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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
SNOMED CT: Deficiency of argininosuccinate lyase (41013004); ASL-gene related argininosuccinate lyase deficiency (41013004); Argininosuccinate lyase deficiency (41013004); Argininosuccinic aciduria (41013004); ASAL deficiency (41013004); ASL deficiency (41013004)
Modes of inheritance:
 
ASL (7q11.21)
 
HPO: HP:0025630
Monarch Initiative: MONDO:0008815
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, may present as a severe neonatal-onset form or a late-onset form: The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. In contrast, the manifestations of late-onset form range 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: Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability). Liver disease (hepatitis, cirrhosis). Trichorrhexis nodosa (coarse brittle hair that breaks easily). 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 MedlinePlus Genetics
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 a 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, high blood pressure (hypertension), skin lesions, and brittle hair may also be seen.

Occasionally, individuals may inherit a mild form of the disorder. These individuals can have an accumulation of ammonia in the bloodstream only during periods of illness or other stress, or mild intellectual disability or learning disabilities with no evidence of elevated ammonia levels.  https://medlineplus.gov/genetics/condition/argininosuccinic-aciduria

Clinical features

From HPO

Conditions with this feature

Professional guidelines

PubMed

Siri B, Olivieri G, Angeloni A, Cairoli S, Carducci C, Cotugno G, Di Michele S, Giovanniello T, La Marca G, Lepri FR, Novelli A, Rossi C, Semeraro M, Dionisi-Vici C
Mol Genet Metab 2022 Apr;135(4):327-332. Epub 2022 Feb 20 doi: 10.1016/j.ymgme.2022.02.008. PMID: 35279366
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
Sander J, Janzen N, Sander S, Steuerwald U, Das AM, Scholl S, Trefz FK, Koch HG, Häberle J, Korall H, Marquardt I, Korenke C
Eur J Pediatr 2003 Jun;162(6):417-20. Epub 2003 Apr 8 doi: 10.1007/s00431-003-1177-z. PMID: 12684898

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Elevated Citrulline], Amino Acidemia/Urea Cycle Disorder, 2022

American College of Medical Genetics and Genomics, Elevated Citrulline: Amino Acidemia Algorithm, 2022

American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Argininosuccinic Acidemia, [Urea Cycle Disorder], 2012

Recent clinical studies

Etiology

Kho J, Polak U, Jiang MM, Odom JD, Hunter JV, Ali SM, Burrage LC, Nagamani SC, Pautler RG, Thompson HP, Urayama A, Jin Z, Lee B
JCI Insight 2023 Sep 8;8(17) doi: 10.1172/jci.insight.168475. PMID: 37490345Free PMC Article
Burrage LC, Madan S, Li X, Ali S, Mohammad M, Stroup BM, Jiang MM, Cela R, Bertin T, Jin Z, Dai J, Guffey D, Finegold M; Members of the Urea Cycle Disorders Consortium (UCDC), Nagamani S, Minard CG, Marini J, Masand P, Schady D, Shneider BL, Leung DH, Bali D, Lee B
JCI Insight 2020 Feb 27;5(4) doi: 10.1172/jci.insight.132342. PMID: 31990680Free PMC Article
Kho J, Tian X, Wong WT, Bertin T, Jiang MM, Chen S, Jin Z, Shchelochkov OA, Burrage LC, Reddy AK, Jiang H, Abo-Zahrah R, Ma S, Zhang P, Bissig KD, Kim JJ, Devaraj S, Rodney GG, Erez A, Bryan NS, Nagamani SCS, Lee BH
Am J Hum Genet 2018 Aug 2;103(2):276-287. doi: 10.1016/j.ajhg.2018.07.008. PMID: 30075114Free PMC Article
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

