Glycine is the simplest amino acid and a fundamental neurotransmitter in the central nervous system (CNS). Its activity is mainly inhibitory in caudal regions of CNS, but it also has a co-agonist role at a specific subtype of glutamate receptors present throughout the CNS.

Extracellular glycine levels are regulated by two types of transporters, called GlyT1 and GlyT2. GlyT1 is found on astrocytes, and it is essential for the uptake of glycine from the extracellular space. GlyT2, localized on the pre-synaptic glycinergic terminals, has a site-specific role.

There are various disorders associated with a failure in glycine-dependent neurotransmission, such as non-ketotic hyperglycinemia (NKH), hyperekplexia, chronic pain, epilepsy, and other psychiatric disorders. The authors of the study here described focused their attention on a particular, novel case of NKH.

NKH, also known as glycine encephalopathy, is caused, in the majority of cases observed so far, by the malfunction of the glycine cleavage system (GCS), a group of enzymes responsible for the catabolism of glycine. NKH symptoms appear just after birth, and consist, among others, of respiratory failure, lack of neonatal reflexes, encephalopathy, hypotonia, seizure episodes, startle reflexes.

Nevertheless, there are few NKH-like cases that present almost the same symptoms of NKH, but are caused by the malfunction of GlyT1 transporter. The scientists analyzed two families whose children suffered NKH. Three of them died few weeks or few months after birth, while just one survived more than two years, and mildly recovered (he was alive when the study was published).

Genetic analysis showed in all cases a deletion of five nucleotides in the gene codifying for GlyT1, in homozygous conditions. The deletion generated a premature stop codon that produced a truncated form of the GlyT1 protein, provoking the loss of its biological function. As expected, biochemical analyses showed an accumulation of glycine in the cerebrospinal fluid (CSF), as occurs in classic NKH form. However, in this case, glycine levels in serum were normal, while in the classical NKH form they are elevated.

These findings may have a logical explanation: GlyT1 is mainly expressed in a specific region of the brain, but it is not present in peripheral tissues like liver, muscle and skin. In contrast, GCS is also present in peripheral tissues, therefore its failure leads to the accumulation of glycine in plasma as well. So, a possible marker to distinguish between NKH caused by GlyT1 or GCS failure is the CSF/plasma glycine ratio. A high ratio is an indicator of the GlyT1 loss of function, while a lower ratio leads to the GCS failure hypothesis.

A final consideration: one of the four children described in the study survived and reached the age of two with a slightly improvement of his symptoms. He overcame the post-natal respiratory failure, and after few months he was able to breath independently without the aid of a mechanical ventilation system. A possible explanation lies in theoretical compensation mechanisms that activate in the caudal region of brain: GlyT1 function, that is essential in the neonatal period, could be substituted by other mechanisms during the following phases of growth. However, the molecular nature of these compensatory mechanisms is still unknown.


A novel form of NKH due to a mutation of GlyT1 transporter has been described. The high CSF/plasma glycine ratio is the main marker to distinguish the GlyT1-subtype NKH from the classic NKH form due to the dysfunction of the GCS system.



Kurolap A. et al. Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine. Am J Hum Genet. 2016 Nov 3;99(5):1172-1180.



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).