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Argininosuccinate Lyase Deficiency

Synonyms: Argininosuccinic Acid Lyase Deficiency (ASLD), Argininosuccinic Aciduria (ASA)

, MBBS, MD, , MD, PhD, and , MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: August 14, 2025.

Estimated reading time: 42 minutes

Summary

Clinical characteristics.

Argininosuccinate lyase deficiency (ASLD), an inborn error of urea synthesis, may present as a neonatal- or late-onset disease.

Neonatal-onset ASLD: Characterized by hyperammonemia within the first few days after birth that can manifest as increasing vomiting, lethargy, refusal to feed, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death.

Late-onset ASLD: Manifestations 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.

Long-term manifestations of ASLD: Acute hyperammonemia and its associated complications; neurologic and neurocognitive features including attention-deficit/hyperactivity disorder, intellectual and developmental disabilities, learning disabilities, seizures, and abnormalities of motor functioning and coordination; liver disease, including hepatomegaly, hepatitis, steatosis, fibrosis, and cirrhosis; trichorrhexis nodosa (coarse, brittle hair that breaks easily); systemic hypertension; and hypokalemia.

Diagnosis/testing.

The diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine; or identification of biallelic pathogenic variants in ASL by molecular genetic testing.

Management.

Targeted therapies: Dietary treatment includes protein restriction, supplementation with non-protein-containing formulas to provide age-appropriate caloric requirements, and arginine base supplementation; nitrogen-scavenging medications are required in those with hyperammonemia or suboptimal metabolic control.

Treatment of metabolic decompensation: The focus for treatment of metabolic decompensation is to rapidly decrease blood ammonia. Treatment of acute hyperammonemic episodes involves temporary cessation of oral protein intake, intravenous lipids and/or glucose, and intravenous nitrogen-scavenging therapy. Treatment of severe hyperammonemia often requires kidney replacement therapy with hemodialysis or continuous venovenous hemofiltration.

Supportive care: Developmental and educational support; treatment of seizures per neurologist; treatment of abnormal motor functioning and coordination per neurologist, physical medicine and rehabilitation specialist, and physical and occupational therapists; orthotopic liver transplantation should be considered in individuals with recurrent hyperammonemia or metabolic decompensations that are resistant to conventional medical therapy; salt restriction, antihypertensive medications, and nitrites and nitrate-containing supplements for hypertension; potassium supplementation as needed; encourage medical alert bracelet; provide letters and written protocol for management in the setting of catabolic stressors; provide family with letters for optimizing social and school functioning; appropriate precautions should be taken during pre- and perioperative periods to prevent catabolic stress that could lead to hyperammonemia.

Surveillance: Assessment with metabolic dietitian and clinical biochemical geneticist including height, weight, body mass index, and laboratory indices of nutritional status; plasma ammonia and amino acids with frequency based on age and metabolic status; developmental, educational, and behavioral assessment annually; assess for seizures, abnormal motor function, and problems with coordination at each visit; ALT, AST, albumin, and INR every six to 12 months or as needed; consider liver ultrasound and noninvasive monitoring for hepatic fibrosis every one to two years; blood pressure measurement at each visit; plasma potassium levels at least annually.

Agents/circumstances to avoid: Excess protein intake; large boluses of protein or amino acids; less than recommended intake of protein; prolonged fasting or starvation; exposure to communicable diseases; valproic acid; oral or parenteral administration of corticosteroids; hepatotoxic drugs (in those with liver disease).

Evaluation of relatives at risk: For at-risk newborn sibs when prenatal testing was not performed: measure plasma amino acids (to specifically assess for argininosuccinate) and plasma ammonia immediately in the newborn period in parallel with newborn screening and molecular genetic testing for the familial ASL pathogenic variants (if known).

Pregnancy management: As pregnancy and the postpartum period pose significant stress in females in all urea cycle disorders, close monitoring and management is recommended for prevention of hyperammonemia.

Genetic counseling.

ASLD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ASL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ASL pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

Suggested guidelines for the diagnosis of argininosuccinate lyase deficiency (ASLD) have been published [Häberle et al 2019].

Suggestive Findings

ASLD should be suspected in:

Infant with Out-of-Range NBS Result

NBS for ASLD is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify citrulline concentrations by tandem mass spectrometry (MS/MS). In the United States most NBS laboratories determine their own levels for results that are considered out of range. For information on NBS by state in the US, see www.newbornscreening.hrsa.gov/your-state.

Immediately on receipt of out-of-range NBS results (i.e., elevated citrulline), further evaluation to establish a diagnosis is required and presumptive management should be considered. For recommendations on presumptive treatment, consult a metabolic specialist to discuss immediate care needs. If a metabolic specialist is not available, the following treatment should be initiated immediately (see Management):

  • Inform the family of the out-of-range NBS result.
  • Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea).
  • Consult with a metabolic specialist immediately.
  • If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist.
  • Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw).
  • Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist.
  • Provide family with basic information about the possible diagnosis and its management.

Note: Citrulline values above the cutoff reported by the NBS laboratory are considered positive, but elevation of citrulline can also be seen in other disorders (see Differential Diagnosis); hence, confirmation of the diagnosis of ASLD requires follow-up biochemical testing (see Elevated Citrulline ACMG ACT Sheet; Elevated Citrulline: Amino Acidemia Algorithm; and NCC Knowledge Nugget Series: Amino Acidemias - Elevated Citrulline ACT Sheet Video).

If follow-up biochemical testing supports a diagnosis of ASLD, additional testing is not typically required prior to initiation of treatment. However, molecular genetic testing is recommended for molecular confirmation of the diagnosis (see Establishing the Diagnosis).

Severe Neonatal-Onset Manifestations

An infant with severe neonatal-onset manifestations (age <28 days) can have (1) onset of clinical findings prior to availability of NBS results or (2) untreated neonatal-onset ASLD due to NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Suggestive clinical and laboratory findings in a symptomatic infant include:

Clinical findings

  • Lethargy, somnolence, refusal to feed
  • Vomiting
  • Tachypnea

Laboratory findings

  • Hyperammonemia
    The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L.
  • Respiratory alkalosis
  • Elevated plasma citrulline
    The initial citrulline concentration is typically 100-300 µmol/L.
  • Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L.
    Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate.

Proband with Suggestive Findings

A proband of any age (including late onset) may have the following suggestive clinical, laboratory, and imaging findings and family history.

