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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); Argininosuccinate lyase deficiency (41013004); Argininosuccinic aciduria (41013004); ASAL deficiency (41013004); ASL deficiency (41013004)
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): 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
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Orotic aciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size 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.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
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.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
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).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
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.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
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.
Elevated CSF argininosuccinic acid concentration
MedGen UID:
1841602
Concept ID:
C5826623
Finding
Concentration of argininosuccinic acid in the cerebrospinal fluid (CSF) above the upper limit of normal.
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
Alkalosis due to excess loss of carbon dioxide from the body.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Hyperglutaminemia
MedGen UID:
326901
Concept ID:
C1839533
Finding
An increased concentration of glutamine in the blood.
Episodic ammonia intoxication
MedGen UID:
333343
Concept ID:
C1839541
Finding
Hypoargininemia
MedGen UID:
892673
Concept ID:
C4025095
Finding
A decreased concentration of arginine in the blood.
Increased circulating argininosuccinic acid
MedGen UID:
1705835
Concept ID:
C5139381
Finding
An increased level of the non-proteinogenic amino acid argininosuccinic acid in the blood circulation.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Trichorrhexis nodosa
MedGen UID:
82668
Concept ID:
C0263485
Disease or Syndrome
Trichorrhexis nodosa is the formation of nodes along the hair shaft through which breakage readily occurs. It is thus a focal defect in the hair fiber that is characterized by thickening or weak points (nodes) that cause the hair to break off easily. The result is defective, abnormally fragile hair.
Brittle hair
MedGen UID:
120480
Concept ID:
C0263490
Disease or Syndrome
Fragile, easily breakable hair, i.e., with reduced tensile strength.
Dry hair
MedGen UID:
75809
Concept ID:
C0277960
Finding
Hair that lacks the luster (shine or gleam) of normal hair.

Conditions with this feature

Citrullinemia type II
MedGen UID:
350276
Concept ID:
C1863844
Disease or Syndrome
Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. NICCD. Children younger than age one year have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, although liver transplantation has been required in rare instances. FTTDCD. Beyond age one year, many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. Clinical abnormalities may include growth restriction, hypoglycemia, pancreatitis, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid (TCA) cycle metabolites. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2. CTLN2. Presentation is sudden and usually between ages 20 and 50 years. Manifestations are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Affected individuals may or may not have a prior history of NICCD or FTTDCD.

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

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
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
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
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

Pritchard AB, Izumi K, Payan-Walters I, Yudkoff M, Rand EB, Bhoj E
Am J Med Genet A 2022 May;188(5):1443-1447. Epub 2022 Jan 23 doi: 10.1002/ajmg.a.62659. PMID: 35068050
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
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

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
Ediger K, Hicks A, Siriwardena K, Joynt C
BMJ Case Rep 2021 Mar 31;14(3) doi: 10.1136/bcr-2020-241032. PMID: 33789861Free 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
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

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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