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Non-ketotic hyperglycinemia(GCE)

MedGen UID:
155625
Concept ID:
C0751748
Disease or Syndrome
Synonyms: AMT-Related Glycine Encephalopathy; GCE; GCSH-Related Glycine Encephalopathy; GLDC-Related Glycine Encephalopathy; Glycine encephalopathy; Nonketotic hyperglycinemia
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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Non ketotic hyperglycinemia (237939006); Disorder of glycine cleavage enzyme complex (237939006); NKH - Non-ketotic hyperglycinemia (237939006); Non-ketotic hyperglycinemia (237939006)
 
Genes (locations): AMT (3p21.31); GCSH (16q23.2); GLDC (9p24.1)
OMIM®: 605899
HPO: HP:0008288
Orphanet: ORPHA407

Disease characteristics

Excerpted from the GeneReview: Glycine Encephalopathy
Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme and, as a consequence, accumulation of large quantities of glycine in all body tissues including the brain. The majority of glycine encephalopathy presents in the neonatal period (85% as the neonatal severe form and 15% as the neonatal attenuated form). Of those presenting in infancy, 50% have the infantile attenuated form and 50% have the infantile severe form. Overall, 20% of all children presenting as either neonates or infants have a less severe outcome, defined as developmental quotient greater than 20. A minority of patients have mild or atypical forms of glycine encephalopathy. The neonatal form manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have profound intellectual disability and intractable seizures. The infantile form is characterized by hypotonia, developmental delay, and seizures. The atypical forms range from milder disease, with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset. [from GeneReviews]
Authors:
Johan Van Hove  |  Curtis Coughlin  |  Gunter Scharer   view full author information

Additional description

From GHR
Glycine encephalopathy, which is also known as nonketotic hyperglycinemia or NKH, is a genetic disorder characterized by abnormally high levels of a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Glycine encephalopathy is caused by the shortage of an enzyme that normally breaks down glycine in the body. A lack of this enzyme allows excess glycine to build up in tissues and organs, particularly the brain, leading to serious medical problems.The most common form of glycine encephalopathy, called the classical type, appears shortly after birth. Affected infants experience a progressive lack of energy (lethargy), feeding difficulties, weak muscle tone (hypotonia), abnormal jerking movements, and life-threatening problems with breathing. Most children who survive these early signs and symptoms develop profound intellectual disability and seizures that are difficult to treat. For unknown reasons, affected males are more likely to survive and have less severe developmental problems than affected females.Researchers have identified several other types of glycine encephalopathy with variable signs and symptoms. The most common of these atypical types is called the infantile form. Children with this condition develop normally until they are about 6 months old, when they experience delayed development and may begin having seizures. As they get older, many develop intellectual disability, abnormal movements, and behavioral problems. Other atypical types of glycine encephalopathy appear later in childhood or adulthood and cause a variety of medical problems that primarily affect the nervous system.Rarely, the characteristic features of classical glycine encephalopathy improve with time. These cases are classified as transient glycine encephalopathy. In this form of the condition, glycine levels decrease to normal or near-normal after being very high at birth. Many children with temporarily high glycine levels go on to develop normally and experience few long-term medical problems. Intellectual disability and seizures occur in some affected individuals, however, even after glycine levels decrease.  https://ghr.nlm.nih.gov/condition/glycine-encephalopathy

Clinical features

Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
A verbal or physical act of hostility.
Recurrent singultus
MedGen UID:
6835
Concept ID:
C0019521
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.
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
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
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
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
Increased motor activity that is not goal directed.
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).
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
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. PMID: 12418798

Diagnosis

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
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. PMID: 12493053

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. 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. 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. PMID: 1126035

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