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.