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Glutathione synthetase deficiency with 5-oxoprolinuria

MedGen UID:
97988
Concept ID:
C0398746
Disease or Syndrome
Synonyms: 5-Oxoprolinuria; 5-OXOPROLINURIA DUE TO GLUTATHIONE SYNTHETASE DEFICIENCY; Gluthathione synthetase deficiency; PYROGLUTAMIC ACIDURIA; Reduced glutathione synthetase level
SNOMED CT: Deficiency of glutathione synthetase (124706000); Deficiency of glutathione synthase (124706000); Glutathione synthetase deficiency (234589002); Pyroglutamicaciduria (234589002)
 
Gene (location): GSS (20q11.22)
 
HPO: HP:0003343
Monarch Initiative: MONDO:0009947
OMIM®: 266130
Orphanet: ORPHA289846

Definition

5-Oxoprolinuria can be caused by genetic defects in either of 2 enzymes involved in the gamma-glutamyl cycle of glutathione metabolism: glutathione synthetase (GSS) or 5-oxoprolinase (OPLAH; 614243). Glutathione synthetase deficiency (GSSD) is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline (Larsson and Anderson, 2001). See 5-oxoprolinuria due to 5-oxoprolinase deficiency (260005). [from OMIM]

Additional description

From MedlinePlus Genetics
Glutathione synthetase deficiency is a disorder that prevents the production of an important molecule called glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

In addition to the features present in moderate glutathione synthetase deficiency, individuals affected by the severe form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); intellectual disability; and a loss of coordination (ataxia). Some people with severe glutathione synthetase deficiency also develop recurrent bacterial infections.

Glutathione synthetase deficiency can be classified into three types: mild, moderate, and severe. Mild glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). In addition, affected individuals may release large amounts of a compound called 5-oxoproline in their urine (5-oxoprolinuria). This compound builds up when glutathione is not processed correctly in cells.

Individuals with moderate glutathione synthetase deficiency may experience symptoms beginning shortly after birth including hemolytic anemia, 5-oxoprolinuria, and elevated acidity in the blood and tissues (metabolic acidosis).  https://medlineplus.gov/genetics/condition/glutathione-synthetase-deficiency

Clinical features

From HPO
Increased level of L-pyroglutamic acid in urine
MedGen UID:
1641941
Concept ID:
C4703642
Finding
An increase in the level of L-pyroglutamic acid in the urine.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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.
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Psychotic mentation
MedGen UID:
871301
Concept ID:
C4025789
Mental or Behavioral Dysfunction
A pattern of thinking and perceiving characterized by a loss of contact with reality, leading to significant changes in thoughts, perceptions, and behaviors.
Intention tremor
MedGen UID:
1642960
Concept ID:
C4551520
Sign or Symptom
A type of kinetic tremor that occurs during target directed movement is called intention tremor. That is, an oscillatory cerebellar ataxia that tends to be absent when the limbs are inactive and during the first part of voluntary movement but worsening as the movement continues and greater precision is required (e.g., in touching a target such as the patient's nose or a physician's finger).
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Glutathione synthetase deficiency with 5-oxoprolinuria
MedGen UID:
97988
Concept ID:
C0398746
Disease or Syndrome
5-Oxoprolinuria can be caused by genetic defects in either of 2 enzymes involved in the gamma-glutamyl cycle of glutathione metabolism: glutathione synthetase (GSS) or 5-oxoprolinase (OPLAH; 614243). Glutathione synthetase deficiency (GSSD) is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline (Larsson and Anderson, 2001). See 5-oxoprolinuria due to 5-oxoprolinase deficiency (260005).
Chronic metabolic acidosis
MedGen UID:
488930
Concept ID:
C0740749
Disease or Syndrome
Longstanding metabolic acidosis.
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Glutathione synthetase deficiency with 5-oxoprolinuria in Orphanet.

Conditions with this feature

Glutathione synthetase deficiency with 5-oxoprolinuria
MedGen UID:
97988
Concept ID:
C0398746
Disease or Syndrome
5-Oxoprolinuria can be caused by genetic defects in either of 2 enzymes involved in the gamma-glutamyl cycle of glutathione metabolism: glutathione synthetase (GSS) or 5-oxoprolinase (OPLAH; 614243). Glutathione synthetase deficiency (GSSD) is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline (Larsson and Anderson, 2001). See 5-oxoprolinuria due to 5-oxoprolinase deficiency (260005).
Glutathione synthetase deficiency without 5-oxoprolinuria
MedGen UID:
343541
Concept ID:
C1856399
Disease or Syndrome
Two forms of glutathione synthetase deficiency have been described: a mild form, here referred to as congenital nonspherocytic hemolytic anemia-6 (CNSHA6), and a more severe form causing 5-oxoprolinuria with secondary neurologic involvement (266130).

