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

  Within days of birth, infant may display lethargy, poor feeding, somnolence, hypothermia, tachypnea, vomiting, and failure to thrive. Severe neonatal-onset form may lead to seizures, coma, and death if left untreated. [visualdx.com]

  In the severe, early onset form of this condition, infants may have vomiting, lethargy (low energy), poor feeding and hypothermia (a lower body temperature than normal). [my46.org]

  Case 1 A 3-day-old male infant was referred to the emergency ward because of vomiting, poor feeding, lethargy and respiratory distress. [ijp.tums.pub]

  Clinical features of the neonatal onset of the disorder include poor feeding, vomiting, lethargy, seizures, tachypnea, coma, and death. [decs.bvs.br]

  The most serious form of this condition usually occurs in the first few days of life, causing vomiting, lethargy and poor feeding. There is also a less serious form of the condition with milder and more varied symptoms. [eugenelabs.com]

• Turkish

  Authors : Zübarioğlu, Adil Umut1; Bülbül, Ali1; Dursun, Mesut1 Source: Turkish Pediatrics Archive / Turk Pediatri Arsivi. 5/1/2014, Vol. 49 Issue Supp 1, pS5-S6. 2p. [library.dctabudhabi.ae]

  Turkish Pediatrics Archive, 2011, p. 84+. Accessed 20 Apr. 2020. Gale Document Number: GALE|A252555286 [go.gale.com]

  […] axit arginine 80 millions of speakers Translator Korean - Tamil அர்ஜினைன் அமிலம் சிறுநீர் 75 millions of speakers Translator Korean - Marathi प्रथनाचे पचन होऊन निर्माण झालेले एक आवश्यक ऍमिनो आम्ल ऍसिड मूत्र 75 millions of speakers Translator Korean - Turkish [educalingo.com]

  […] mansion), the old Bibliothèque Nationale d'Alger —a Turkish palace built in 1799–1800—and the new National Library, built in a style reminiscent of the British Library. [en.wikipedia.org]

• Fatigue

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 13, 2019 [patientslikeme.com]

  Some FTTDCD patients have growth retardation, hypoglycemia, hyperlipidemia, pancreatitis, fatty liver, hepatoma, and fatigue. [themedicalbiochemistrypage.org]

  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]

• Gaucher Disease

  Lipid lysosomal storage diseases (lipidoses) sphingolipidosis ceramidosis glycosylceramide lipidosis ( Gaucher disease) ceramidase (Farber disease ou Farber lipogranulomatosis) glycosphingolipidosis Fabry disease gangliosidosis type I (GM1) gangliosidosis [humpath.com]

  (Craniofacial Dysostosis) Cryptophthalmos Syndrome Cutis Laxa Syndromes – Recessive Form Cytomegalic Inclusion Disease, Congenital G Galactosemia Gastroschisis, Congenital Gaucher’s Disease Glycinemia Gm1Gangliosidosis Gm2 Gangliosidosis (TaySachs or [anybabycan.org]

• Vietnamese

  […] millions of speakers Translator Korean - German Argininsäure Urin 180 millions of speakers Translator Korean - Japanese アール持つコハク酸尿 130 millions of speakers Translator Korean - Javanese cipratan asam arginina 85 millions of speakers Translator Korean - Vietnamese [educalingo.com]

• Respiratory Distress

  Case 1 A 3-day-old male infant was referred to the emergency ward because of vomiting, poor feeding, lethargy and respiratory distress. [ijp.tums.pub]

  […] disease급성 호흡기 질환ARD adult respiratory distress성인 호흡 곤란, 성인성 호흡장애ARD antibiotic removal device항생제 제거 장치ARD antibiotic retrieval device항생제 검색 장치ARD aphakic retinal detachment무수정체성 망막 박리ARDS acute respiratory distress syndrome급성 호흡 곤란 증후군ARDS adult respiratory [m.blog.naver.com]

