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Argininosuccinic Aciduria

Argininosuccinic aciduria (AA) is an urea cycle disorder caused by deficiency of argininosuccinic acid lyase (ASL), an enzyme catalyzing the conversion of argininosuccinate to fumarate and arginine. Consequently, argininosuccinate accumulates in blood and urine. Increased serum concentrations and urinary excretion of argininosuccinate are the biochemical hallmarks of the disease and of major importance for the diagnosis of the disease. This diagnosis must be confirmed by means of genetic testing. Treatment is mainly based on dietary restriction and arginine supplementation.


AA usually manifests early in life, but may occasionally not be noted until childhood or even adulthood. Some authors distinguish severe neonatal-onset AA (onset within the first month of life) from mild to moderate late-onset ASL deficiency (onset in patients older than one month) [1] [2].

The clinical picture is not different from that observed in other urea cycle disorders and varies according to disease severity: Parents may claim feeding problems, lethargy and irritability in their child, report vomiting, tremor, and ataxia, or present their offspring due to an acute hyperammonemic crisis. Hyperammonemia induces hypothermia, tachypnea and respiratory alkalosis, which usually precede seizures and profound loss of consciousness. In severe cases, hyperammonemic coma and even death may occur within the first days of life. Less severe forms of the disease are characterized by episodic hyperammonemia, triggered by infectious disease, fasting, stress or non-compliance with dietary restrictions and/or medication [2]. Hyperammonemia may cause irreversible brain damage and thus, untreated AA may lead to learning difficulties, intellectual disability and cognitive impairment, or abnormal behavior. Such long-term sequelae may arise after repeated hyperammonemic crises or even in the absence of any documented episodes of metabolic decompensation [2].

Additionally, skin lesions, hepatomegaly and trichorrhexis nodosa, i.e., coarse and brittle hair, may be noted in AA patients [3]. The latter is considered specific for ASL deficiency but don't suffice for a reliable diagnosis. Also, the absence of hair shaft defects does not rule out ASL deficiency [2].

Poor Feeding
  • The neonatal presentation is characterized with a normal delivery followed by lethargy, vomiting, poor feeding, hypothermia, hyperventilation, decreased consciousness and coma, while later-onset patients usually present with less severe symptoms including[genedx.com]
  • The severe neonatal form is characterized by hyperammonemia within the first few days of life with poor feeding, vomiting, lethargy, and seizures, with subsequent progression to coma.[bmcmedgenet.biomedcentral.com]
  • Follow-up Testing after Positive Screen Quantitative plasma ammonia and amino acid analysis, urine orotic acid Primary Care Management Upon Notification of the Screen Contact the family and evaluate the infant for poor feeding, vomiting, lethargy; Measure[medicalhomeportal.org]
  • An accumulation of ammonia during the first few days of life leads to poor feeding, vomiting , seizures , and the other signs and symptoms of type I citrullinemia.[en.wikipedia.org]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019[patientslikeme.com]
  • The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group ( P  .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue.[jamanetwork.com]
  • Some FTTDCD patients have growth retardation, hypoglycemia, hyperlipidemia, pancreatitis, fatty liver, hepatoma, and fatigue.[themedicalbiochemistrypage.org]
Respiratory Abnormalities
  • Affected infants may also experience seizures, breathing (respiratory) abnormalities, the accumulation of fluid in the brain (cerebral edema), and an abnormally large liver (hepatomegaly).[rarediseases.org]
Severe Clinical Course
  • In conclusion, there are patients of different ethnic backgrounds who are characterized by residual activity of argininosuccinate lyase and who present with less severe clinical courses.[ncbi.nlm.nih.gov]
Neonatal Jaundice
  • At 7 days of age, he was admitted to the hospital with presumed neonatal sepsis, neonatal conjunctivitis and neonatal jaundice. He was lethargic with poor responses and had ocular hyperemia with purulent secretions from eyes.[bmcmedgenet.biomedcentral.com]
Dry, Brittle Hair
  • , brittle hair (trichorrhexis nodosa) Cerebral edema Seizures Mental retardation Death Treatment includes a low protein diet, arginine supplementation and the use of sodium benzoate or phenylbutyrate to remove the nitrogen load using an alternative mechanism[medicalhomeportal.org]
  • Affected infants and children may also have dry, brittle hair. Some individuals with the late onset form may not develop any symptoms (asymptomatic). Infants with the mild form may alternate between periods of wellness and hyperammonemia.[rarediseases.org]
  • Some common symptoms in children who are not treated are: poor growth dry, brittle hair hyperactivity behavior problems learning disabilities or intellectual disability avoidance of meat and other high protein foods enlarged liver small head size episodes[newbornscreening.info]
  • We suggest that orthotopic liver transplantation should be considered for patients with argininosuccinic aciduria even in the absence of cirrhosis, with the aim of correcting (at least in part) central nervous system metabolism, thereby preventing further[ncbi.nlm.nih.gov]
  • […] characterized with a normal delivery followed by lethargy, vomiting, poor feeding, hypothermia, hyperventilation, decreased consciousness and coma, while later-onset patients usually present with less severe symptoms including vomiting, failure to thrive, irritability[genedx.com]
  • Additional symptoms of AA comprise loss of appetite, lethargy, irritability, hypothermia, high respiratory rate, tremor and ataxia.[symptoma.com]
  • Symptoms of ASA include poor appetite, irritability, vomiting, tiredness, seizures, trouble breathing, uncontrolled body movements, or delayed growth.[diseaseinfosearch.org]
  • Irritable 0000737 Lethargy 0001254 Neonatal onset 0003623 Protein avoidance 0002038 Respiratory alkalosis 0001950 Seizures Seizure 0001250 Vomiting Throwing up 0002013 Showing of 30 Last updated: 7/1/2019 Making a diagnosis for a genetic or rare disease[rarediseases.info.nih.gov]
Positive Romberg Sign
  • Her clinical symptoms consisted of ataxia, disturbance of coordination, clumsiness, intention treMor and a positive Romberg's sign. The laboratory findings were consistent with the mild, late-onset type of ASA-uria.[ncbi.nlm.nih.gov]
  • Her clinical symptoms consisted of ataxia, disturbance of coordination, clumsiness, intention treMor and a positive Romberg's sign. The laboratory findings were consistent with the mild, late-onset type of ASA-uria.[ncbi.nlm.nih.gov]


