LAUSR

Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age‐related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross‐sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d‐serine and l‐serine levels were stereoselectively determined in seven NKH patients and compared to 29 age‐matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age‐adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age‐adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d‐serine was more reduced than l‐serine, with a decreased d/l‐serine ratio, indicating a specific impact on d‐serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l‐serine, d‐serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one‐carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored.