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Non-ketotic hyperglycinemia(NKH; GCE1)

MedGen UID:
155625
Concept ID:
C0751748
Disease or Syndrome
Synonyms: AMT-Related Glycine Encephalopathy; GLDC-Related Glycine Encephalopathy; Glycine encephalopathy; Nonketotic hyperglycinemia
SNOMED CT: Non ketotic hyperglycinemia (237939006); Disorder of glycine cleavage enzyme complex (237939006); NKH - Non-ketotic hyperglycinemia (237939006); Non-ketotic hyperglycinemia (237939006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Genes (locations): AMT (3p21.31); GLDC (9p24.1)
 
HPO: HP:0008288
Monarch Initiative: MONDO:0011612
OMIM®: 238300; 605899
OMIM® Phenotypic series: PS605899
Orphanet: ORPHA407

Disease characteristics

Excerpted from the GeneReview: Nonketotic Hyperglycinemia
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. [from GeneReviews]
Authors:
Johan LK Van Hove  |  Curtis Coughlin  |  Michael Swanson, et. al.   view full author information

Additional description

From MedlinePlus Genetics
Nonketotic hyperglycinemia is a disorder characterized by abnormally high levels of a molecule called glycine in the body (hyperglycinemia). The excess glycine builds up in tissues and organs, particularly the brain. Affected individuals have serious neurological problems.

Nonketotic hyperglycinemia has two forms, the severe form and the attenuated form. Both forms usually begin shortly after birth, although in some cases, signs and symptoms can begin in the first few months of life. Only the attenuated form begins later in infancy. The forms are distinguished by the seriousness of the signs and symptoms. Severe nonketotic hyperglycinemia is more common. Affected babies experience extreme sleepiness (lethargy) that worsens over time and can lead to coma. They can also have weak muscle tone (hypotonia) and life-threatening breathing problems in the first days or weeks of life. Most children who survive these early signs and symptoms develop feeding difficulties, abnormal muscle stiffness (spasticity), profound intellectual disability and seizures that are difficult to control. Most affected children do not achieve normal developmental milestones, such as drinking from a bottle, sitting up, or grabbing objects, and they may lose any acquired skills over time.

The signs and symptoms of the attenuated form of nonketotic hyperglycinemia are similar to, but milder than, those of the severe form of the condition. Children with attenuated nonketotic hyperglycinemia typically reach developmental milestones, although the skills they achieve vary widely. Despite delayed development, many affected children eventually learn to walk and are able to interact with others, often using sign language. Some affected children develop seizures; if present, seizures are usually mild and can be treated. Other features can include spasticity, involuntary jerking movements (chorea), or hyperactivity.

Individuals with nonketotic hyperglycinemia can also have certain changes in the brain, which can be seen using magnetic resonance imaging (MRI). For example, in children with the severe form of the condition, the tissue that connects the left and right halves of the brain (the corpus callosum) is smaller than average.  https://medlineplus.gov/genetics/condition/nonketotic-hyperglycinemia

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVNon-ketotic hyperglycinemia
Follow this link to review classifications for Non-ketotic hyperglycinemia in Orphanet.

Conditions with this feature

D-Glyceric aciduria
MedGen UID:
452447
Concept ID:
C0342765
Disease or Syndrome
D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).
Glycine encephalopathy 2
MedGen UID:
1841195
Concept ID:
C5830559
Disease or Syndrome
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).

