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Argininosuccinate lyase deficiency

MedGen UID:
78687
Concept ID:
C0268547
Disease or Syndrome
Synonyms: Arginino succinase deficiency; Argininosuccinate acidemia; Argininosuccinic acid lyase deficiency; Argininosuccinic Aciduria; ASA deficiency; ASL deficiency; Inborn error of urea synthesis, arginino succinic type; Urea cycle disorder, arginino succinase type
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).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Deficiency of argininosuccinate lyase (41013004); Argininosuccinate lyase deficiency (41013004); Argininosuccinic aciduria (41013004); ASAL deficiency (41013004); ASL deficiency (41013004)
 
Gene (location): ASL (7q11.21)
OMIM®: 207900
Orphanet: ORPHA23

Definition

Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, is characterized by a severe neonatal onset form and a late onset form. The severe neonatal onset form, which is indistinguishable from that of other urea cycle disorders, is characterized by hyperammonemia within the first few days after birth accompanied by vomiting, lethargy, hypothermia, and poor feeding. In the absence of treatment, lethargy, seizures, and coma worsen, resulting in death. In contrast, the late onset form ranges from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency that appear to be unrelated to the severity or duration of hyperammonemic episodes include: (1) neurocognitive deficiencies (attention deficit hyperactivity disorder [ADHD], developmental disability, seizures, and learning disability); (2) liver disease (hepatitis, cirrhosis); (3) trichorrhexis nodosa (coarse brittle hair that breaks easily); and (4) systemic hypertension. [from GeneReviews]

Additional descriptions

From OMIM
Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency (237300), argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency, and arginase deficiency (207800). Erez (2013) reviewed argininosuccinic aciduria and progress in understanding it as a monogenic disorder that, like other inborn errors of metabolism, manifests as a multifactorial disorder at the phenotypic level.  http://www.omim.org/entry/207900
From GHR
Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with argininosuccinic aciduria may be lacking in energy (lethargic) or unwilling to eat, and have poorly controlled breathing rate or body temperature. Some babies with this disorder experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and intellectual disability. Progressive liver damage, skin lesions, and brittle hair may also be seen.Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the bloodstream only during periods of illness or other stress.  https://ghr.nlm.nih.gov/condition/argininosuccinic-aciduria

Clinical features

Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Protein avoidance
MedGen UID:
326521
Concept ID:
C1839531
Finding
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Hyperammonaemia
MedGen UID:
113136
Concept ID:
C0220994
Pathologic Function
Elevated level of AMMONIA in the blood. It is a sign of defective CATABOLISM of AMINO ACIDS or ammonia to UREA.
Episodic ammonia intoxication
MedGen UID:
333343
Concept ID:
C1839541
Finding

Recent clinical studies

Etiology

Nagamani SC, Erez A, Lee B
Genet Med 2012 May;14(5):501-7. Epub 2012 Jan 5 doi: 10.1038/gim.2011.1. PMID: 22241104Free PMC Article
Erez A, Nagamani SC, Lee B
Am J Med Genet C Semin Med Genet 2011 Feb 15;157C(1):45-53. Epub 2011 Feb 10 doi: 10.1002/ajmg.c.30289. PMID: 21312326Free PMC Article
Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter S, Muehl A, Stöckler-Ipsiroglu S
Mol Genet Metab 2010 May;100(1):24-8. Epub 2010 Feb 4 doi: 10.1016/j.ymgme.2010.01.013. PMID: 20236848
Ficicioglu C, Mandell R, Shih VE
Mol Genet Metab 2009 Nov;98(3):273-7. Epub 2009 Jun 25 doi: 10.1016/j.ymgme.2009.06.011. PMID: 19635676Free PMC Article
Mori T, Nagai K, Mori M, Nagao M, Imamura M, Iijima M, Kobayashi K
Pediatr Dev Pathol 2002 Nov-Dec;5(6):597-601. Epub 2002 Oct 10 doi: 10.1007/s10024-002-0109-7. PMID: 12370774

