GLYT1 encephalopathy
{{Infobox medical condition
| name =
| synonym = Glycine encephalopathy with normal serum glycine.
| image = Person with GLyT1 encephalopathy (cropped).webp
| alt =
| caption = Photo of person with GLyT1 Encephalopathy, with decreased size of head, inward turning cross eye, receding lower jaw, deep prominent philtrum, thin eyebrows.
| specialty = Medical genetics, Neurology
| onset = In infancy
| differential = Glycine encephalopathy
| treatment = Supportive
}}
GLYT1 encephalopathy is a rare autosmal recessive, metabolic and genetic disorder which is caused by a mutation in the SLC6A9 gene.{{Cite web |title=Entry - #617301 - GLYCINE ENCEPHALOPATHY WITH NORMAL SERUM GLYCINE - OMIM |url=https://www.omim.org/entry/617301#:~:text=on%20chromosome%2011p15.-,Description,clonus,%20and%20delayed%20psychomotor%20development. |access-date=2025-04-19 |website=www.omim.org |language=en-us}}
The main features of this disorder are: severely diminished muscle tone, respiratory failure, absence of neonatal reflexes, encephalopathy, reduced consciousness and unresponsiveness, also it can present with arthrogryposis/ligament laxity, and normal serum glycine.{{Citation |last1=Kurolap |first1=Alina |title=GLYT1 Encephalopathy |date=1993 |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |url=https://www.ncbi.nlm.nih.gov/books/NBK465013/ |access-date=2025-04-19 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=29190063 |last2=Hershkovitz |first2=Tova |last3=Baris |first3=Hagit N. |editor2-last=Feldman |editor2-first=Jerry |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}
Symptoms
Someone with GLYT1 encphalopathy can present with facial dysmorphism, arthrogryposis and diminished muscle tone that progresses into muscle hypertonicity with so called startle-like clonus (which means that they have startle-like response to vocal and visual stimuli) and normal serum glycine level.{{Cite journal |last1=Kurolap |first1=Alina |last2=Armbruster |first2=Anja |last3=Hershkovitz |first3=Tova |last4=Hauf |first4=Katharina |last5=Mory |first5=Adi |last6=Paperna |first6=Tamar |last7=Hannappel |first7=Ewald |last8=Tal |first8=Galit |last9=Nijem |first9=Yusif |last10=Sella |first10=Ella |last11=Mahajnah |first11=Muhammad |last12=Ilivitzki |first12=Anat |last13=Hershkovitz |first13=Dov |last14=Ekhilevitch |first14=Nina |last15=Mandel |first15=Hanna |date=2016-11-03 |title=Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine |journal=The American Journal of Human Genetics |volume=99 |issue=5 |pages=1172–1180 |doi=10.1016/j.ajhg.2016.09.004 |pmid=27773429 |pmc=5097939 |issn=0002-9297}}
Facial features of this disorder might include: thin eyebrows, saddle nose, retrognathism, long myopathic face, piggy noses, tent-shaped mouth, low-set ears.
Diagnosis
Diagnosis of this disorder can be suspected by symptoms (such as: drowsiness, diminished muscle tone, and seizures) and by high glycine levels in cerebrospinal fluid and normal levels of enzymes and glycine in plasma, consequently diagnosis can be confirmed by genetic testing of GLYT1.{{Cite journal |last1=Bhumika |first1=S. |last2=Basalingappa |first2=Kanthesh M. |last3=Gopenath |first3=T. S. |last4=Basavaraju |first4=Suman |date=2022-11-17 |title=Glycine encephalopathy |journal=The Egyptian Journal of Neurology, Psychiatry and Neurosurgery |volume=58 |issue=1 |pages=132 |doi=10.1186/s41983-022-00567-6 |doi-access=free |issn=1687-8329 |pmc=9672649 |pmid=36415754}}
Cause
This disorder is caused by a mutation in a gene SLC6A9, which encodes Sodium- and chloride-dependent glycine transporter 1 protein, which is located on chromosome 1.{{Cite web |title=Orphanet: SLC6A9-solute carrier family 6 member 9 |url=https://www.orpha.net/en/disease/gene/SLC6A9 |access-date=2025-04-19 |website=www.orpha.net |language=en}}
Pathophysiology
Glycine is the simplest amino acid, that doesn't have any stereoisomers.{{Cite web |last=Team |first=EBI Web |title=glycine (CHEBI:15428) |url=https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:15428 |access-date=2025-04-19 |website=www.ebi.ac.uk |language=en}} Glycine participates in protein synthesis, but it can act as neurotransmitter, in the spinal cord and in the brain stem, it acts as inhibitory neurotransmitter by activating glycine channels.