The above-described symptoms may raise suspicion for an urea cycle disorder, but are not specific for AA. Furthermore, they may not allow for a reliable differentiation of urea cycle disorders and organic acidemias. Valuable hints at the nature of the disease can be obtained during familial and personal anamnesis. Parents of affected children should be asked for possible metabolic disorders or symptoms thereof in past generations or living relatives. It should be considered that the course of the disease in affected family members may be more or less severe than in the patient at hand. With regards to the latter, certain information concerning their medical history and eating habits may also point at an urea cycle disorder, even in the absence of documented hyperammonemic crises. For instance, patients suffering from an urea cycle disorder are prone to behavioral disorders and are known to avoid protein-rich food [4] [5].

Important measures to confirm that the patient does indeed suffer from an urea cycle disorder consist in measuring serum ammonia levels and checking for metabolic acidosis. An AA patient will suffer from hyperammonemia, but not from metabolic acidosis, but rather from respiratory alkalosis. Laboratory analyses of blood samples should also reveal citrullinemia (citrulline levels of 100 to 300 µmol/l) and increased concentrations of argininosuccinate (50 to 110 µmol/l) [2]. Additional findings typically comprise low levels of arginine and ornithine.

Urinary argininosuccinate levels may reach 10,000 µmol/g creatinine [2]. In fact, urine analysis is considered more sensitive with regards to the detection of mild forms of AA than blood analysis. Even if reliable conclusions can't be drawn from laboratory analyses of blood samples, urine amino acid profiles should reveal the exact type of urea cycle disorder [6]. Urinary excretion of orotic acid may also be increased in AA patients.

Enzyme activity can be assessed in skin fibroblasts, red blood cells or - if a liver biopsy is performed - in hepatocytes. In order to do so, argininosuccinate may be provided and its breakdown observed by means of fluorometric measurements. Alternatively, the conversion of fumarate and arginine to argininosuccinate may be evaluated. Contradictory results have been published regarding the correlation of test results and disease severity, though [2] [7]. Therefore, some authors recommend carrying out indirect assays (e.g., citrulline incorporation) instead of direct enzyme activity measurements: They argue indirect assays to be more sensitive and predict a better correlation between test results and the patient's phenotype [2]. Others recommend enzyme assays only in case of inconclusive results of molecular genetic testing [6], as described subsequently.

Genetic analyses should be done in any case to confirm causal mutations of the ASL gene. Furthermore, mutation identification facilitates prenatal diagnosis in subsequent generations [5].

