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Glycine encephalopathy 2(GCE2)

MedGen UID:
1841195
Concept ID:
C5830559
Disease or Syndrome
Synonym: GCE2
 
Gene (location): AMT (3p21.31)
 
Monarch Initiative: MONDO:0958192
OMIM®: 620398

Definition

Glycine encephalopathy (GCE), also called nonketotic hyperglycinemia (NKH), is an inborn error of metabolism characterized by accumulation of a large amount of glycine in body fluids. Typical cases have severe neurologic features, including seizures, lethargy, and muscular hypotonia soon after birth, and most die with the neonatal period; atypical cases have later onset and less severe psychomotor development (summary by Nanao et al., 1994). For a general description and a discussion of genetic heterogeneity of glycine encephalopathy, see GCE1 (605899). [from OMIM]

Clinical features

From HPO
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
EEG with burst suppression
MedGen UID:
369943
Concept ID:
C1969156
Finding
The burst suppression pattern in electroencephalography refers to a characteristic periodic pattern of low voltage (<10 microvolts) suppressed background and a relatively shorter pattern of higher amplitude slow, sharp, and spiking complexes.
Mild global developmental delay
MedGen UID:
861405
Concept ID:
C4012968
Finding
A mild delay in the achievement of motor or mental milestones in the domains of development of a child.
Increased CSF glycine concentration
MedGen UID:
1691638
Concept ID:
C5139615
Finding
Abnormally increased levels of glycine in cerebrospinal fluid.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Non-ketotic hyperglycinemia
MedGen UID:
155625
Concept ID:
C0751748
Disease or Syndrome
Nonketotic hyperglycinemia (NKH) is the inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme system (GCS), which results in accumulation of large quantities of glycine in all body tissues including the brain. Based on ultimate outcome NKH is categorized into severe NKH (no developmental progress and intractable epilepsy) and attenuated NKH (variable developmental progress and treatable or no epilepsy). The majority of children with NKH have onset in the neonatal period manifest as progressive lethargy evolving into profound coma and marked hypotonia; 85% have severe NKH and 15% attenuated NKH. Those with onset between two weeks and three months typically present with hypotonia; 50% have severe NKH and 50% attenuated NKH. Those with onset after age three months have attenuated NKH. Severe versus attenuated NKH is consistent within families, but the degree of developmental progress in those with attenuated NKH can vary.

Professional guidelines

PubMed

Farris J, Calhoun B, Alam MS, Lee S, Haldar K
PLoS Comput Biol 2020 May;16(5):e1007871. Epub 2020 May 18 doi: 10.1371/journal.pcbi.1007871. PMID: 32421718Free PMC Article
Bjoraker KJ, Swanson MA, Coughlin CR 2nd, Christodoulou J, Tan ES, Fergeson M, Dyack S, Ahmad A, Friederich MW, Spector EB, Creadon-Swindell G, Hodge MA, Gaughan S, Burns C, Van Hove JL
J Pediatr 2016 Mar;170:234-9. Epub 2016 Jan 1 doi: 10.1016/j.jpeds.2015.12.027. PMID: 26749113
Boneh A, Allan S, Mendelson D, Spriggs M, Gillam LH, Korman SH
Mol Genet Metab 2008 Jun;94(2):143-7. Epub 2008 Apr 18 doi: 10.1016/j.ymgme.2008.02.010. PMID: 18395481