Clinical findings

  • History of protein aversion, self-protein restriction
  • Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination
  • Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis
  • Trichorrhexis nodosa (coarse, brittle hair that breaks easily)
  • Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes

Laboratory findings

  • Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications)
  • Elevated liver transaminases
  • Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium
  • Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs).
  • Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed.

Imaging findings

  • Brain imaging. During acute hyperammonemia, brain MRI might demonstrate edema of the cerebral cortex and the subcortical white matter, which most severely affects the perirolandic and peri-insular cortex [Poretti et al 2013]. These findings can also be observed during hyperammonemic episodes due to other UCDs. Although there are no neuroimaging findings characteristic of ASLD, anecdotally, increased hyperintensities on T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI localized to the putamen, globus pallidus, and caudate nuclei have been observed [Kho et al 2023, Gurung et al 2024].
  • Liver imaging. Grayscale ultrasound can demonstrate hepatomegaly and increased echogenicity, and ultrasound with shear-wave elastography may reveal evidence of increased liver stiffness [Ranucci et al 2019, Burrage et al 2020, Nagamani et al 2021].

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Biochemical Diagnosis

The biochemical diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine.

Molecular Diagnosis

The molecular diagnosis of ASLD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in ASL by molecular genetic testing (see Table 1). Because of its relatively high sensitivity, ASL molecular genetic testing can obviate the need for measurement of argininosuccinate lyase (ASL) enzyme activity, which is not widely available.

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic ASL variants of uncertain significance (or of one known ASL pathogenic variant and one ASL variant of uncertain significance) does not establish or rule out the diagnosis. (3) Measurement of ASL enzyme activity is neither widely available nor used for diagnosis, as the specific pattern of metabolites found in affected individuals and molecular genetic testing are sufficient to establish the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When NBS results, clinical findings, or other laboratory findings suggest the diagnosis of ASLD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of ASL can detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing technology used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one variant or no variants are detected by the sequencing test, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes ASL and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2

Exome or genome sequencing can be used. Ordering rapid-turnaround exome or genome sequencing is necessary in critically ill infants. To date, the majority of ASL pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Argininosuccinate Lyase Deficiency

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
ASL Sequence analysis 3>90% 4
Gene-targeted deletion/duplication analysis 5None reported 4, 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

To date, no large intragenic deletions/duplications have been reported in individuals with ASLD.

Clinical Characteristics

Clinical Description

The clinical presentation of arginosuccinate lyase deficiency (ASLD) is variable.

Neonatal-Onset ASLD

The clinical presentation of neonatal-onset ASLD is indistinguishable from that of other urea cycle disorders (UCDs). Newborns typically appear healthy for the first 24 hours after birth. Hyperammonemia occurs within the first few days after birth. Within days, vomiting, lethargy, refusal to accept feeds, tachypnea, and respiratory alkalosis develops [Brusilow & Horwich 2001]. Failure to recognize and treat the defect in ureagenesis leads to worsening lethargy, seizures, coma, and even death.

The findings of hepatomegaly and trichorrhexis nodosa at this early stage may be the only clinical findings that suggest a diagnosis of ASLD [Brusilow & Horwich 2001].

Late-Onset ASLD

In contrast to the neonatal-onset form, the manifestations of late-onset ASLD range from episodic hyperammonemia (triggered by acute infection, stress, or nonadherence to dietary and/or medication recommendations) to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia [Brusilow & Horwich 2001].

Long-Term Manifestations of ASLD

Whereas manifestations secondary to hyperammonemia are common to all UCDs, many individuals with ASLD can present with a complex clinical phenotype. The incidence of (1) neurocognitive deficiencies; (2) hepatitis, hepatomegaly, fibrosis, and cirrhosis; and (3) systemic hypertension is overrepresented in individuals with ASLD [Nagamani et al 2012a, Kölker et al 2015, Kho et al 2018, Ranucci et al 2019, Burrage et al 2020, Nagamani et al 2021]. These manifestations may be unrelated to the severity or duration of hyperammonemic episodes [Saudubray et al 1999, Mori et al 2002, Ficicioglu et al 2009].

Neurologic and Neurocognitive Manifestations

Intellectual and developmental disabilities, learning disabilities, seizures, attention-deficit/hyperactivity disorder (ADHD), and abnormalities of motor functioning and coordination have been reported in individuals with ASLD.

Intellectual and developmental disabilities / neurobehavioral issues. In a cross-sectional study of individuals with UCDs, individuals with ASLD had a higher incidence of developmental delay and neurologic abnormalities than individuals with ornithine transcarbamylase (OTC) deficiency [Tuchman et al 2008]. Individuals with ASLD also had an increased incidence of ADHD, developmental delay, intellectual disability, behavioral abnormalities, learning disability, and/or seizures compared to individuals with all other UCDs [Tuchman et al 2008]. In a retrospective study, developmental delay was observed in 92% (48/52) of individuals with ASLD [Baruteau et al 2017]. In a natural history study, short attention span was reported during at least one study visit in half of individuals with ASLD even in the absence of documented hyperammonemia [Lerner et al 2019].

Seizures. In one cohort from the UK, seizures were prevalent in 43% of individuals with ASLD [Baruteau et al 2017]. Seizure types can vary and include generalized tonic-clonic, partial, absence, and myoclonic seizures [Elkhateeb et al 2023]. Although hyperammonemia-induced neurotoxicity is likely to contribute to prevalence, seizures have also been reported in individuals without documented hyperammonemia [Baruteau et al 2017, Chanvanichtrakool et al 2024].

Abnormalities of motor functioning and coordination. Tremors, hypotonia, and ataxia have been observed in a subset of individuals with ASLD [Baruteau et al 2017, Lerner et al 2021, Gurung et al 2024].

Early diagnosis and treatment. Although neurologic and neurocognitive manifestations are common in individuals with ASLD, they are not universally present. Some individuals, especially those with the late-onset form treated with protein restriction and supplemental arginine, can have normal cognition and development [Widhalm et al 1992, Ficicioglu et al 2009, Posset et al 2019].

The increasing availability of newborn screening (NBS) for ASLD has provided the opportunity to study the effects of early diagnosis and treatment on neurologic and neurocognitive outcomes.

  • Ficicioglu et al [2009] reported the long-term outcome of 13 infants diagnosed between age four and six weeks due to out-of-range NBS results. Despite therapy with protein restriction and arginine supplementation, four of 13 had learning disabilities, three had mild developmental delay, three had seizures, and six had an abnormal EEG pattern including abnormal sharp irregular background activity, frequent bilateral paroxysms, and increased slow wave activity.
  • In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [Mercimek-Mahmutoglu et al 2010].
  • In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [Posset et al 2019].

