricle (IV) of Gldc+/+ (R) but not GldcGT1/GT1 (U) mice. Scale bars: 1 mm (C, H, and M), 5 mm (P–U), and 0.5 mm (other panels).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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