Professional guidelines

PubMed

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
Spielberg SP, Gordon GB
J Clin Invest 1981 Jan;67(1):37-41. doi: 10.1172/JCI110030. PMID: 7451657Free PMC Article

Recent clinical studies

Etiology

Ekuni S, Hirayama K, Nagasaka M, Osumi K, Kondo H, Nakahara E, Shimojima Yamamoto K, Kanno H, Katayama Y
Am J Case Rep 2023 Apr 13;24:e938396. doi: 10.12659/AJCR.938396. PMID: 37050856Free PMC Article
Atwal PS, Medina CR, Burrage LC, Sutton VR
J Hum Genet 2016 Jul;61(7):669-72. Epub 2016 Mar 17 doi: 10.1038/jhg.2016.20. PMID: 26984560Free PMC Article
Njålsson R
Cell Mol Life Sci 2005 Sep;62(17):1938-45. doi: 10.1007/s00018-005-5163-7. PMID: 15990954Free PMC Article
Pejaver RK, Watson AH
J R Soc Med 1994 Mar;87(3):171. doi: 10.1177/014107689408700321. PMID: 8158601Free PMC Article
Spielberg SP, Gordon GB
Clin Pharmacol Ther 1981 Jan;29(1):51-5. doi: 10.1038/clpt.1981.9. PMID: 7460474

Diagnosis

Anklesaria Z, Hunt D, Shah M, Sharpe B, Monash B
J Hosp Med 2017 Mar;12(3):188-192. doi: 10.12788/jhm.2706. PMID: 28272598
Sass JO, Gemperle-Britschgi C, Tarailo-Graovac M, Patel N, Walter M, Jordanova A, Alfadhel M, Barić I, Çoker M, Damli-Huber A, Faqeih EA, García Segarra N, Geraghty MT, Jåtun BM, Kalkan Uçar S, Kriewitz M, Rauchenzauner M, Bilić K, Tournev I, Till C, Sayson B, Beumer D, Ye CX, Zhang LH, Vallance H, Alkuraya FS, van Karnebeek CD
Mol Genet Metab 2016 Sep;119(1-2):44-9. Epub 2016 Jul 22 doi: 10.1016/j.ymgme.2016.07.008. PMID: 27477828
Li X, Ding Y, Liu Y, Ma Y, Song J, Wang Q, Yang Y
Brain Dev 2015 Nov;37(10):952-9. Epub 2015 Apr 4 doi: 10.1016/j.braindev.2015.03.005. PMID: 25851806
Ristoff E, Larsson A
Orphanet J Rare Dis 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. PMID: 17397529Free PMC Article
Njålsson R
Cell Mol Life Sci 2005 Sep;62(17):1938-45. doi: 10.1007/s00018-005-5163-7. PMID: 15990954Free PMC Article

Therapy

Lanoy C, Bouckaert Y
J Med Case Rep 2016 Jun 23;10(1):184. doi: 10.1186/s13256-016-0964-x. PMID: 27339215Free PMC Article
Hulley SL, Perring J, Manning N, Olpin S, Yap S
Eur J Pediatr 2015 Dec;174(12):1685-8. Epub 2015 Jul 1 doi: 10.1007/s00431-015-2585-6. PMID: 26122794
Pereda C, Weppner WG, Balinger A, Goldberger ZD, Baudendistel TE
J Hosp Med 2015 Aug;10(8):547-50. Epub 2015 May 27 doi: 10.1002/jhm.2387. PMID: 26018494
Liss DB, Paden MS, Schwarz ES, Mullins ME
Clin Toxicol (Phila) 2013 Nov;51(9):817-27. Epub 2013 Oct 11 doi: 10.3109/15563650.2013.844822. PMID: 24111553
Larsson A, Wachtmeister L, von Wendt L, Andersson R, Hagenfeldt L, Herrin KM
Neuropediatrics 1985 Aug;16(3):131-6. doi: 10.1055/s-2008-1052557. PMID: 4047346

Prognosis

Ekuni S, Hirayama K, Nagasaka M, Osumi K, Kondo H, Nakahara E, Shimojima Yamamoto K, Kanno H, Katayama Y
Am J Case Rep 2023 Apr 13;24:e938396. doi: 10.12659/AJCR.938396. PMID: 37050856Free PMC Article
Xia H, Ye J, Wang L, Zhu J, He Z
Braz J Med Biol Res 2018 Jan 11;51(3):e6853. doi: 10.1590/1414-431X20176853. PMID: 29340523Free PMC Article
Atwal PS, Medina CR, Burrage LC, Sutton VR
J Hum Genet 2016 Jul;61(7):669-72. Epub 2016 Mar 17 doi: 10.1038/jhg.2016.20. PMID: 26984560Free PMC Article
Ben Ameur S, Aloulou H, Nasrallah F, Kamoun T, Kaabachi N, Hachicha M
Fetal Pediatr Pathol 2015 Feb;34(1):18-20. Epub 2014 Aug 28 doi: 10.3109/15513815.2014.947543. PMID: 25166299
Ristoff E, Larsson A
Orphanet J Rare Dis 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. PMID: 17397529Free PMC Article

Clinical prediction guides

Soylu Ustkoyuncu P, Mutlu FT, Kiraz A, Tag Balkis Z, Yel S
J Pediatr Hematol Oncol 2018 Jan;40(1):e45-e49. doi: 10.1097/MPH.0000000000000811. PMID: 28267090
Liss DB, Paden MS, Schwarz ES, Mullins ME
Clin Toxicol (Phila) 2013 Nov;51(9):817-27. Epub 2013 Oct 11 doi: 10.3109/15563650.2013.844822. PMID: 24111553
Ristoff E, Larsson A
Orphanet J Rare Dis 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. PMID: 17397529Free 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
Spielberg SP, Boxer LA, Oliver JM, Allen JM, Schulman JD
Br J Haematol 1979 Jun;42(2):215-23. doi: 10.1111/j.1365-2141.1979.tb01126.x. PMID: 465367

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