Although these data suggest more favorable neurologic and neurocognitive outcomes in individuals identified by NBS, they must be interpreted within the limitations of each dataset and analyses. Whereas the benefits observed may be due to early initiation of dietary and therapeutic interventions and a decrease in severity of hyperammonemic episodes, it is possible that the results may be confounded by the fact that NBS may have detected individuals with very mild disease, in whom it would be reasonable to expect a milder neurologic phenotype [Posset et al 2020].

Liver Disease

Liver disease has been documented in individuals with neonatal- and late-onset ASLD. Liver disease can develop even in individuals treated with known targeted therapies [Baruteau et al 2017]. Liver disease in ASLD may manifest with elevated plasma aminotransferases alanine transaminase (ALT) and aspartate transaminase (AST), abnormal liver echogenicity on ultrasound, hepatomegaly, liver fibrosis, cirrhosis with portal hypertension, and impaired synthetic function. Common liver histopathologic findings in individuals with ASLD include hepatocyte enlargement with pallor, increased glycogen deposition, steatosis, and fibrosis.

  • In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [Ranucci et al 2019].
  • From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [Burrage et al 2020]. Presence of hyperammonemia and use of nitrogen-scavenging medications were associated with elevated ALT, suggesting that individuals with more severe ASLD are more likely to have liver disease. Furthermore, in a subset who underwent detailed biomarker and imaging evaluation, ultrasound with shear-wave elastography and Fibrotest™, liver disease was detected in a subset [Burrage et al 2020, Nagamani et al 2021].
Hypertension

There have been anecdotal reports of hypertension in individuals with ASLD. Preclinical data and systematic analysis of blood pressures from one controlled clinical trial have shown that ASLD can directly result in endothelial dysfunction and hypertension [Kho et al 2018]. Usually, no secondary causes of hypertension are detected, suggesting that this finding is related to the tissue-autonomous loss of argininosuccinate lyase (ASL) in the vascular endothelium.

Other

Trichorrhexis nodosa is characterized by nodular swellings of the hair shaft accompanied by frayed fibers and loss of cuticles. About half of individuals with ASLD have an abnormality of the hair manifesting as dull, brittle hair surrounded by areas of partial alopecia [Fichtel et al 2007].

Electrolyte imbalances. Some individuals develop electrolyte imbalances such as hypokalemia. Hypokalemia is observed even in individuals who are not treated with sodium phenylbutyrate. The etiology is unclear; increased kidney wasting has been suggested.

Genotype-Phenotype Correlations

Homozygosity for a few pathogenic variants (e.g., p.Arg12Gln, p.Asp31Asn, p.Arg95Cys, p.Ile100Thr, p.Val178Met, p.Glu189Gly, p.Arg191Trp, p.Val335Leu, p.Arg379Cys, p.Arg385Cys, and p.Arg445Pro) has been observed in individuals with a milder phenotype [Zielonka et al 2020, Balmer et al 2014]. However, most individuals with ASLD are compound heterozygous. It has been difficult to identify definitive genotype-phenotype correlations.

c.1060C>T (p.Gln354Ter). Homozygosity for ASL pathogenic variant c.1060C>T (p.Gln354Ter) is associated with the severe neonatal form of ASLD [Al-Sayed et al 2005].

Prevalence

The estimated prevalence is 1:70,000-218,000 live births [Brusilow & Horwich 2001, Summar et al 2013] (see also NORD). However, ASLD is likely underdiagnosed, making it difficult to assess the true frequency in the general population.

Three pathogenic variants with a founder effect have been identified:

Differential Diagnosis

Elevated citrulline. Elevation of citrulline can be seen in other disorders such as citrullinemia type 1, citrin deficiency, pyruvate carboxylase deficiency, and dihydrolipoamide dehydrogenase deficiency.

Neonatal-onset arginosuccinate lyase deficiency (ASLD). The clinical presentation of neonatal-onset ASLD is indistinguishable from that of other urea cycle disorders (UCDs) (see Urea Cycle Disorders Overview).

Late-onset ASLD. A late-onset phenotype may be seen in other UCDs (e.g., ornithine transcarbamylase deficiency and citrullinemia type I); however, elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD and differentiates ASLD from these UCDs.

Management

When arginosuccinate lyase deficiency (ASLD) is suspected during the diagnostic evaluation due to out-of-range newborn screening (NBS) result or suggestive clinical/biochemical features, metabolic treatment should be initiated immediately.

Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of adverse effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.

Evaluation of a Newborn with an Out-of-Range NBS Result

Table 2.

Arginosuccinate Lyase Deficiency: Recommended Evaluations Following an Out-of-Range Newborn Screening Result

System/ConcernEvaluationComment
Biochemical Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian 1
  • Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
  • Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
Laboratory eva
  • Plasma ammonia
  • Plasma (or urine) amino acids
  • Urine organic acids
  • Urine orotic acid
  • Comprehensive metabolic panel
Genetic counseling Genetic counseling by genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of ASLD to facilitate medical & personal decision making

ASLD = argininosuccinate lyase deficiency; MOI = mode of inheritance

1.

After a new diagnosis of ASLD in a child, the closest hospital and local pediatrician should also be informed.

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant).

Evaluations Following Initial Confirmatory Diagnosis

To establish the extent of disease and needs of an individual with ASLD following diagnosis, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Argininosuccinate Lyase Deficiency: Recommended Evaluations After Confirming a Diagnosis

System/ConcernEvaluationComment
Biochemical Consult w/metabolic physician / biochemical geneticist & metabolic dietitian 1
  • Transfer to a specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
  • Consider a visit or short hospitalization as required at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute crises) for caregivers.
Laboratory eval
  • Plasma ammonia concentration
  • Plasma amino acid analysis
  • Laboratory values that reflect nutritional status (e.g., prealbumin, 25-hydroxyvitamin D, vitamin B12)
  • Kidney function tests (BUN, creatinine)
  • Electrolytes (sodium, potassium, chloride, bicarbonate)
Developmental Developmental assessment
  • Consider referral to developmental pediatrician, psychologist, &/or neurologist at appropriate age(s).
  • Consider referral to physical, occupational, & speech therapist as needed.
Neurologic Neurology referralConsider referral to neurologist for mgmt of seizures, motor abnormalities.
Liver disease Eval for liver disease
  • Plasma AST, ALT, bilirubin, albumin, PT, & INR
  • Liver ultrasound to identify hepatomegaly, fibrosis, & additional complications
  • Referral to hepatologist as required
Hypertension Blood pressure measurementSystolic & diastolic blood pressure centiles in children & systolic & diastolic blood pressure values in adults
Genetic counseling Genetic counseling by genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of ASLD to facilitate medical & personal decision making

ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BUN = blood urea nitrogen; INR = international normalized ratio; MOI = mode of inheritance; PT = prothrombin time

1.

