# A Nonketotic Hyperglycinemia Mouse Shows Wide‐Ranging Biochemical Consequences of Elevated Glycine, Reduced Folate One‐Carbon Charging, and Serine Deficiency

## TL;DR

A mouse model of nonketotic hyperglycinemia reveals biochemical changes like elevated glycine and reduced folate and serine, which could guide new treatments for this severe neurological disorder.

## Contribution

The study identifies three key biochemical components in nonketotic hyperglycinemia: elevated glycine, reduced folate one-carbon charging, and decreased L- and D-serine.

## Key findings

- Increased glycine levels in multiple tissues lead to neurotoxic metabolites and upregulation of the glycine transporter Slc6a20.
- Reduced folate one-carbon charging and serine deficiency affect myelination-related lipids like sphingosine and ceramide.
- Region-specific D-serine deficiency in the cortex and hippocampus correlates with symptom severity in young mice.

## Abstract

Nonketotic hyperglycinemia is a severe neonatal epileptic encephalopathy caused by deficient glycine cleavage enzyme activity, for which currently no effective treatment exists. Incomplete understanding of brain biochemistry represents a major knowledge gap to develop new treatments. We examined the biochemistry in blood, liver, cortex, hippocampus, and cerebellum of a mouse model homozygous for the Gldc variant p.Ala394Val. Glycine was increased in all compartments and caused increased brain neurotoxic metabolites guanidinoacetate and methylglyoxal, and also N‐acetylglycine and cystathionine. The glycine extruding transporter Slc6a20 was increased. There was reduced one‐carbon folate charging with secondarily reduced methionine in the cortex, and reduced alternative one‐carbon donors L‐serine and formate. Serine deficiency was associated with reduced amounts of sphingosine, sphingomyelin, and ceramide species important for myelination, but not phosphatidylserines. There was a region‐specific deficiency of D‐serine in the cortex and hippocampus. This difference, also present in humans, was strain‐ and age‐related, most evident in young J129X1/SvJ mice, reflecting symptomatology. There was no evidence of oxidative stress or a bioenergetic defect. The biochemistry of the nonketotic hyperglycinemia mouse model can be traced to three components: increased glycine, reduced folate one‐carbon charging, and decreased L‐ and D‐serine. These changes will need to be addressed in new therapeutic approaches.