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
Appavu B, Vanatta L, Condie J, Kerrigan JF, Jarrar R
Seizure 2016 Oct;41:62-5. Epub 2016 Jul 21 doi: 10.1016/j.seizure.2016.07.006. PMID: 27475280
Tan ES, Wiley V, Carpenter K, Wilcken B
Mol Genet Metab 2007 Apr;90(4):446-8. Epub 2007 Jan 4 doi: 10.1016/j.ymgme.2006.11.010. PMID: 17207649

Recent clinical studies

Therapy

Van Hirtum LDFM, Van Damme T, Van Hove JLK, Steyaert JG
Orphanet J Rare Dis 2024 Apr 8;19(1):150. doi: 10.1186/s13023-024-03172-3. PMID: 38589924Free PMC Article
Scholl-Bürgi S, Höller A, Pichler K, Michel M, Haberlandt E, Karall D
J Inherit Metab Dis 2015 Jul;38(4):765-73. Epub 2015 Jun 25 doi: 10.1007/s10545-015-9872-2. PMID: 26109259
Cusmai R, Martinelli D, Moavero R, Dionisi Vici C, Vigevano F, Castana C, Elia M, Bernabei S, Bevivino E
Eur J Paediatr Neurol 2012 Sep;16(5):509-13. Epub 2012 Jan 18 doi: 10.1016/j.ejpn.2011.12.015. PMID: 22261077
Kamate M, Mahantshetti N, Chetal V
Indian Pediatr 2009 Sep;46(9):804-6. PMID: 19812426
Van Hove JL, Kishnani P, Muenzer J, Wenstrup RJ, Summar ML, Brummond MR, Lachiewicz AM, Millington DS, Kahler SG
Am J Med Genet 1995 Dec 4;59(4):444-53. doi: 10.1002/ajmg.1320590410. PMID: 8585564

Prognosis

Sankaran BP, Gupta S, Tchan M, Devanapalli B, Rahman Y, Procopis P, Bhattacharya K
Orphanet J Rare Dis 2021 Nov 3;16(1):465. doi: 10.1186/s13023-021-02073-z. PMID: 34732213Free PMC Article
Farris J, Alam MS, Rajashekara AM, Haldar K
PLoS Genet 2021 Feb;17(2):e1009307. Epub 2021 Feb 1 doi: 10.1371/journal.pgen.1009307. PMID: 33524012Free PMC Article
Lin Y, Zheng Z, Sun W, Fu Q
BMC Med Genet 2018 Jan 5;19(1):5. doi: 10.1186/s12881-017-0517-1. PMID: 29304759Free PMC Article
Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR 2nd, Spector E, Wempe MF, Van Hove JL
Brain 2014 Feb;137(Pt 2):366-79. Epub 2013 Dec 11 doi: 10.1093/brain/awt328. PMID: 24334290Free PMC Article
Dalla Bernardina B, Dulac O, Fejerman N, Dravet C, Capovilla G, Bondavalli S, Colamaria V, Roger J
Eur J Pediatr 1983 Jun-Jul;140(3):248-52. doi: 10.1007/BF00443371. PMID: 6414818

Clinical prediction guides

Van Hirtum LDFM, Van Damme T, Van Hove JLK, Steyaert JG
Orphanet J Rare Dis 2024 Apr 8;19(1):150. doi: 10.1186/s13023-024-03172-3. PMID: 38589924Free PMC Article
Sankaran BP, Gupta S, Tchan M, Devanapalli B, Rahman Y, Procopis P, Bhattacharya K
Orphanet J Rare Dis 2021 Nov 3;16(1):465. doi: 10.1186/s13023-021-02073-z. PMID: 34732213Free PMC Article
Kisa PT, Uzun OU, Gunduz M, Bulbul FS, Kose E, Arslan N
Arch Pediatr 2021 Nov;28(8):702-706. Epub 2021 Oct 5 doi: 10.1016/j.arcped.2021.09.008. PMID: 34620546
Lin Y, Zheng Z, Sun W, Fu Q
BMC Med Genet 2018 Jan 5;19(1):5. doi: 10.1186/s12881-017-0517-1. PMID: 29304759Free PMC Article
Dalla Bernardina B, Dulac O, Fejerman N, Dravet C, Capovilla G, Bondavalli S, Colamaria V, Roger J
Eur J Pediatr 1983 Jun-Jul;140(3):248-52. doi: 10.1007/BF00443371. PMID: 6414818

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