After a new diagnosis of ASLD in a child, the closest hospital and local pediatrician should also be informed.

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Treatment involves rapid control of hyperammonemia during metabolic compensation, prevention of episodes of hyperammonemia, and management of long-term complications [Burrage et al 2018, Häberle et al 2019].

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Table 4.

Argininosuccinate Lyase Deficiency: Targeted Therapies

TypeTreatmentDoseConsideration/Other
Dietary Dietary protein restriction is required lifelong & requires services of metabolic dietitian. 1
  • Protein intake is typically limited to minimal daily requirement for age.
  • Typically, half the protein is provided as essential amino acids supplement.
  • Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories.
  • Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels.
  • Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible.
Arginine base supplementation
  • 100-300 mg/kg/day in persons weighing ˂20 kg
  • 2.2-5.5 g/m2/day in those weighing >20 kg
  • Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate.
  • Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis.
  • In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. 2 Thus, arginine doses should be 100-250 mg/kg/day, whenever possible.
Nitrogen-scavenging medications Sodium phenylbutyrate
  • 450-600 mg/kg/day for persons weighing ≤20 kg
  • 9.9-13 g/m2 BSA/day for those weighing >20 kg
  • These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation.
  • Phenylbutyrate metabolite levels can be used for monitoring therapy.
Glycerol phenylbutyrate4.4-11.2 mL/m2 BSA/day
Sodium benzoate250 mg/kg/day or 5.5 g/m2 BSA/day

ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BCAA = branched-chain amino acids; BSA = body surface area; DRI = dietary reference intakes

1.

Some of the correlations between adherence to the prescribed diet and outcome are contradictory. Although in some individuals dietary therapy along with arginine supplementation have been shown to reverse the hair abnormalities, improve cognitive outcome, and reverse abnormalities on EEG [Coryell et al 1964, Kvedar et al 1991, Ficicioglu et al 2009], in many individuals, dietary therapy has not been shown to influence the outcome of liver disease or cognitive impairment [Mori et al 2002, Mercimek-Mahmutoglu et al 2010].

2.

Supportive Care

Outpatient Routine Treatment of Manifestations

Table 5.

Argininosuccinate Lyase Deficiency: Outpatient Routine Treatment of Manifestations

Manifestation Treatment Consideration/Other
Developmental delay / Intellectual disability / Neurobehavioral issues See Intellectual and Developmental Disabilities Management Issues.
Seizures Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Valproic acid may induce hyperammonemia & should be avoided.
  • Education of parents/caregivers 1
Abnormal motor functioning & coordination Treatment per neurologist / physical medicine & rehab specialist / PT & OTSee Intellectual and Developmental Disabilities Management Issues.
Liver disease Treatment per hepatologist incl targeted therapies; may incl liver transplantLiver transplant recommended in those w/recurrent hyperammonemia; suboptimal metabolic control despite dietary therapy, arginine supplementation, & nitrogen scavenger therapy; significant liver fibrosis or cirrhosis; or unavailability of specialist care near their place of residence.
Hypertension
  • Salt restriction
  • Antihypertensive medications
  • Nitrites & nitrate-containing supplements
  • There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD.
  • Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. 2
  • NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. 3 However, efficacy has not been demonstrated in controlled clinical trial settings.
  • Dietary foods rich in nitrates might be considered as a supplemental treatment.
Hypokalemia Electrolyte (potassium) supplementationAs needed
Care coordination
  • Encourage medical alert bracelet.
  • Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors.
  • Provide families w/letter to optimize social & school services.
Invaluable for coordinating treatment at centers w/o expertise in mgmt of hyperammonemia or during travel

ASL = argininosuccinate lyase; ASLD = argininosuccinate lyase deficiency; NO = nitric oxide; OT = occupational therapist; PT = physical therapist

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

2.
3.
Liver Transplantation

In one systematic analysis of outcomes with liver transplantation versus medical management conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from the severe phenotype group included nine individuals with ASLD who had undergone liver transplantation and 12 individuals whose liver disease was managed medically. The median z scores for cognitive outcomes as assessed by neuropsychological testing were not different between liver transplantation and medical management. However, in a case series of nine children with neonatal-onset disease who underwent liver transplantation, prevention of further hyperammonemic episodes and improvements in cognitive and developmental functioning, behavior, and quality of life were reported [Siri et al 2025].

Intellectual and Developmental Disabilities Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine the services and therapies needed and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding types of therapy can be made by a developmental pediatrician.
    • As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Emergency Management

Table 6.

Argininosuccinate Lyase Deficiency: Emergency Management

IndicationTreatmentConsideration/Other
Catabolism caused by infection, fever, vomiting or diarrhea leading to lethargy, weakness, encephalopathy, & hypoglycemia Immediate transport to emergency room for treatment of acute hyperammonemiaSee Table 7.
Fever AntipyreticsIn persons w/liver disease, consider avoiding acetaminophen.

Acute Inpatient Treatment

Table 7.

Argininosuccinate Lyase Deficiency: Acute Inpatient Treatment

Manifestation/
Concern		Treatment 1Consideration/Other
↑ catabolism, 2 hypoglycemia
  • Temporary withholding of oral protein intake (~24 hrs)
  • Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism
Calorie provision should be 100%-120% of recommended intake.
Secondary carnitine deficiency L-carnitine supplementation (100 mg/kg) divided into 4 doses/day PO or IVAlthough this recommendation is included in published guidelines it is not universally recommended. 3
Critical care mgmt
  • Mgmt of airway, circulation, seizures, & intracranial pressure
  • Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment.
  • Assessment of hemodynamic status
  • Continuous assessment of neurologic status is critical.
Mgmt should be done under supervision of critical care team
Rapid reduction of plasma ammonia IV nitrogen-scavenging therapy.
Priming/bolus infusion (given continuously over 90 mins, dissolved in D10W [25-35 mL/kg if <20 kg; in 1 L if >20 kg]):
  • Sodium benzoate: <20 kg: 250 mg/kg; >20 kg: 5.5 g/m2
  • Sodium phenylacetate: <20 kg: 250 mg/kg; >20 kg: 5.5 g/m2
  • 10% arginine HCl: <20 kg: 600 mg/kg; >20 kg: 600 mg/kg
Maintenance infusion (given continuously over 24 hrs, dissolved in D10W [25-35 mL/kg if <20 kg; in 1 L if >20 kg]):
  • Sodium benzoate: <20 kg: 250 mg/kg; >20 kg: 5.5 g/m2
  • Sodium phenylacetate: <20 kg: 250 mg/kg; >20 kg: 5.5 g/m2
  • 10% arginine HCl: <20 kg: 600 mg/kg; >20 kg: 600 mg/kg
  • When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. 4
  • Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. 5
  • In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid.
Kidney replacement therapy (KRT) 6
  • KRT should be initial therapy for treatment of severe hyperammonemia.
  • Failure to control ammonia w/scavenger therapy requires emergency KRT.
  • Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist
  • Some centers use extracorporeal membrane oxygenation w/hemodialysis
Liver involvement Monitor for evidence of liver damage (measurement of liver transaminases).

