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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 characterised 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 sub-commissural 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 one-carbon units to the folate cycle. We showed that inadequate one-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 pre-natal stages, and post-natal 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 one-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 pre-natal aqueduct stenosis and resultant hydrocephalus. These defects are preventable by maternal supplementation with formate, which acts as a one-carbon donor.
This article was published in the following journal.
Name: The Journal of clinical investigation
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Flavoproteins that catalyze reversibly the reduction of carbon dioxide to formate. Many compounds can act as acceptors, but the only physiologically active acceptor is NAD. The enzymes are active in the fermentation of sugars and other compounds to carbon dioxide and are the key enzymes in obtaining energy when bacteria are grown on formate as the main carbon source. They have been purified from bovine blood. EC 188.8.131.52.
A carbon-nitrogen ligase that catalyzes the formation of 10-formyltetrahydrofolate from formate and tetrahydrofolate in the presence of ATP. In higher eukaryotes the enzyme also contains METHYLENETETRAHYDROFOLATE DEHYDROGENASE (NADP+) and METHENYLTETRAHYDROFOLATE CYCLOHYDROLASE activity.
Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, INTRACRANIAL HYPERTENSION; HEADACHE; lethargy; URINARY INCONTINENCE; and ATAXIA (and in infants macrocephaly). This condition may be caused by obstruction of cerebrospinal fluid pathways due to neurologic abnormalities, INTRACRANIAL HEMORRHAGES; CENTRAL NERVOUS SYSTEM INFECTIONS; BRAIN NEOPLASMS; CRANIOCEREBRAL TRAUMA; and other conditions. Impaired resorption of cerebrospinal fluid from the arachnoid villi results in a communicating form of hydrocephalus. Hydrocephalus ex-vacuo refers to ventricular dilation that occurs as a result of brain substance loss from CEREBRAL INFARCTION and other conditions.
An inhibitor of folate metabolism. It is used as a coccidiostat in poultry.
A subtype of GPI-anchored folate receptors that is expressed in PLACENTA and hematopoietic cells.
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