Recent clinical studies

Etiology

Leyne E, Anselem O, Jordan P, Vivanti AJ, Benachi A, Salomon L, Jacquier M, Jouannic JM, Dhombres F, Cambier T, Rosenblatt J, Pannier E, Goffinet F, Tsatsaris V, Athiel Y
Acta Obstet Gynecol Scand 2024 Jan;103(1):51-58. Epub 2023 Nov 9 doi: 10.1111/aogs.14716. PMID: 37942915Free PMC Article
Kuseyri Hübschmann O, Juliá-Palacios NA, Olivella M, Guder P, Zafeiriou DI, Horvath G, Kulhánek J, Pearson TS, Kuster A, Cortès-Saladelafont E, Ibáñez S, García-Jiménez MC, Honzík T, Santer R, Jeltsch K, Garbade SF, Hoffmann GF, Opladen T, García-Cazorla Á
Ann Neurol 2022 Aug;92(2):292-303. Epub 2022 Jun 16 doi: 10.1002/ana.26423. PMID: 35616651
Baysal-Kirac L, Tuzun E, Altindag E, Ekizoglu E, Kinay D, Bilgic B, Tekturk P, Baykan B
Clin EEG Neurosci 2016 Jul;47(3):224-34. Epub 2015 Aug 2 doi: 10.1177/1550059415595907. PMID: 26240088
Carvajal-González A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, Lang B, Pettingill P, Carr A, Sheerin UM, Press R, Press R, Lunn MP, Lim M, Maddison P, Meinck HM, Vandenberghe W, Vincent A
Brain 2014 Aug;137(Pt 8):2178-92. Epub 2014 Jun 20 doi: 10.1093/brain/awu142. PMID: 24951641Free PMC Article
Kikuchi G, Motokawa Y, Yoshida T, Hiraga K
Proc Jpn Acad Ser B Phys Biol Sci 2008;84(7):246-63. doi: 10.2183/pjab.84.246. PMID: 18941301Free PMC Article

Diagnosis

Leyne E, Anselem O, Jordan P, Vivanti AJ, Benachi A, Salomon L, Jacquier M, Jouannic JM, Dhombres F, Cambier T, Rosenblatt J, Pannier E, Goffinet F, Tsatsaris V, Athiel Y
Acta Obstet Gynecol Scand 2024 Jan;103(1):51-58. Epub 2023 Nov 9 doi: 10.1111/aogs.14716. PMID: 37942915Free PMC Article
Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL
Ann Neurol 2015 Oct;78(4):606-18. Epub 2015 Aug 10 doi: 10.1002/ana.24485. PMID: 26179960Free PMC Article
Ondo WG
Handb Clin Neurol 2011;100:287-91. doi: 10.1016/B978-0-444-52014-2.00021-5. PMID: 21496588
Kure S
Brain Dev 2011 Oct;33(9):753-7. Epub 2011 Apr 5 doi: 10.1016/j.braindev.2011.03.001. PMID: 21470805
Biasioli S, D'Andrea G, Feriani M, Chiaramonte S, Fabris A, Ronco C, La Greca G
Clin Nephrol 1986 Feb;25(2):57-63. PMID: 3516476

Therapy

Shelkowitz E, Saneto RP, Al-Hertani W, Lubout CMA, Stence NV, Brown MS, Long P, Walleigh D, Nelson JA, Perez FE, Shaw DWW, Michl EJ, Van Hove JLK
Orphanet J Rare Dis 2022 Dec 5;17(1):423. doi: 10.1186/s13023-022-02581-6. PMID: 36471344Free PMC Article
Deutsch SI, Rosse RB, Mastropaolo J
Clin Neuropharmacol 1998 Mar-Apr;21(2):71-9. PMID: 9579291
Langan TJ, Pueschel SM
Curr Probl Pediatr 1983 Jan;13(3):1-30. doi: 10.1016/0045-9380(83)90016-6. PMID: 6301756
Mendelson IS
J Ment Defic Res 1982 Jun;26 (Pt 2):107-10. doi: 10.1111/j.1365-2788.1982.tb00134.x. PMID: 6809951
Similä S, von Wendt L, Linna SL, Saukkonen AL, Huhtaniemi I
Neuropadiatrie 1979 May;10(2):158-60. doi: 10.1055/s-0028-1085322. PMID: 386163