IV = intravenous; PO = oral

1.

Inpatient emergency treatment should: (1) take place at the closest medical facility equipped to treat individuals with metabolic disorders; (2) be started without delay; and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.

2.

Due to fever, perioperative/peri-interventional fasting periods, repeated vomiting/diarrhea

3.

S Nagamani, personal observation

4.
5.
6.

Anticipatory Perioperative Management

Table 8.

Argininosuccinate Lyase Deficiency: Anticipatory Perioperative Management

ConcernTreatmentConsiderations/Other
Prevent complications such as catabolic stress that could lead to hyperammonemia & metabolic acidosis during surgery or procedure (incl dental procedures)
  • Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. 1, 2
  • Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
Consider placing a "flag" in affected person's medical record such that all care providers are aware of diagnosis & need to solicit opinions & guidance from designated metabolic specialists in the setting of certain procedures.
1.

Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary.

2.

Perioperative/perianesthetic management precautions may include visits at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications.

Surveillance

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Table 9 are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Table 9.

Argininosuccinate Lyase Deficiency: Recommended Surveillance

Manifestation/
Concern		EvaluationFrequency/Comment
Metabolic Assessment w/metabolic dietician & clinical biochemical geneticist incl:
  • Height, weight, body mass index
  • Laboratory indices of nutritional status (e.g., prealbumin, BCAAs [leucine, isoleucine, & valine], plasma amino acids, & plasma ammonia to identify deficiency of essential amino acids & assess for impending hyperammonemia 1
  • Phenylbutyrate metabolite levels may be used for monitoring persons on phenylbutyrate medications.
Lab & clinical monitoring frequency depend on metabolic status of affected person. In general:
  • Neonates: every 2 wks
  • Infants (age 2 mos-1 yr): every 1-3 mos
  • Children (age ≥2 yrs): every 3-4 mos
Development / Neurobehavioral issues
  • Assess developmental progress & educational needs.
  • Behavioral assessment incl ADHD assessment
Annually or as needed
Seizures / Abnormal motor function & coordination
  • Assess for new manifestations such as seizures, abnormal motor function, & problems w/coordination.
  • PT &/or OT assessment as needed
At each visit
Liver disease ALT, AST, & liver function testing (albumin, INR)Every 6-12 mos or as needed
Liver ultrasoundConsider every 1-2 yrs. 2
Non-invasive monitoring for hepatic fibrosis using serum biomarkers (e.g., FibroTest™), or ultrasound techniques such as vibration-controlled transient elastography (e.g., FibroScan®) or shear-wave elastrography in persons w/evidence of liver diseaseConsider every 1-2 yrs. 2
Hypertension Measurement of blood pressure using appropriate-sized cuff; systolic & diastolic BP centiles should be calculated.At each visit
Hypokalemia Plasma potassium levelAt least annually (persons w/hypokalemia may need more frequent monitoring)

ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; AST = aspartate transaminase; BCAA = branched-chain amino acids; INR = international normalized ratio; OT = occupational therapy; PT= physical therapy

1.

Early signs of impending hyperammonemic episodes in older individuals include mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus, and elevated plasma concentrations of glutamine, alanine, and glycine. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration in such individuals.

2.

S Nagamani, LC Burrage, and B Lee, unpublished data

Agents/Circumstances to Avoid

Avoid the following:

  • Excess protein intake; large boluses of protein or amino acids
  • Less than recommended intake of protein; prolonged fasting or starvation
  • Exposure to communicable diseases
  • Valproic acid
  • Oral or parenteral administration of corticosteroids, if possible. If steroids are medically required for treatment of a coexisting medical condition, contact the metabolic specialist for recommendations to prevent hyperammonemia with steroid therapy.
  • Hepatotoxic drugs in individuals with liver disease

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. If the pathogenic variants causing ASLD in the family are known, molecular genetic prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to allow prompt institution of appropriate treatment/surveillance at birth before a metabolic crisis occurs (see Treatment of Manifestations).

At-risk newborn sib. If prenatal testing has not been performed, measure plasma amino acids (to specifically assess for argininosuccinate) and plasma ammonia immediately in the newborn period in parallel with newborn screening and molecular genetic testing for the familial ASL pathogenic variants (if known). Pending the results of these evaluations, the neonate should be closely monitored for signs of hyperammonemia and treated with dietary therapy and potentially arginine (see Table 4).

At-risk older sibs. The genetic status of older sibs (even if asymptomatic) should be clarified by plasma amino acids (to specifically assess for argininosuccinate) and/or molecular genetic testing (if the ASL pathogenic variants in the family are known) so that appropriate treatment and surveillance can be instituted in a timely manner.

