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Gamma-glutamylcysteine synthetase deficiency(CNSHA7)

MedGen UID:
347272
Concept ID:
C1856603
Disease or Syndrome
Synonyms: ANEMIA, CONGENITAL, NONSPHEROCYTIC HEMOLYTIC, 7; CNSHA7; Gamma-glutamylcysteine synthetase deficiency, hemolytic anemia due to
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).
 
Gene (location): GCLC (6p12.1)
 
Monarch Initiative: MONDO:0009259
OMIM®: 230450
Orphanet: ORPHA33574

Definition

Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other 3 disorders are glutathione synthetase deficiency (231900), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (266130), and gamma-glutamyl transpeptidase deficiency (231950). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (Larsson and Anderson, 2001). Some patients with CNSHA7 may develop progressive neurologic abnormalities, including ataxic gait, speech impairment, and spinocerebellar degeneration (Konrad et al., 1972). The hemolytic anemia caused by mutation in the GCLC gene is here designated congenital nonspherocytic hemolytic anemia-7 (CNSHA7). [from OMIM]

Clinical features

From HPO
Elevated urinary gamma-glutamylcysteine level
MedGen UID:
1053964
Concept ID:
CN377982
Finding
The amount of gamma-glutamylcysteine in the urine, normalized for urine concentration, is above the upper limit of normal.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A generalized disorder of peripheral nerves.
Late-onset spinocerebellar degeneration
MedGen UID:
347273
Concept ID:
C1856604
Finding
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Reticulocytosis
MedGen UID:
60089
Concept ID:
C0206160
Finding
An elevation in the number of reticulocytes (immature erythrocytes) in the peripheral blood circulation.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Increased circulating lactate dehydrogenase concentration
MedGen UID:
1377250
Concept ID:
C4477095
Finding
An elevated level of the enzyme lactate dehydrogenase in the blood circulation.
Reduced erythrocyte gamma-glutamyl cysteine synthetase activity
MedGen UID:
1052439
Concept ID:
CN376641
Finding
Activity of gamma-glutamylcysteine synthetase (EC 6.3.2.2) in erythrocytes below the lower limit of normal.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVGamma-glutamylcysteine synthetase deficiency
Follow this link to review classifications for Gamma-glutamylcysteine synthetase deficiency in Orphanet.

Professional guidelines

PubMed

Rom O, Liu Y, Finney AC, Ghrayeb A, Zhao Y, Shukha Y, Wang L, Rajanayake KK, Das S, Rashdan NA, Weissman N, Delgadillo L, Wen B, Garcia-Barrio MT, Aviram M, Kevil CG, Yurdagul A Jr, Pattillo CB, Zhang J, Sun D, Hayek T, Gottlieb E, Mor I, Chen YE
Redox Biol 2022 Jun;52:102313. Epub 2022 Apr 13 doi: 10.1016/j.redox.2022.102313. PMID: 35447412Free PMC Article
Njålsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S
Hum Genet 2005 Apr;116(5):384-9. Epub 2005 Feb 17 doi: 10.1007/s00439-005-1255-6. PMID: 15717202

Recent clinical studies

Diagnosis

Mañú Pereira M, Gelbart T, Ristoff E, Crain KC, Bergua JM, López Lafuente A, Kalko SG, García Mateos E, Beutler E, Vives Corrons JL
Haematologica 2007 Nov;92(11):e102-5. doi: 10.3324/haematol.11238. PMID: 18024385
Ristoff E, Larsson A
Orphanet J Rare Dis 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. PMID: 17397529Free PMC Article

Prognosis

Mañú Pereira M, Gelbart T, Ristoff E, Crain KC, Bergua JM, López Lafuente A, Kalko SG, García Mateos E, Beutler E, Vives Corrons JL
Haematologica 2007 Nov;92(11):e102-5. doi: 10.3324/haematol.11238. PMID: 18024385
Ristoff E, Larsson A
Orphanet J Rare Dis 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. PMID: 17397529Free PMC Article
Beutler E, Gelbart T, Kondo T, Matsunaga AT
Blood 1999 Oct 15;94(8):2890-4. PMID: 10515893

Clinical prediction guides

Mañú Pereira M, Gelbart T, Ristoff E, Crain KC, Bergua JM, López Lafuente A, Kalko SG, García Mateos E, Beutler E, Vives Corrons JL
Haematologica 2007 Nov;92(11):e102-5. doi: 10.3324/haematol.11238. PMID: 18024385
Ristoff E, Larsson A
Orphanet J Rare Dis 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. PMID: 17397529Free PMC Article

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