Diagnosis

Nagamani SC, Erez A, Lee B
Genet Med 2012 May;14(5):501-7. Epub 2012 Jan 5 doi: 10.1038/gim.2011.1. PMID: 22241104Free PMC Article
Erez A, Nagamani SC, Lee B
Am J Med Genet C Semin Med Genet 2011 Feb 15;157C(1):45-53. Epub 2011 Feb 10 doi: 10.1002/ajmg.c.30289. PMID: 21312326Free PMC Article
Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter S, Muehl A, Stöckler-Ipsiroglu S
Mol Genet Metab 2010 May;100(1):24-8. Epub 2010 Feb 4 doi: 10.1016/j.ymgme.2010.01.013. PMID: 20236848
Ficicioglu C, Mandell R, Shih VE
Mol Genet Metab 2009 Nov;98(3):273-7. Epub 2009 Jun 25 doi: 10.1016/j.ymgme.2009.06.011. PMID: 19635676Free PMC Article
Arndt T, Gressner A, Herwig J, Meier U, Sewell AC
Clin Chim Acta 2006 Nov;373(1-2):117-20. Epub 2006 May 19 doi: 10.1016/j.cca.2006.05.015. PMID: 16808909

Therapy

Nagamani SC, Erez A, Lee B
Genet Med 2012 May;14(5):501-7. Epub 2012 Jan 5 doi: 10.1038/gim.2011.1. PMID: 22241104Free PMC Article
Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter S, Muehl A, Stöckler-Ipsiroglu S
Mol Genet Metab 2010 May;100(1):24-8. Epub 2010 Feb 4 doi: 10.1016/j.ymgme.2010.01.013. PMID: 20236848
Mori T, Nagai K, Mori M, Nagao M, Imamura M, Iijima M, Kobayashi K
Pediatr Dev Pathol 2002 Nov-Dec;5(6):597-601. Epub 2002 Oct 10 doi: 10.1007/s10024-002-0109-7. PMID: 12370774
Linnebank M, Homberger A, Rapp B, Winter C, Marquardt T, Harms E, Koch HG
J Inherit Metab Dis 2000 Jun;23(4):308-12. PMID: 10896281
Renner C, Sewell AC, Bervoets K, Förster H, Böhles H
Eur J Pediatr 1995 Nov;154(11):909-14. PMID: 8582405

Prognosis

Balmer C, Pandey AV, Rüfenacht V, Nuoffer JM, Fang P, Wong LJ, Häberle J
Hum Mutat 2014 Jan;35(1):27-35. Epub 2013 Nov 25 doi: 10.1002/humu.22469. PMID: 24166829
Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter S, Muehl A, Stöckler-Ipsiroglu S
Mol Genet Metab 2010 May;100(1):24-8. Epub 2010 Feb 4 doi: 10.1016/j.ymgme.2010.01.013. PMID: 20236848
Ficicioglu C, Mandell R, Shih VE
Mol Genet Metab 2009 Nov;98(3):273-7. Epub 2009 Jun 25 doi: 10.1016/j.ymgme.2009.06.011. PMID: 19635676Free PMC Article
Trevisson E, Salviati L, Baldoin MC, Toldo I, Casarin A, Sacconi S, Cesaro L, Basso G, Burlina AB
Hum Mutat 2007 Jul;28(7):694-702. doi: 10.1002/humu.20498. PMID: 17326097
Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, Simola KO, Arslan-Kirchner M, Battini R, Briones P, Cardo E, Mandel H, Tschiedel E, Wanders RJ, Koch HG
J Inherit Metab Dis 2002 Sep;25(5):399-410. PMID: 12408190

Clinical prediction guides

Smith W, Diaz GA, Lichter-Konecki U, Berry SA, Harding CO, McCandless SE, LeMons C, Mauney J, Dickinson K, Coakley DF, Moors T, Mokhtarani M, Scharschmidt BF, Lee B
J Pediatr 2013 Jun;162(6):1228-34, 1234.e1. Epub 2013 Jan 13 doi: 10.1016/j.jpeds.2012.11.084. PMID: 23324524Free PMC Article
Trevisson E, Salviati L, Baldoin MC, Toldo I, Casarin A, Sacconi S, Cesaro L, Basso G, Burlina AB
Hum Mutat 2007 Jul;28(7):694-702. doi: 10.1002/humu.20498. PMID: 17326097
Lee B, Yu H, Jahoor F, O'Brien W, Beaudet AL, Reeds P
Proc Natl Acad Sci U S A 2000 Jul 5;97(14):8021-6. doi: 10.1073/pnas.140082197. PMID: 10869432Free PMC Article
Renner C, Sewell AC, Bervoets K, Förster H, Böhles H
Eur J Pediatr 1995 Nov;154(11):909-14. PMID: 8582405
McInnes RR, Shih V, Chilton S
Proc Natl Acad Sci U S A 1984 Jul;81(14):4480-4. PMID: 6589607Free PMC Article

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