See Genetic Counseling for issues related to testing at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no guidelines for management of pregnancy in affected females. However, as pregnancy can pose significant stress in females with all UCDs, close monitoring and management is recommended for prevention of hyperammonemia in females with ASLD.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Arginosuccinate lyase deficiency (ASLD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are presumed to be heterozygous for an ASL pathogenic variant.
  • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an ASL pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an ASL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Though the phenotypic manifestations may vary, affected sibs of a proband with severe neonatal-onset ASLD are likely to have neonatal-onset disease.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has ASLD or is a carrier, offspring will be obligate heterozygotes (carriers) for an ASL pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ASL pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ASL pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with ASL deficiency, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Table 10).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the ASL pathogenic variants have been identified in an affected family member, molecular genetic prenatal testing and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Argininosuccinate Lyase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ASL 7q11​.21 Argininosuccinate lyase ASL @ LOVD ASL ASL

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Argininosuccinate Lyase Deficiency (View All in OMIM)

207900ARGININOSUCCINIC ACIDURIA
608310ARGININOSUCCINATE LYASE; ASL

Molecular Pathogenesis

In the liver, the site of ureagenesis, argininosuccinate lyase (ASL) cleaves argininosuccinate to produce arginine and fumarate. Arginine is hydrolyzed by arginase 1 to urea, which is excreted by the kidney, and ornithine, which reenters the urea cycle (see Urea Cycles Disorders Overview, Figure 1). ASL is expressed widely in many tissues, where one of its functions is to synthesize arginine from citrulline. ASL is the only enzyme responsible for de novo synthesis of arginine. Arginine is a precursor for creatinine, polyamines, agmatine, and nitric oxide. The liver, the major site of arginine metabolism, rapidly converts arginine generated in the urea cycle to urea and ornithine and does not contribute to the circulating pool of arginine. In ASL deficiency (ASLD), arginine becomes an essential amino acid because of tissue-specific loss of ASL. Furthermore, studies in preclinical and human model systems have shown that ASL is an important component of a complex that channels extracellular arginine into the cell for the purpose of nitric oxide synthesis. To do so, it maintains a complex that involves nitric oxide synthase, the arginine transporter CAT1, and HSP90 [Erez et al 2011]. Loss of ASL leads to loss of this complex and an inability to generate nitric oxide even with supplemental arginine.

ASLD is characterized by accumulation of argininosuccinate and depletion of arginine [Burrage et al 2019]. The block in ureagenesis can cause hyperammonemia. Argininosuccinate has been hypothesized to be a potential toxic metabolite but the specific phenotypic features that can result from elevated argininosuccinate are not yet clearly defined. Finally, loss of ASL leads to loss of production of nitric oxide from nitric oxide synthase-dependent mechanisms. This dysregulation of nitric oxide has been shown to cause hypertension and some of the neurocognitive features of ASLD [Godshalk & Flynn 1990, Erez et al 2011, Baruteau et al 2018, Kho et al 2018, Baruteau et al 2019, Lerner et al 2019, Kho et al 2023].

Mechanism of disease causation. Loss of function

ASL-specific laboratory considerations. Analysis of ASL is complicated by the presence of a pseudogene, ASLP1, located approximately 3 Mb upstream of ASL. Homologous regions include intron 2, exon 3, and part of intron 3 of ASL [Trevisson et al 2007].

Table 10.

Notable ASL Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein
Change		Comment [Reference]
NM_000048​.4
NP_000039​.2 		c.346C>Tp.Gln116TerFounder variant reported in persons of Arab ancestry from the Kingdom of Saudi Arabia [Al-Sayed et al 2005]; also present in persons of Druze ancestry in Israel [Falik-Zaccai et al 2008]
NM_000048​.4 c.446+1G>A--Founder variant reported in persons of Druze ancestry in Israel [Avnat et al 2023]
NM_000048​.4
NP_000039​.2 		c.1060C>Tp.Gln354TerFounder variant reported in persons of Arab ancestry from the Kingdom of Saudi Arabia [Al-Sayed et al 2005]
c.1153C>Tp.Arg385CysFounder variant reported in persons of Finnish ancestry [Kleijer et al 2002]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Acknowledgments

The authors would like to acknowledge The Urea Cycle Disorders Consortium (UCDC; U54HD061221) which is part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the National Center for Advancing Translational Science (NCATS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute for Diabetes and Digestive and Kidney Diseases. The UCDC has also been supported by the O'Malley Foundation, the Rotenberg Family Fund, the Dietmar Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation.

Sandesh Nagamani is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Award Number P50HD103555 for use of the BCM IDDRC.

Lindsay C Burrage is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK126786 and by a Burroughs Wellcome Career Award for Medical Scientists.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author History

Lindsay C Burrage, MD, PhD (2025-present)
Ayelet Erez, MD, PhD; Weizmann Institute of Science (2011-2025)
Brendan Lee, MD, PhD (2011-present)
Sandesh CS Nagamani, MBBS, MD (2011-present)

Revision History

  • 14 August 2025 (sw) Comprehensive update posted live
  • 28 March 2019 (ha) Comprehensive update posted live
  • 3 February 2011 (me) Review posted live
  • 31 August 2010 (ae) Original submission

