Glycine is one of the 20 amino acids that constitute the structure of proteins. In addition to that, glycine takes an active part in the synthesis of other molecules such as serine, heme, purine, creatine, and glutathione. Also, it acts as an inhibitory neurotransmitter in the central nervous system (CNS). Two main control systems regulate glycine levels in CNS: the glycine cleavage system (GCS) and the glycine transport system.

GCS is formed by three enzymes – P, T and H protein – responsible for the degradation of glycine; each of them is encoded by a specific gene. If GCS doesn’t work, a disease called glycine encephalopathy, or non-ketotic hyperglycinemia (NKH), develops. All NKH cases described so far are due to some fail of one of the GCS components.

In the CNS, the glycine transport system does not degrade glycine, but acts through atrans-membrane transport channel (GlyT1) that regulate the extracellular concentration of glycine. Mutations of GlyT1 were not associated to NKH until now, but a team of researchers from Saudi Arabia has shown for the first time that NKH may be caused by the dysfunction of GlyT1.

NKH is a rare, genetic metabolic disorder in which glycine accumulates in tissues and fluids of the body. It is a monogenic recessive disorder, so it appears with 25% of probability when both parents have one copy of the dysfunctional gene, as occurred in the case of the daughter of the Saudi couple described in the study.There is a severe form and an attenuate form of NKH; the severe form is more frequent, and no cure is available to date.

As described in the study, NKH appeared immediately after the birth of the baby, that presented a respiratory failure that required intubation and mechanical ventilation during one month. Moreover, three days after birth, the baby suffered seizure episodes and showed exaggerated startle reflex in response to sounds and tactile stimuli. After six months, these symptoms had gradually disappeared, but just after then she started to show hypotonia, microcephaly, and psychomotor delay. Most of symptoms were typical of the known form of NKH.

The researchers analyzed the genome regions associated with the glycine metabolism and found a mutation in the SLC6A9 gene, that encodes for GlyT1. The mutation causeda single substitution in the amino acidic sequence of the GlyT1 protein: a glycine was substituted by a serine. This was enough to modify the whole 3D structure of the protein, that lost its biological function. A possible explication is that, without the presence of a functional trans-membrane transporter, glycine accumulates in the extracellular matrix of neurons, thus causing the disease.

Magnetic resonance images of child’s brain also revealed some abnormal changes in the white matter. These findings suggest the importance of GlyT1 in the brain development and in the control of the respiratory function (localized in the brainstem).

Biochemical analysis showed high levels of glycine in plasma and in the cerebrospinal fluid (CSF), but there was a difference with respect to the classic NKH form: in this case, CSF/plasma glycine ratio was 0.07, a higher value than the one in classic NKH patients, whose CSF/plasma ratio is normally more than 0.08.

A mouse model with the same GlyT1 dysfunction should be useful to better investigate NKH. Unfortunately, mice carrying homozygous SLC6A9 mutation die just after birth, thus making impossible any study of the phenotype and of the disease progress.


The first case of NKH due to a novel mutation of SLC6A9 gene has been recently described. This mutation affects the functionality of the GlyT1, a transport protein involved in glycine neurotransmission in brain, and it has to be considered together with the classical form of non-ketotic hyperglycinemia.



Alfadhel M et al. Mutation in SLC6A9 encoding a glycine transporter causesa novel form of non‑ketotic hyperglycinemia in humans. Hum Genet (2016) 135:1263–1268.



The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).