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Non-ketotic hyperglycinemia(GCE)

MedGen UID:
155625
Concept ID:
C0751748
Disease or Syndrome
Synonyms: AMT-Related Glycine Encephalopathy; GCE; 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
Sources: HPO, OMIM, 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).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Genes (locations): AMT (3p21.31); GCSH (16q23.2); GLDC (9p24.1)
 
HPO: HP:0008288
Monarch Initiative: MONDO:0011612
OMIM®: 605899
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 GHR
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://ghr.nlm.nih.gov/condition/nonketotic-hyperglycinemia

Clinical features

From HPO
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
A verbal or physical act of hostility.
Impulsivity
MedGen UID:
43850
Concept ID:
C0021125
Mental or Behavioral Dysfunction
Acting on the spur of the moment in response to immediate stimuli; acting on a momentary basis without a plan or consideration of outcomes; difficulty establishing or following plans; a sense of urgency and self-harming behavior under emotional distress.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to DEPRESSION or DRUG ADDICTION.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Hyperglycinemia
MedGen UID:
82817
Concept ID:
C0268559
Disease or Syndrome
An elevated concentration of glycine in the blood.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a state of constantly being unusually or abnormally active, including in situations in which it is not appropriate.
Hyperglycinuria
MedGen UID:
107456
Concept ID:
C0543541
Disease or Syndrome
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Recurrent singultus
MedGen UID:
893074
Concept ID:
C0744897
Finding
A contraction of the diaphragm that repeats several times per minute. In humans, the abrupt rush of air into the lungs causes the epiglottis to close, creating a hic sound. Also known as synchronous diaphragmatic flutter (SDF), or singultus, from the Latin singult, the act of catching one's breath while sobbing. The hiccup is an involuntary action involving a reflex arc.
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Encephalopathy
MedGen UID:
368408
Concept ID:
C1963101
Finding
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
Feelings of annoyance, impatience, and anger.
Restlessness
MedGen UID:
854457
Concept ID:
C3887611
Sign or Symptom
A state of unease characterized by diffuse motor activity or motion subject to limited control, nonproductive or disorganized behavior, and subjective distress.

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

Deficiency of glycerate kinase
MedGen UID:
226941
Concept ID:
C1291386
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).

Recent clinical studies

Etiology

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
Okamura-Ikeda K, Hosaka H, Yoshimura M, Yamashita E, Toma S, Nakagawa A, Fujiwara K, Motokawa Y, Taniguchi H
J Mol Biol 2005 Sep 2;351(5):1146-59. doi: 10.1016/j.jmb.2005.06.056. PMID: 16051266
Kaźmierczuk-Skubis ME, Zatorska-Karpuś M, Pac-Kozuchowska E, Bojko-Jaworska J, Furmaga-Jabłońska W
Ann Univ Mariae Curie Sklodowska Med 2004;59(1):237-41. PMID: 16145987
Korman SH, Gutman A
Dev Med Child Neurol 2002 Oct;44(10):712-20. doi: 10.1017/s0012162201002808. PMID: 12418798

Diagnosis

Gazeteci-Tekin H, Demir M, Aktan G, Tekgül H, Gökben S
Turk J Pediatr 2019;61(4):599-603. doi: 10.24953/turkjped.2019.04.019. PMID: 31990480
Kose E, Yis U, Hiz S, Arslan N
Neurosciences (Riyadh) 2017 Apr;22(2):131-133. doi: 10.17712/nsj.2017.2.20160468. PMID: 28416785Free 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
Terek D, Koroglu OA, Gunes S, Yalaz M, Akisu M, Uçar SK, Gokben S, Coker M, Kultursay N
Pediatr Int 2012 Oct;54(5):717-20. doi: 10.1111/j.1442-200X.2012.03591.x. PMID: 23005907
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

Therapy

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
Korman SH, Gutman A
Dev Med Child Neurol 2002 Oct;44(10):712-20. doi: 10.1017/s0012162201002808. PMID: 12418798
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
Koepp P, de Groot CJ, Grüttner R, Rybak C
Helv Paediatr Acta 1973 Nov;28(5):459-65. PMID: 4773226

Prognosis

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
Alfadhel M, Nashabat M, Qahtani HA, Alfares A, Mutairi FA, Shaalan HA, Douglas GV, Wierenga K, Juusola J, Alrifai MT, Arold ST, Alkuraya F, Ali QA
Hum Genet 2016 Nov;135(11):1263-1268. Epub 2016 Aug 1 doi: 10.1007/s00439-016-1719-x. PMID: 27481395Free 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
Kaźmierczuk-Skubis ME, Zatorska-Karpuś M, Pac-Kozuchowska E, Bojko-Jaworska J, Furmaga-Jabłońska W
Ann Univ Mariae Curie Sklodowska Med 2004;59(1):237-41. PMID: 16145987
Paupe A, Bidat L, Sonigo P, Lenclen R, Molho M, Ville Y
Ultrasound Obstet Gynecol 2002 Dec;20(6):616-9. doi: 10.1046/j.1469-0705.2002.00869.x. PMID: 12493053

Clinical prediction guides

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
Khraim W, Abu-Libdeh B, Ayesh S, Dweikat I
Brain Dev 2017 Aug;39(7):601-605. Epub 2017 Mar 18 doi: 10.1016/j.braindev.2017.03.005. PMID: 28325525
Alfadhel M, Nashabat M, Qahtani HA, Alfares A, Mutairi FA, Shaalan HA, Douglas GV, Wierenga K, Juusola J, Alrifai MT, Arold ST, Alkuraya F, Ali QA
Hum Genet 2016 Nov;135(11):1263-1268. Epub 2016 Aug 1 doi: 10.1007/s00439-016-1719-x. PMID: 27481395Free PMC Article
Holmgren G, son Blomquist HK
Neuropadiatrie 1977 Feb;8(1):67-72. doi: 10.1055/s-0028-1091506. PMID: 576734
Geison RL, Rowley BO, Gerritsen T
Clin Chim Acta 1975 Apr 16;60(2):137-42. doi: 10.1016/0009-8981(75)90118-7. PMID: 1126035

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