References

Literature Cited

  • Al-Sayed M, Alahmed S, Alsmadi O, Khalil H, Rashed MS, Imtiaz F, Meyer BF. Identification of a common novel mutation in Saudi patients with argininosuccinic aciduria. J Inherit Metab Dis. 2005;28:877–83. [PubMed: 16435180]
  • Ames EG, Powell C, Engen RM, Weaver DJ, Jr., Mansuri A, Rheault MN, Sanderson K, Lichter-Konecki U, Daga A, Burrage LC, Ahmad A, Wenderfer SE, Luckritz KE. Multisite retrospective review of outcomes in renal replacement therapy for neonates with inborn errors of metabolism. J Pediatr. 2022;246:116-122.e1. [PMC free article: PMC9233075] [PubMed: 35358588]
  • Avnat E, Shapira G, Shoval S, Israel-Elgali I, Alkelai A, Shuldiner AR, Gonzaga-Jauregui C, Zidan J, Maray T, Shomron N, Friedman E. Comprehensive genetic analysis of Druze provides insights into carrier screening. Genes (Basel). 2023;14:937. [PMC free article: PMC10137689] [PubMed: 37107695]
  • Balmer C, Pandey AV, Rufenacht V, Nuoffer JM, Fang P, Wong LJ, Haberle J. Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. Hum Mutat. 2014;35:27-35. [PubMed: 24166829]
  • Baruteau J, Diez-Fernandez C, Lerner S, Ranucci G, Gissen P, Dionisi-Vici C, Nagamani S, Erez A, Häberle J. Argininosuccinic aciduria: recent pathophysiological insights and therapeutic prospects. J Inherit Metab Dis. 2019;42:1147-61. [PubMed: 30723942]
  • Baruteau J, Jameson E, Morris AA, Chakrapani A, Santra S, Vijay S, Kocadag H, Beesley CE, Grunewald S, Murphy E, Cleary M, Mundy H, Abulhoul L, Broomfield A, Lachmann R, Rahman Y, Robinson PH, MacPherson L, Foster K, Chong WK, Ridout DA, Bounford KM, Waddington SN, Mills PB, Gissen P, Davison JE. Expanding the phenotype in argininosuccinic aciduria: need for new therapies. J Inherit Metab Dis. 2017;40:357–68. [PMC free article: PMC5393288] [PubMed: 28251416]
  • Baruteau J, Perocheau DP, Hanley J, Lorvellec M, Rocha-Ferreira E, Karda R, Ng J, Suff N, Diaz JA, Rahim AA, Hughes MP, Banushi B, Prunty H, Hristova M, Ridout DA, Virasami A, Heales S, Howe SJ, Buckley SMK, Mills PB, Gissen P, Waddington SN. Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer. Nat Commun. 2018;9:3505. [PMC free article: PMC6115417] [PubMed: 30158522]
  • Brusilow S, Horwich A. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. Chapter 85. New York: McGraw-Hill; 2001:1909-63.
  • Burrage LC, Lee B, Nagamani SCS. Urea cycle disorders. In: Kline MW, ed. Rudolph's Pediatrics. 23rd ed. New York, NY: McGraw-Hill Education; 2018.
  • 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, Nagamani S, Minard CG, Marini J, Masand P, Schady D, Shneider BL, Leung DH, Bali D, Lee B, et al. Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency. JCI Insight. 2020;5:e132342. [PMC free article: PMC7101134] [PubMed: 31990680]
  • Burrage LC, Thistlethwaite L, Stroup BM, Sun Q, Miller MJ, Nagamani SCS, Craigen W, Scaglia F, Sutton VR, Graham B, Kennedy AD, Milosavljevic A, Lee BH, Elsea SH, et al. Untargeted metabolomic profiling reveals multiple pathway perturbations and new clinical biomarkers in urea cycle disorders. Genet Med. 2019;21:1977-86. [PMC free article: PMC6650380] [PubMed: 30670878]
  • Chanvanichtrakool M, Schreiber JM, Chen WL, Barber J, Zhang A, Ah Mew N, Schulze A, Wilkening G, Nagamani SCS, Gropman A, Urea Cycle Disease C. Unraveling the link: seizure characteristics and ammonia levels in urea cycle disorder during hyperammonemic crises. Pediatr Neurol. 2024;159:48-55. [PMC free article: PMC11381174] [PubMed: 39121557]
  • Coryell ME, Hall WK, Thevaos TG, Welter DA, Gatz AJ, Horton BF, Sisson BD, Looper JW Jr, Farrow RT. A familial study of a human enzyme defect, argininosuccinic aciduria. Biochem Biophys Res Commun. 1964;14:307–12. [PubMed: 5836520]
  • Elkhateeb N, Olivieri G, Siri B, Boyd S, Stepien KM, Sharma R, Morris AAM, Hartley T, Crowther L, Grunewald S, Cleary M, Mundy H, Chakrapani A, Lachmann R, Murphy E, Santra S, Uudelepp ML, Yeo M, Bernhardt I, Sudakhar S, Chan A, Mills P, Ridout D, Gissen P, Dionisi-Vici C, Baruteau J. Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: a retrospective international study. Epilepsia. 2023;64:1612-26. [PubMed: 36994644]
  • Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, Garg HK, Li L, Mian A, Bertin TK, Black JO, Zeng H, Tang Y, Reddy AK, Summar M, O'Brien WE, Harrison DG, Mitch WE, Marini JC, Aschner JL, Bryan NS, Lee B. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. 2011;17:1619-26. [PMC free article: PMC3348956] [PubMed: 22081021]
  • Falik-Zaccai TC, Kfir N, Frenkel P, Cohen C, Tanus M, Mandel H, Shihab S, Morkos S, Aaref S, Summar ML, Khayat M. Population screening in a Druze community: the challenge and the reward. Genet Med. 2008;10:903-9. [PubMed: 19092443]
  • Fichtel JC, Richards JA, Davis LS. Trichorrhexis nodosa secondary to argininosuccinicaciduria. Pediatr Dermatol. 2007;24:25–7. [PubMed: 17300644]
  • Ficicioglu C, Mandell R, Shih VE. Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening. Mol Genet Metab. 2009;98:273–7. [PMC free article: PMC2773214] [PubMed: 19635676]
  • Glinton KE, Minard CG, Liu N, Sun Q, Elsea SH, Burrage LC, Nagamani SCS. Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: still many lessons to learn. Mol Genet Metab. 2023;140:107699. [PMC free article: PMC11162249] [PubMed: 37717413]
  • Godshalk CP, Flynn PJ. What is your diagnosis? Diffuse bronchointerstitial pattern consistent with a pulmonary infiltrate. J Am Vet Med Assoc. 1990;197:1213-4. [PubMed: 2254155]
  • Gurung S, Karamched S, Perocheau D, Seunarine KK, Baldwin T, Alrashidi H, Touramanidou L, Duff C, Elkhateeb N, Stepien KM, Sharma R, Morris A, Hartley T, Crowther L, Grunewald S, Cleary M, Mundy H, Chakrapani A, Batzios S, Davison J, Footitt E, Tuschl K, Lachmann R, Murphy E, Santra S, Uudelepp ML, Yeo M, Finn PF, Cavedon A, Siddiqui S, Rice L, Martini PGV, Frassetto A, Heales S, Mills PB, Gissen P, Clayden JD, Clark CA, Eaton S, Kalber TL, Baruteau J. The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria. J Inherit Metab Dis. 2024;47:1213-27. [PMC free article: PMC11586606] [PubMed: 38044746]
  • Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42:1192-230. [PubMed: 30982989]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
  • Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. 2008;97:1412–9. [PubMed: 18616627]
