GLYT1 encephalopathy

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GLYT1 encephalopathy
Other namesGlycine encephalopathy with normal serum glycine.
Person with GLyT1 encephalopathy (cropped).webp
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
Usual onsetIn infancy
Differential diagnosis Glycine encephalopathy
TreatmentSupportive

GLYT1 encephalopathy is a rare autosmal recessive, metabolic and genetic disorder which is caused by a mutation in the SLC6A9 gene. [1]

Contents

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. [2]

About 10 cases had been reported as of 2022. [3]

Symptoms

Someone with GLYT1 encephalopathy 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. [4] [2]

Facial features of this disorder might include: thin eyebrows, saddle nose, retrognathism, long myopathic face, piggy noses, tent-shaped mouth, low-set ears. [3]

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. [5]

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. [6]

Pathophysiology

Glycine is the simplest amino acid, that doesn't have any stereoisomers. [7] 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. [8] [9] Although it has excitatory effect in neocortex (by co-activating NMDAR). [10] [11]

GLYT1 protein is located on astrocytes that are next to glycinergic neurons to clear glycine swiftly from the synaptic cleft. [12] [13] Consequently, this mechanism is disrupted in this disease by hyperactivating NMDA receptors and glycine receptors. [14] [15]

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. [16] One patient was treated sodium benzoate and ketamine, but it didn't show any results. [4]

Prognosis

This disorder is usually fatal in infancy. Only 2 patients survived till childhood (at the time of the article's publication). [16]

History

This disorder was first reported by Alfadhel and colleagues in 2016. [14]

See also

References

  1. ↑ "Entry - #617301 - GLYCINE ENCEPHALOPATHY WITH NORMAL SERUM GLYCINE - OMIM". www.omim.org. Retrieved 2025-04-19.
  2. 1 2 Kurolap, Alina; Hershkovitz, Tova; Baris, Hagit N. (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "GLYT1 Encephalopathy", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   29190063 , retrieved 2025-04-19
  3. 1 2 Daşar, Tuğba; Şimşek-Kiper, Pelin Özlem; Taşkıran, Ekim Zihni; Çağan, Murat; Özyüncü, Özgür; Deren, Özgür; Utine, Gülen Eda; Güçer, Kadri Şafak; Boduroğlu, Koray (2022-12-01). "A lethal and rare cause of arthrogryposis: Glyt1 encephalopathy" . European Journal of Medical Genetics. 65 (12): 104631. doi: 10.1016/j.ejmg.2022.104631 . ISSN   1769-7212. PMID   36195292.
  4. 1 2 Kurolap, Alina; Armbruster, Anja; Hershkovitz, Tova; Hauf, Katharina; Mory, Adi; Paperna, Tamar; Hannappel, Ewald; Tal, Galit; Nijem, Yusif; Sella, Ella; Mahajnah, Muhammad; Ilivitzki, Anat; Hershkovitz, Dov; Ekhilevitch, Nina; Mandel, Hanna (2016-11-03). "Loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine". The American Journal of Human Genetics. 99 (5): 1172–1180. doi:10.1016/j.ajhg.2016.09.004. ISSN   0002-9297. PMC   5097939 . PMID   27773429.
  5. ↑ Bhumika, S.; Basalingappa, Kanthesh M.; Gopenath, T. S.; Basavaraju, Suman (2022-11-17). "Glycine encephalopathy". The Egyptian Journal of Neurology, Psychiatry and Neurosurgery. 58 (1): 132. doi: 10.1186/s41983-022-00567-6 . ISSN   1687-8329. PMC   9672649 . PMID   36415754.
  6. ↑ "Orphanet: SLC6A9-solute carrier family 6 member 9". www.orpha.net. Retrieved 2025-04-19.
  7. ↑ Team, EBI Web. "glycine (CHEBI:15428)". www.ebi.ac.uk. Retrieved 2025-04-19.
  8. ↑ Béchade, Catherine; Sur, Cyrille; Triller, Antoine (1994). "The inhibitory neuronal glycine receptor" . BioEssays. 16 (10): 735–744. doi:10.1002/bies.950161008. ISSN   1521-1878. PMID   7980477.
  9. ↑ Lynch, Joseph W. (2004-10-01). "Molecular Structure and Function of the Glycine Receptor Chloride Channel" . Physiological Reviews. 84 (4): 1051–1095. doi:10.1152/physrev.00042.2003 (inactive 28 April 2025). ISSN   0031-9333. PMID   15383648.{{cite journal}}: CS1 maint: DOI inactive as of April 2025 (link)
  10. ↑ Aragón, Carmen; López-Corcuera, Beatriz (2005-06-01). "Glycine transporters: crucial roles of pharmacological interest revealed by gene deletion" . Trends in Pharmacological Sciences. 26 (6): 283–286. doi:10.1016/j.tips.2005.04.007. ISSN   0165-6147. PMID   15925702.
  11. ↑ He, Miaomiao; Wollmuth, Lonnie P. (2023-05-03). "Activation of excitatory glycine NMDA receptors: At the mercy of a whimsical GluN1 subunit". Journal of General Physiology. 155 (6): e202313391. doi:10.1085/jgp.202313391. ISSN   0022-1295. PMC   10163841 . PMID   37133818.
  12. ↑ Wang, Xiaolu; Yue, Ming; Cheung, Jason Pui Yin; Cheung, Prudence Wing Hang; Fan, Yanhui; Wu, Meicheng; Wang, Xiaojun; Zhao, Sen; Khanshour, Anas M.; Rios, Jonathan J.; Chen, Zheyi; Wang, Xiwei; Tu, Wenwei; Chan, Danny; Yuan, Qiuju (2024-01-16). "Impaired glycine neurotransmission causes adolescent idiopathic scoliosis". The Journal of Clinical Investigation. 134 (2). doi:10.1172/JCI168783. ISSN   0021-9738. PMC   10786698 . PMID   37962965.
  13. ↑ Eulenburg, Volker; Armsen, Wencke; Betz, Heinrich; Gomeza, Jesús (2005-06-01). "Glycine transporters: essential regulators of neurotransmission" . Trends in Biochemical Sciences. 30 (6): 325–333. doi:10.1016/j.tibs.2005.04.004. ISSN   0968-0004. PMID   15950877.
  14. 1 2 Alfadhel, Majid; Nashabat, Marwan; Qahtani, Hanan Al; Alfares, Ahmed; Mutairi, Fuad Al; Shaalan, Hesham Al; Douglas, Ganka V.; Wierenga, Klaas; Juusola, Jane; Alrifai, Muhammad Talal; Arold, Stefan T.; Alkuraya, Fowzan; Ali, Qais Abu (2016-11-01). "Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans". Human Genetics. 135 (11): 1263–1268. doi:10.1007/s00439-016-1719-x. ISSN   1432-1203. PMC   5052303 . PMID   27481395.
  15. ↑ Mademont-Soler, Irene; Casellas-Vidal, Dolors; Trujillo, Alberto; Espuña-Capote, Núria; Maroto, Anna; García-González, Maria del Mar; Ruiz, María Dolores; Diego-Álvarez, Dan; Queralt, Xavier; Perapoch, Josep; Obón, María (2021). "GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms" . American Journal of Medical Genetics Part A. 185 (2): 476–485. doi:10.1002/ajmg.a.61996. ISSN   1552-4833. PMID   33269555.
  16. 1 2 Alfallaj, Rayan; Alfadhel, Majid (2019-01-01). "Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review". Child Neurology Open. 6: 2329048X19831486. doi:10.1177/2329048X19831486. ISSN   2329-048X. PMC   6383083 . PMID   30815509.
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