Prognosis

Kuseyri Hübschmann O, Juliá-Palacios NA, Olivella M, Guder P, Zafeiriou DI, Horvath G, Kulhánek J, Pearson TS, Kuster A, Cortès-Saladelafont E, Ibáñez S, García-Jiménez MC, Honzík T, Santer R, Jeltsch K, Garbade SF, Hoffmann GF, Opladen T, García-Cazorla Á
Ann Neurol 2022 Aug;92(2):292-303. Epub 2022 Jun 16 doi: 10.1002/ana.26423. PMID: 35616651
Mademont-Soler I, Casellas-Vidal D, Trujillo A, Espuña-Capote N, Maroto A, García-González MDM, Ruiz MD, Diego-Álvarez D, Queralt X, Perapoch J, Obón M
Am J Med Genet A 2021 Feb;185(2):476-485. Epub 2020 Dec 2 doi: 10.1002/ajmg.a.61996. PMID: 33269555
Zekeridou A, McKeon A, Lennon VA
JAMA Neurol 2016 Jul 1;73(7):853-9. doi: 10.1001/jamaneurol.2016.0603. PMID: 27135398
Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL
Ann Neurol 2015 Oct;78(4):606-18. Epub 2015 Aug 10 doi: 10.1002/ana.24485. PMID: 26179960Free PMC Article
Carvajal-González A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, Lang B, Pettingill P, Carr A, Sheerin UM, Press R, Press R, Lunn MP, Lim M, Maddison P, Meinck HM, Vandenberghe W, Vincent A
Brain 2014 Aug;137(Pt 8):2178-92. Epub 2014 Jun 20 doi: 10.1093/brain/awu142. PMID: 24951641Free PMC Article

Clinical prediction guides

Shelkowitz E, Saneto RP, Al-Hertani W, Lubout CMA, Stence NV, Brown MS, Long P, Walleigh D, Nelson JA, Perez FE, Shaw DWW, Michl EJ, Van Hove JLK
Orphanet J Rare Dis 2022 Dec 5;17(1):423. doi: 10.1186/s13023-022-02581-6. PMID: 36471344Free PMC Article
Kuseyri Hübschmann O, Juliá-Palacios NA, Olivella M, Guder P, Zafeiriou DI, Horvath G, Kulhánek J, Pearson TS, Kuster A, Cortès-Saladelafont E, Ibáñez S, García-Jiménez MC, Honzík T, Santer R, Jeltsch K, Garbade SF, Hoffmann GF, Opladen T, García-Cazorla Á
Ann Neurol 2022 Aug;92(2):292-303. Epub 2022 Jun 16 doi: 10.1002/ana.26423. PMID: 35616651
Swanson MA, Coughlin CR Jr, Scharer GH, Szerlong HJ, Bjoraker KJ, Spector EB, Creadon-Swindell G, Mahieu V, Matthijs G, Hennermann JB, Applegarth DA, Toone JR, Tong S, Williams K, Van Hove JL
Ann Neurol 2015 Oct;78(4):606-18. Epub 2015 Aug 10 doi: 10.1002/ana.24485. PMID: 26179960Free PMC Article
Carvajal-González A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, Lang B, Pettingill P, Carr A, Sheerin UM, Press R, Press R, Lunn MP, Lim M, Maddison P, Meinck HM, Vandenberghe W, Vincent A
Brain 2014 Aug;137(Pt 8):2178-92. Epub 2014 Jun 20 doi: 10.1093/brain/awu142. PMID: 24951641Free PMC Article
Hennermann JB, Berger JM, Grieben U, Scharer G, Van Hove JL
J Inherit Metab Dis 2012 Mar;35(2):253-61. Epub 2011 Oct 15 doi: 10.1007/s10545-011-9398-1. PMID: 22002442

Recent systematic reviews

Lora-Tamayo J, Palom X, Sarrá J, Gasch O, Isern V, Fernández de Sevilla A, Pujol R
Clin Lymphoma Myeloma 2008 Dec;8(6):363-9. doi: 10.3816/CLM.2008.n.054. PMID: 19064403

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