{{Cite journal |last1=Béchade |first1=Catherine |last2=Sur |first2=Cyrille |last3=Triller |first3=Antoine |date=1994 |title=The inhibitory neuronal glycine receptor |url=https://onlinelibrary.wiley.com/doi/10.1002/bies.950161008 |journal=BioEssays |language=en |volume=16 |issue=10 |pages=735–744 |doi=10.1002/bies.950161008 |issn=1521-1878}}{{Cite journal |last=Lynch |first=Joseph W. |date=2004-10-01 |title=Molecular Structure and Function of the Glycine Receptor Chloride Channel |url=https://journals.physiology.org/doi/full/10.1152/physrev.00042.2003 |journal=Physiological Reviews |volume=84 |issue=4 |pages=1051–1095 |doi=10.1152/physrev.00042.2003 |pmid=15383648 |issn=0031-9333}} Although it has excitatory effect in neocortex (by co-activating NMDAR).{{Cite journal |last1=Aragón |first1=Carmen |last2=López-Corcuera |first2=Beatriz |date=2005-06-01 |title=Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion |url=https://www.sciencedirect.com/science/article/abs/pii/S0165614705001082 |journal=Trends in Pharmacological Sciences |volume=26 |issue=6 |pages=283–286 |doi=10.1016/j.tips.2005.04.007 |pmid=15925702 |issn=0165-6147}}{{Cite journal |last1=He |first1=Miaomiao |last2=Wollmuth |first2=Lonnie P. |date=2023-05-03 |title=Activation of excitatory glycine NMDA receptors: At the mercy of a whimsical GluN1 subunit |url=https://rupress.org/jgp/article/155/6/e202313391/214088/Activation-of-excitatory-glycine-NMDA-receptors-At |journal=Journal of General Physiology |volume=155 |issue=6 |pages=e202313391 |doi=10.1085/jgp.202313391 |pmid=37133818 |issn=0022-1295}}
GLYT1 protein is located on astrocytes that are next to glycinergic neurons to clear glycine swiftly from the synaptic cleft.{{Cite journal |last1=Wang |first1=Xiaolu |last2=Yue |first2=Ming |last3=Cheung |first3=Jason Pui Yin |last4=Cheung |first4=Prudence Wing Hang |last5=Fan |first5=Yanhui |last6=Wu |first6=Meicheng |last7=Wang |first7=Xiaojun |last8=Zhao |first8=Sen |last9=Khanshour |first9=Anas M. |last10=Rios |first10=Jonathan J. |last11=Chen |first11=Zheyi |last12=Wang |first12=Xiwei |last13=Tu |first13=Wenwei |last14=Chan |first14=Danny |last15=Yuan |first15=Qiuju |date=2024-01-16 |title=Impaired glycine neurotransmission causes adolescent idiopathic scoliosis |journal=The Journal of Clinical Investigation |language=en |volume=134 |issue=2 |doi=10.1172/JCI168783 |pmid=37962965 |pmc=10786698 |issn=0021-9738}}{{Cite journal |last1=Eulenburg |first1=Volker |last2=Armsen |first2=Wencke |last3=Betz |first3=Heinrich |last4=Gomeza |first4=Jesús |date=2005-06-01 |title=Glycine transporters: essential regulators of neurotransmission |url=https://www.cell.com/trends/biochemical-sciences/abstract/S0968-0004(05)00094-0?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S0968000405000940?showall=true |journal=Trends in Biochemical Sciences |language=English |volume=30 |issue=6 |pages=325–333 |doi=10.1016/j.tibs.2005.04.004 |issn=0968-0004 |pmid=15950877}} Consequently, this mechanism is disrupted in this disease by hyperactivating NMDA receptors and glycine receptors.{{Cite journal |last1=Alfadhel |first1=Majid |last2=Nashabat |first2=Marwan |last3=Qahtani |first3=Hanan Al |last4=Alfares |first4=Ahmed |last5=Mutairi |first5=Fuad Al |last6=Shaalan |first6=Hesham Al |last7=Douglas |first7=Ganka V. |last8=Wierenga |first8=Klaas |last9=Juusola |first9=Jane |last10=Alrifai |first10=Muhammad Talal |last11=Arold |first11=Stefan T. |last12=Alkuraya |first12=Fowzan |last13=Ali |first13=Qais Abu |date=2016-11-01 |title=Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans |url=https://link.springer.com/article/10.1007/s00439-016-1719-x |journal=Human Genetics |language=en |volume=135 |issue=11 |pages=1263–1268 |doi=10.1007/s00439-016-1719-x |issn=1432-1203}}{{Cite journal |last1=Mademont-Soler |first1=Irene |last2=Casellas-Vidal |first2=Dolors |last3=Trujillo |first3=Alberto |last4=Espuña-Capote |first4=Núria |last5=Maroto |first5=Anna |last6=García-González |first6=Maria del Mar |last7=Ruiz |first7=María Dolores |last8=Diego-Álvarez |first8=Dan |last9=Queralt |first9=Xavier |last10=Perapoch |first10=Josep |last11=Obón |first11=María |date=2021 |title=GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.a.61996 |journal=American Journal of Medical Genetics Part A |language=en |volume=185 |issue=2 |pages=476–485 |doi=10.1002/ajmg.a.61996 |issn=1552-4833}}
Treatment
GLYT1 encephalopathy doesn't have a cure and its management is supportive, and it requires a multidisciplinary team (that may consist of geneticists, paediatricians, physiotherapists, etc) to control symptoms.{{Cite journal |last1=Alfallaj |first1=Rayan |last2=Alfadhel |first2=Majid |date=2019-01-01 |title=Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review |journal=Child Neurology Open |language=EN |volume=6 |pages=2329048X19831486 |doi=10.1177/2329048X19831486 |pmid=30815509 |pmc=6383083 |issn=2329-048X}} One patient was treated sodium benzoate and ketamine, but it didn't show any results.