Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine.
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PMID:Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine. 2777 29

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.
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PMID:Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review. 3081 9

GLYT1 encephalopathy is a form of glycine encephalopathy caused by disturbance of glycine transport. The phenotypic spectrum of the disease has not yet been completely described, as only four unrelated families with the disorder have been reported to date. Common features of affected patients include neonatal hypotonia, respiratory failure, encephalopathy, myoclonic jerks, dysmorphic features, and musculoeskeletal anomalies. All reported affected patients harbor biallelic genetic variants in SLC6A9. SNP array together with Sanger sequencing were performed in a newborn with arthrogryposis and severe neurological impairment. The novel genetic variant c.997delC in SLC6A9 was detected in homozygous state in the patient. At protein level, the predicted change is p.(Arg333Alafs*3), which most probably results in a loss of protein function. The variant cosegregated with the disease in the family. A subsequent pregnancy with ultrasound anomalies was also affected. The proband presented the core phenotypic features of GLYT1 encephalopathy, but also a burst suppression pattern on the electroencephalogram, a clinical feature not previously associated with the disorder. Our results suggest that the appearance of this pattern correlates with higher cerebrospinal fluid glycine levels and cerebrospinal fluid/plasma glycine ratios. A detailed discussion on the possible pathophysiological mechanisms of the disorder is also provided.
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PMID:GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms. 3326 55