Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review

Abstract

Glycine transporter 1 encephalopathy (OMIM# 617301; glycine encephalopathy with normal serum glycine, GLYT1 transporter dysfunction, and nonketotic hyperglycinemia) is caused by mutations in the SLC6A9 gene. To date, 6 cases have been reported in the literature, characterized as having neonatal onset, respiratory failure that required mechanical ventilation, severe hypotonia at birth that progressed to limb hypertonicity, and startle-like responses provoked by sudden loud noises and tactile stimulation. Additional characteristics included dysmorphic features, musculoskeletal abnormalities, and abnormal antenatal findings. Initial diagnosis include elevated levels of glycine in cerebrospinal fluid and an elevated cerebrospinal fluid to plasma glycine ratio. Abnormal magnetic resonance imaging findings included white matter abnormalities, thin corpus callosum, dilatation of the lateral and third ventricles, caudate atrophy, and tiny cysts. Patients reported so far showed normal electroencephalogram results. Treatment was supportive and appeared severe as 50% of the patients died between 2 days and 7 months of age, while surviving children had global developmental delay. In this report, we reviewed the published cases having glycine transporter 1 encephalopathy and retrospectively characterizing the disease phenotypes, affected biochemical pathways, neuroradiological abnormalities, diagnosis, genetic issues, and treatment; additionally, key discussion points are also presented.

Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits

“…3 of the 6 affected individuals died within 7 months of age (one death was pre-natal) due to respiratory failure. All patients manifest encephalopathy, shallow breathing, hyperekplexia (exaggerated startle reflex, see below), hypotonia, which paradoxically progresses to muscle hypertonicity resulting in arthrogryposis (joint contracture), and facial dysmorphism ( Alfallaj & Alfadhel, 2019 ). The 2 surviving patients overcame respiratory failure, in a manner similar to some GlyT1 −/− mice (see above).…”

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…All patients reported in the literature had neonatal disease onset, respiratory failure with a requirement for mechanical ventilation, severe hypotonia at birth and subsequent limb hypertonicity, and startle-like responses caused by tactile stimulation and sudden loud sounds. In addition, dysmorphic features, musculoskeletal system abnormalities (joint laxity, hip dislocation, hyperextension of knees, or other musculoskeletal abnormalities), abnormal antenatal findings, abnormal brain magnetic resonance imaging (MRI), high glycine concentrations in cerebrospinal fluid, and a high cerebrospinal fluid to plasma glycine ratio were also found in these patients [111,112,115]. The abnormal antenatal findings were cervical cysts, nuchal translucency, clenched fists, fourth ventriculomegaly, bilateral clubfeet, overriding toes, hyperextension of the knees, joint contractures, arthrogryposis, and hydrops fetalis [111,112,115].…”

“…In addition, dysmorphic features, musculoskeletal system abnormalities (joint laxity, hip dislocation, hyperextension of knees, or other musculoskeletal abnormalities), abnormal antenatal findings, abnormal brain magnetic resonance imaging (MRI), high glycine concentrations in cerebrospinal fluid, and a high cerebrospinal fluid to plasma glycine ratio were also found in these patients [111,112,115]. The abnormal antenatal findings were cervical cysts, nuchal translucency, clenched fists, fourth ventriculomegaly, bilateral clubfeet, overriding toes, hyperextension of the knees, joint contractures, arthrogryposis, and hydrops fetalis [111,112,115]. In addition to the previously mentioned clinical findings, a diagnosis can be made based on high cerebrospinal fluid glycine levels, normal plasma glycine levels, an elevated cerebrospinal fluid to plasma glycine ratio, and genetic testing for SLC6A9 mutations [112].…”

“…In 2016, a new type of nonketotic hyperglycinemia that arises from biallelic mutations in the SLC6A9 gene, which encodes glycine transporter 1 (GLYT1), was reported [111]. GLYT1 is mainly located in the caudal regions of the brain (spinal cord, brain stem, and cerebellum), mainly in astrocytes [112]. It is key for the transport of glycine from the extracellular space and glycinergic transmission termination [113,114].…”

“…The abnormal antenatal findings were cervical cysts, nuchal translucency, clenched fists, fourth ventriculomegaly, bilateral clubfeet, overriding toes, hyperextension of the knees, joint contractures, arthrogryposis, and hydrops fetalis [111,112,115]. In addition to the previously mentioned clinical findings, a diagnosis can be made based on high cerebrospinal fluid glycine levels, normal plasma glycine levels, an elevated cerebrospinal fluid to plasma glycine ratio, and genetic testing for SLC6A9 mutations [112]. There is currently no curative treatment available.…”