  • Interestingly, frequent thrombocytosis with the mean level of 717 10 9 /L (range   457-1169   10 9 /L) was observed in 96% of the patients with no clear explanation. Copyright 2018 Elsevier Masson SAS. All rights reserved.[ncbi.nlm.nih.gov]


Dietary measures are the mainstay of AA treatment. In order to diminish protein catabolism, protein intake should be limited. It may be necessary to supplement essential amino acids to compensate for dietary restrictions and to avoid nutrient deficiencies. Arginine is usually applied in an intent to favor the formation of argininosuccinate: This seemingly apparently contradictory strategy is followed because argininosuccinate does contain two waste nitrogen atoms and has a high renal clearance. By this means, hyperammonemia can be controlled. However, doubts remain on whether arginine itself exerts neurotoxic effects [5]. Thus, arginine should not be over-supplemented. Serum arginine levels should ideally remain below 200 µmol/l [5]. For as of yet unknown reasons, AA patients tend to present with hypokalemia and may require potassium supplementation [5].

Treatment in case of acute metabolic decompensation does not differ from measures to be taken in case of other urea cycle disorders during hyperammonemic crisis. Here, the main objectives of therapy are to lower ammonia levels and to reverse protein catabolism. In order to do so, ammonia scavengers may be administered, dextrose, insulin and intra-lipids. Protein intake should be radically reduced for at least 48 hours and arginine has to be supplemented. Eventually, patients may be considered for hemodialysis or hemofiltration [5]. AA patients have occasionally been treated by means of liver transplantation [8] [9].


If left untreated, ASL deficiency may ensue severe developmental delays and intellectual disability [10]. However, neurocognitive deficiencies have also been described in AA patients who did not suffer from hyperammonemic crises [2]. They may possibly be explained by argininosuccinate-mediated neurotoxicity [11], but other pathomechanism have been proposed, too [5]. Additionally, argininosuccinate is known to exert toxic effects on hepatocytes, which is why AA patients are considered to be at higher risks of developing hepatic diseases and liver fibrosis [6]. Affected individuals have also been proposed to be predisposed for hypertension [12]. Fortunately, most of those long-term sequelae can be avoided or, at the very least, reduced by means of proper treatment. The overall mortality (neonatal plus late-onset disease) has been estimated to 6% [13].


AA is inherited in an autosomal recessive manner and has been associated with distinct mutations of the ASL gene, which is located on chromosome 7 and encodes for an enzyme of the same name required for catalyzing the breakdown of argininosuccinate in the late urea cycle [1]. Data regarding the genotype–phenotype correlation have been provided, but are not necessarily consistent in different studies [1] [14]. According to current knowledge, other genes are not involved in the pathogenesis of AA.


For the United States, the overall incidence of urea cycle disorders has been estimated to 1 in 35,000 inhabitants. According to Summar et al., ornithine transcarbamylase deficiency is the most common urea cycle disorder (incidence of 1 in 56,500 individuals), followed by ASL deficiency or AA, which affects 1 in 218,750 people [15]. Even though precise data are lacking for developing regions, incidence rates are expected to be significantly higher in countries characterized by the practice of consanguineous marriage, i.e., most Arab and the Middle Eastern countries. Indeed, according to a recently published review, the incidence of AA may be as high as 1 in 70,000 individuals [10]. Men and women are affected equally.

Sex distribution
Age distribution


ASL catalyzes the conversion of argininosuccinate to fumarate and arginine in the late urea cycle. Fumarate is required for the generation of malate, whereas arginine is converted to urea and ornithine. The former reaction is catalyzed by cytosolic fumarase, the latter by arginase. In patients suffering from AA, cleavage of argininosuccinate is considerably restricted and substrates for fumarase and arginase are supplied in small amounts only. On the one hand, this leads to an accumulation of argininosuccinate in blood and urine, which, in turn, slows down earlier reactions of the urea cycle: In AA patients, citrulline-consuming formation of argininosuccinate is restricted and serum citrulline levels rise. On the other hand, levels of arginine and ornithine may decrease to below reference ranges. Indeed, lack of arginine is what causes affected individuals to develop trichorrhexis nodosa, a hair shaft anomaly that may be recognized during microscopic examination.


Early diagnosis of urea cycle disorders is crucial for avoiding hyperammonemic crises and thus, irreversible damage to the central nervous system. Although ALS deficiency is usually considered a rather mild urea cycle disorder, it is no exception to this rule.

Prevention of AA and long-term sequelae comprises the following steps:

  • Genetic counseling. The disease is inherited in an autosomal recessive fashion and its incidence is particularly high in children from consanguineous couples. Families with a known history of ASL deficiency are thus recommended to attend genetic counseling if they are planning a child.
  • Prenatal diagnosis. Chorionic villus, amniocyte or amniotic fluid samples can be used to check for mutations of the ASL gene.
  • Newborn screen. In some countries, neonates are routinely screened for a number of inborn errors of metabolism, including aminoacidopathies like AA.