• Abdominal Pain

  pain, chest pain, headache, eye problems, and severe leg pains 복통, 흉통, 두통, 눈의 문제 및 심한 다리 통증ACIAnkle chronic instability　ACIautologous chondrocyte implantation자가 연골 세포 이식ACI adrenal cortical insufficiency부신 피질 기능 부전ACI aftercare instructions추후치료 지시, 요양지시ACJ [m.blog.naver.com]

• Small Head

  Some common symptoms in children who are not treated are: poor growth dry, brittle hair hyperactivity behavior problems learning or intellectual disabilities avoidance of meat and other high protein foods enlarged liver small head size high blood pressure [newbornscreening.info]

• Skin Lesion

  lesions Brittle hair Treatment of argininosuccinic aciduria may include a high-calorie, protein-restrictive diet, arginine supplementation, administration of sodium benzoate and sodium phenylacetate. [stlouischildrens.org]

  The disease is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness. [uniprot.org]

  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. [medlineplus.gov]

  ARGINSA is characterized by mental and physical retardation, liver enlargement, skin lesions, dry and brittle hair showing trichorrhexis nodosa microscopically and fluorescing red, convulsions, and episodic unconsciousness. [genome.jp]

• Dry, Brittle Hair

  A milder, late-onset form may be triggered by infection or stress and present recurring episodes of hyperammonemia, with vomiting, irritability, behavioral dysfunction, hepatomegaly, trichorrhexis nodosa (dry, brittle hair), intellectual disability, and [visualdx.com]

  Subsequent symptoms may include: Poor growth/failure to thrive Liver enlargement Muscle weakness Short, dry, brittle hair (trichorrhexis nodosa) Cerebral edema Seizures Intellectual disability Death Treatment includes a low-protein diet, arginine supplementation [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]

• Irritability

  Untreated people with Cit-1 may present, but are not limited to, symptoms of NAGS may appear as early as the first few days of such as lack of appetite, irritability, laboured breathing, lethargy, and vomiting. [metabolicdietapp.org]

  A milder, late-onset form may be triggered by infection or stress and present recurring episodes of hyperammonemia, with vomiting, irritability, behavioral dysfunction, hepatomegaly, trichorrhexis nodosa (dry, brittle hair), intellectual disability, and [visualdx.com]

  Ornithine-transcarbamoylase (OTC) deficiency (311250) OTC OTC (Xp21.1)* Biochemical profile: Elevated ornithine and glutamine, decreased citrulline and arginine, markedly increased urine orotate Clinical features: In males, recurrent vomiting, irritability [msdmanuals.com]

  Later onset results in milder set of clinical features including vomiting, failure to thrive, irritability, behavioral problems, or psychomotor retardation. Mutations in the ARGININOSUCCINATE LYASE gene cause the disorder. [decs.bvs.br]

  Symptoms of ASA include poor appetite, irritability, vomiting, tiredness, seizures, trouble breathing, uncontrolled body movements, or delayed growth. [diseaseinfosearch.org]

• Encephalopathy

  Ten patients who presented with acute neonatal hyperammonemic encephalopathy had markedly elevated blood ammonia (> 430 micromol/L) within the first few days of life. [ncbi.nlm.nih.gov]

  Treatment of hepatic encephalopathy by alteration of intestinal flora with lactobacillus acidophilus. Lancet. 1965; 1: 399 Silen W. Harper H.A. Mawdsley D.L. Weirich W.L. [amjmed.com]

  Survivors of the neonatal onset and childhood/adult onset disorders share common risks for encephalopathies, metabolic, inborn; and respiratory alkalosis due to hyperammonemia Applies To Argininosuccinic aciduria Citrullinemia Disorders of metabolism [icd9data.com]

  I.V. nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate/phenylbutyrate) should normalize ammonia levels, but if unsuccessful or in case of severe hyperammonemic encephalopathy, hemodialysis is recommended. [orpha.net]

• Tremor

  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]

  Additional symptoms of AA comprise loss of appetite, lethargy, irritability, hypothermia, high respiratory rate, tremor and ataxia. [symptoma.com]

  Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors. [en.wikipedia.org]

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].

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.

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.

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.