Glycine transporter 1 encephalopathy (GLYT1 encephalopathy) is a form of glycine encephalopathy caused by disturbance of glycine transport, which leads to accumulation in the glycinergic synapses of glycine, an amino acid with a crucial role in the central nervous system as an inhibitory and excitatory neurotransmitter. The disorder is also known as glycine encephalopathy with normal serum glycine (OMIM #617301).
The phenotypic spectrum of the disease has not yet been completely described. However, common features of GLYT1 encephalopathy include neonatal onset, respiratory failure, severe hypotonia at birth that progresses to limb hypertonicity, absent neonatal reflexes, myoclonic jerks provoked by sudden loud sounds and tactile stimulation, severe global developmental delay, dysmorphic features and musculoskeletal abnormalities (including arthrogryposis multiplex congenita in all cases). All reported cases present high levels of glycine in cerebrospinal fluid and normal or slightly elevated levels of glycine in serum. Additional characteristics include abnormal brain magnetic resonance imaging, electroencephalographic alterations and genitourinary malformations. Abnormal findings including polyhydramnios and arthrogryposis are present antenatally. Most patients die in infancy.
The prevalence of GLYT1 encephalopathy is unknown. To date, only ten affected individuals from five unrelated families have been reported in the literature. All of them harbored biallelic genetic variants in the gene SLC6A9 (thus the inheritance pattern is autosomal recessive). This gene codifies the protein sodium- and chloride-dependent glycine transporter 1 (GLYT1), whose main function is to modulate the synaptic concentration of glycine.
The achievement of a clinical and molecular diagnosis in patients with GLYT1 encephalopathy is fundamental for proper management, establishing prognosis, genetic counselling, and family planning. Of note, the risk of recurrence in these families is high, hence the possibility of prenatal or preimplantation genetic diagnosis should be discussed with the couples.
Of note, there are other disorders with features overlapping with GLYT1 encephalopathy that should be considered in the differential diagnosis, including classic nonketotic hyperglycinemia, variant nonketotic hyperglycinemia, X-linked cobalamin disorder, and hyperekplexia.
SLC6A9