AA results from ASL deficiency, a rare inborn error of metabolism. This enzyme is required for catalyzing the cleavage of argininosuccinate in the late urea cycle, which is why AA pertains to the group of urea cycle disorders. Accordingly, AA patients may present with symptoms of hyperammonemic encephalopathy during their first month of life or, in case of less severe disease, suffer from metabolic decompensation in times of increased demand and subsequent protein catabolism. Clinical findings rarely allow for a reliable diagnosis of AA, with hepatomegaly and hair shaft anomalies being the only symptoms that presumably distinguish this disease from other urea cycle disorders. A detailed metabolic profile is required to arrange for the enzyme assays and genetic analyses necessary to confirm the diagnosis. Treatment mainly rests on restricted protein intake and arginine supplementation. Even though hyperammonemia can usually be controlled applying these measures, AA patients remain at high risks of slowly progressive neurocognitive decline. Further research is needed to shed more light on the causes of this development and to be able to adapt treatment recommendations accordingly.

Patient Information

In the human body, ammonia detoxification rests on a series of biochemical reactions forming the so-called urea cycle. Distinct enzymes catalyze single reactions within that cycle, break down metabolic intermediates and supply substrates for the following reaction. Argininosuccinic acid lyase (ASL) is one of those enzymes and catalyzes the conversion of argininosuccinate to fumarate and arginine. In patients suffering from argininosuccinic aciduria (AA), mutations of the gene encoding for ASL cause a considerable reduction of the activity of this enzyme. Consequently argininosuccinate cannot be sufficiently cleaved to fumarate and arginine. It accumulates in the patient's blood and urine. This metabolic block also impairs ammonia detoxification in general and thus, affected individuals may develop hyperammonemia, i.e., increased concentrations of ammonia in their blood. Ammonia exerts toxic effects on the brain and if its concentrations increase beyond certain limits, AA patients may suffer from acute encephalopathy - presenting as seizures and profound loss of consciousness - or progressive neurodegeneration. The latter eventually results in developmental delays and intellectual disability. Additional symptoms of AA comprise loss of appetite, lethargy, irritability, hypothermia, high respiratory rate, tremor and ataxia. These symptoms often become apparent during the neonatal period, but may occasionally not be noted until well into childhood. Appropriate dietary measures can be taken as soon as the diagnosis is confirmed. In most cases, hyperammonemia and its consequences can be avoided or, at the very least, reduced.



  1. Baruteau J, Jameson E, Morris AA, et al. Expanding the phenotype in argininosuccinic aciduria: need for new therapies. J Inherit Metab Dis. 2017; 40(3):357-368.
  2. Nagamani SC, Erez A, Lee B. Argininosuccinate lyase deficiency. Genet Med. 2012; 14(5):501-507.
  3. Fichtel JC, Richards JA, Davis LS. Trichorrhexis nodosa secondary to argininosuccinicaciduria. Pediatr Dermatol. 2007; 24(1):25-27.
  4. Ganetzky RD, Bedoukian E, Deardorff MA, Ficicioglu C. Argininosuccinic Acid Lyase Deficiency Missed by Newborn Screen. JIMD Rep. 2017; 34:43-47.
  5. Haberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012; 7:32.
  6. Ah Mew N, Simpson KL, Gropman AL, Lanpher BC, Chapman KA, Summar ML. Urea Cycle Disorders Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(R). Seattle (WA): University of Washington, Seattle; 1993.
  7. Ficicioglu C, Mandell R, Shih VE. Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening. Mol Genet Metab. 2009; 98(3):273-277.
  8. Newnham T, Hardikar W, Allen K, et al. Liver transplantation for argininosuccinic aciduria: clinical, biochemical, and metabolic outcome. Liver Transpl. 2008; 14(1):41-45.
  9. Yankol Y, Mecit N, Kanmaz T, Acarli K, Kalayoglu M. Argininosuccinic Aciduria-A Rare Indication for Liver Transplant: Report of Two Cases. Exp Clin Transplant. 2017; 15(5):581-584.
  10. Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H. Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options. Biochem Genet. 2017.
  11. Kolker S, Sauer SW, Surtees RA, Leonard JV. The aetiology of neurological complications of organic acidaemias--a role for the blood-brain barrier. J Inherit Metab Dis. 2006; 29(6):701-704; discussion 705-706.
  12. Brunetti-Pierri N, Erez A, Shchelochkov O, Craigen W, Lee B. Systemic hypertension in two patients with ASL deficiency: a result of nitric oxide deficiency? Mol Genet Metab. 2009; 98(1-2):195-197.
  13. Batshaw ML, Tuchman M, Summar M, Seminara J. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014; 113(1-2):127-130.
  14. Trevisson E, Salviati L, Baldoin MC, et al. Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum Mutat. 2007; 28(7):694-702.
  15. Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. 2013; 110(1-2):179-180.

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Last updated: 2019-07-11 20:31