Diagnosis

Yüksel MF, Doğulu N, Yıldırım M, Köse E, Bektaş Ö, Eminoğlu FT, Teber S
Brain Dev 2024 Jun;46(6):213-218. Epub 2024 Mar 16 doi: 10.1016/j.braindev.2024.03.003. PMID: 38493042
Gurung S, Timmermand OV, Perocheau D, Gil-Martinez AL, Minnion M, Touramanidou L, Fang S, Messina M, Khalil Y, Spiewak J, Barber AR, Edwards RS, Pinto PL, Finn PF, Cavedon A, Siddiqui S, Rice L, Martini PGV, Ridout D, Heywood W, Hargreaves I, Heales S, Mills PB, Waddington SN, Gissen P, Eaton S, Ryten M, Feelisch M, Frassetto A, Witney TH, Baruteau J
Sci Transl Med 2024 Jan 10;16(729):eadh1334. doi: 10.1126/scitranslmed.adh1334. PMID: 38198573Free PMC Article
Kido J, Matsumoto S, Häberle J, Nakajima Y, Wada Y, Mochizuki N, Murayama K, Lee T, Mochizuki H, Watanabe Y, Horikawa R, Kasahara M, Nakamura K
J Inherit Metab Dis 2021 Jul;44(4):826-837. Epub 2021 Apr 18 doi: 10.1002/jimd.12384. PMID: 33840128
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

Therapy

Kho J, Tian X, Wong WT, Bertin T, Jiang MM, Chen S, Jin Z, Shchelochkov OA, Burrage LC, Reddy AK, Jiang H, Abo-Zahrah R, Ma S, Zhang P, Bissig KD, Kim JJ, Devaraj S, Rodney GG, Erez A, Bryan NS, Nagamani SCS, Lee BH
Am J Hum Genet 2018 Aug 2;103(2):276-287. doi: 10.1016/j.ajhg.2018.07.008. PMID: 30075114Free PMC Article
Jiang Y, Almannai M, Sutton VR, Sun Q, Elsea SH
Mol Genet Metab 2017 Nov;122(3):39-45. Epub 2017 Aug 31 doi: 10.1016/j.ymgme.2017.08.011. PMID: 28888854
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
Iafolla AK, Gale DS, Roe CR
J Pediatr 1990 Jul;117(1 Pt 1):102-5. doi: 10.1016/s0022-3476(05)82456-4. PMID: 2370602

Prognosis

Yüksel MF, Doğulu N, Yıldırım M, Köse E, Bektaş Ö, Eminoğlu FT, Teber S
Brain Dev 2024 Jun;46(6):213-218. Epub 2024 Mar 16 doi: 10.1016/j.braindev.2024.03.003. PMID: 38493042
Kido J, Matsumoto S, Häberle J, Nakajima Y, Wada Y, Mochizuki N, Murayama K, Lee T, Mochizuki H, Watanabe Y, Horikawa R, Kasahara M, Nakamura K
J Inherit Metab Dis 2021 Jul;44(4):826-837. Epub 2021 Apr 18 doi: 10.1002/jimd.12384. PMID: 33840128
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
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

Clinical prediction guides

Siri B, Olivieri G, Angeloni A, Cairoli S, Carducci C, Cotugno G, Di Michele S, Giovanniello T, La Marca G, Lepri FR, Novelli A, Rossi C, Semeraro M, Dionisi-Vici C
Mol Genet Metab 2022 Apr;135(4):327-332. Epub 2022 Feb 20 doi: 10.1016/j.ymgme.2022.02.008. PMID: 35279366
Zheng Z, Lin Y, Lin W, Zhu L, Jiang M, Wang W, Fu Q
Mol Genet Genomic Med 2020 Jul;8(7):e1301. Epub 2020 May 15 doi: 10.1002/mgg3.1301. PMID: 32410394Free PMC Article
Burrage LC, Madan S, Li X, Ali S, Mohammad M, Stroup BM, Jiang MM, Cela R, Bertin T, Jin Z, Dai J, Guffey D, Finegold M; Members of the Urea Cycle Disorders Consortium (UCDC), Nagamani S, Minard CG, Marini J, Masand P, Schady D, Shneider BL, Leung DH, Bali D, Lee B
JCI Insight 2020 Feb 27;5(4) doi: 10.1172/jci.insight.132342. PMID: 31990680Free PMC Article
Ranucci G, Rigoldi M, Cotugno G, Bernabei SM, Liguori A, Gasperini S, Goffredo BM, Martinelli D, Monti L, Francalanci P, Candusso M, Parini R, Dionisi-Vici C
J Inherit Metab Dis 2019 Nov;42(6):1118-1127. Epub 2019 Aug 25 doi: 10.1002/jimd.12144. PMID: 31260111
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

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG, ACT Sheet, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Elevated Citrulline], Amino Acidemia/Urea Cycle Disorder, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Elevated Citrulline: Amino Acidemia Algorithm, 2022
    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Argininosuccinic Acidemia, [Urea Cycle Disorder], 2012

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