  • 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. Argininosuccinate lyase deficiency causes blood-brain barrier disruption via nitric oxide-mediated dysregulation of claudin expression. JCI Insight. 2023;8:e168475. [PMC free article: PMC10544197] [PubMed: 37490345]
  • 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. Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension. Am J Hum Genet. 2018;103:276–87. [PMC free article: PMC6080833] [PubMed: 30075114]
  • 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. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families. J Inherit Metab Dis. 2002;25:399–410. [PubMed: 12408190]
  • Kölker S, Valayannopoulos V, Burlina AB, Sykut-Cegielska J, Wijburg FA, Teles EL, Zeman J, Dionisi-Vici C, Barić I, Karall D, Arnoux JB, Avram P, Baumgartner MR, Blasco-Alonso J, Boy SP, Rasmussen MB, Burgard P, Chabrol B, Chakrapani A, Chapman K, Cortès I, Saladelafont E, Couce ML, de Meirleir L, Dobbelaere D, Furlan F, Gleich F, González MJ, Gradowska W, Grünewald S, Honzik T, Hörster F, Ioannou H, Jalan A, Häberle J, Haege G, Langereis E, de Lonlay P, Martinelli D, Matsumoto S, Mühlhausen C, Murphy E, de Baulny HO, Ortez C, Pedrón CC, Pintos-Morell G, Pena-Quintana L, Ramadža DP, Rodrigues E, Scholl-Bürgi S, Sokal E, Summar ML, Thompson N, Vara R, Pinera IV, Walter JH, Williams M, Lund AM, Garcia-Cazorla A. The phenotypic spectrum of organic acidurias and urea cycle disorders. part 2: the evolving clinical phenotype. J Inherit Metab Dis. 2015;38:1059–74. [PubMed: 25875216]
  • Kvedar JC, Baden HP, Baden LA, Shih VE, Kolodny EH. Dietary management reverses grooving and abnormal polarization of hair shafts in argininosuccinase deficiency. Am J Med Genet. 1991;40:211–3. [PubMed: 1897577]
  • Lerner S, Anderzhanova E, Verbitsky S, Eilam R, Kuperman Y, Tsoory M, Kuznetsov Y, Brandis A, Mehlman T, Mazkereth R, Neuropsychologists U, McCarter R, Segal M, Nagamani SCS, Chen A, Erez A. ASL metabolically regulates tyrosine hydroxylase in the nucleus locus coeruleus. Cell Rep. 2019;29:2144-2153.e7. [PMC free article: PMC6902269] [PubMed: 31747589]
  • Lerner S, Eilam R, Adler L, Baruteau J, Kreiser T, Tsoory M, Brandis A, Mehlman T, Ryten M, Botia JA, Ruiz SG, Garcia AC, Dionisi-Vici C, Ranucci G, Spada M, Mazkereth R, McCarter R, Izem R, Balmat TJ, Richesson R, Gazit E, Nagamani SCS, Erez A, et al. ASL expression in ALDH1A1(+) neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype. Hum Genet. 2021;140:1471-85. [PMC free article: PMC8460544] [PubMed: 34417872]
  • Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, Scheibenreiter S, Muehl A, Stöckler-Ipsiroglu S. Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. Mol Genet Metab. 2010;100:24–8. [PubMed: 20236848]
  • Mokhtarani M, Diaz GA, Rhead W, Berry SA, Lichter-Konecki U, Feigenbaum A, Schulze A, Longo N, Bartley J, Berquist W, Gallagher R, Smith W, McCandless SE, Harding C, Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS Jr, Dickinson K, Moors T, Norris C, Coakley D, Milikien DA, Nagamani SC, Lemons C, Lee B, Scharschmidt BF. Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio. Mol Genet Metab. 2013;110:446-53. [PMC free article: PMC4108288] [PubMed: 24144944]
  • Mori T, Nagai K, Mori M, Nagao M, Imamura M, Iijima M, Kobayashi K. Progressive liver fibrosis in late-onset argininosuccinate lyase deficiency. Pediatr Dev Pathol. 2002;5:597–601. [PubMed: 12370774]
  • Nagamani SCS, Ali S, Izem R, Schady D, Masand P, Shneider BL, Leung DH, Burrage LC. Biomarkers for liver disease in urea cycle disorders. Mol Genet Metab. 2021;133:148-56. [PMC free article: PMC8195846] [PubMed: 33846069]
  • Nagamani SC, Campeau PM, Shchelochkov OA, Premkumar MH, Guse K, Brunetti-Pierri N, Chen Y, Sun Q, Tang Y, Palmer D, Reddy AK, Li L, Slesnick TC, Feig DI, Caudle S, Harrison D, Salviati L, Marini JC, Bryan NS, Erez A, Lee B. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012a;90:836–46. [PMC free article: PMC3376491] [PubMed: 22541557]
  • Nagamani SC, Shchelochkov OA, Mullins MA, Carter S, Lanpher BC, Sun Q, Kleppe S, Erez A, O'Brian Smith E, Marini JC, Lee B, et al. A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. Mol Genet Metab. 2012b;107:315-21. [PMC free article: PMC3483446] [PubMed: 23040521]
  • Poretti A, Blaser SI, Lequin MH, Fatemi A, Meoded A, Northington FJ, Boltshauser E, Huisman TA. Neonatal neuroimaging findings in inborn errors of metabolism. J Magn Reson Imaging. 2013;37:294-312. [PMC free article: PMC4000315] [PubMed: 22566357]
  • Posset R, Gropman AL, Nagamani SCS, Burrage LC, Bedoyan JK, Wong D, Berry GT, Baumgartner MR, Yudkoff M, Zielonka M, Hoffmann GF, Burgard P, Schulze A, McCandless SE, Garcia-Cazorla A, Seminara J, Garbade SF, Kolker S, et al. Impact of diagnosis and therapy on cognitive function in urea cycle disorders. Ann Neurol. 2019;86:116-28. [PMC free article: PMC6692656] [PubMed: 31018246]
  • Posset R, Kolker S, Gleich F, Okun JG, Gropman AL, Nagamani SCS, Scharre S, Probst J, Walter ME, Hoffmann GF, Garbade SF, Zielonka M, et al. Severity-adjusted evaluation of newborn screening on the metabolic disease course in individuals with cytosolic urea cycle disorders. Mol Genet Metab. 2020;131:390-7. [PMC free article: PMC8315358] [PubMed: 33288448]
  • 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. Chronic liver involvement in urea cycle disorders. J Inherit Metab Dis. 2019;42:1118-27. [PubMed: 31260111]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Saudubray JM, Touati G, Delonlay P, Jouvet P, Narcy C, Laurent J, Rabier D, Kamoun P, Jan D, Revillon Y. Liver transplantation in urea cycle disorders. Eur J Pediatr. 1999;158 Suppl 2:S55–9. [PubMed: 10603100]
  • Siri B, Greco B, Martinelli D, Cairoli S, Guarnera A, Longo D, Napolitano A, Parrillo C, Rava L, Simeoli R, Spagnoletti G, Taurisano R, Veraldi S, Pietrobattista A, Spada M, Dionisi-Vici C. Positive clinical, neuropsychological, and metabolic impact of liver transplantation in patients with argininosuccinate lyase deficiency. J Inherit Metab Dis. 2025;48:e12843. [PMC free article: PMC11706762] [PubMed: 39776112]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B, et al. The incidence of urea cycle disorders. Mol Genet Metab. 2013;110:179-80. [PMC free article: PMC4364413] [PubMed: 23972786]
  • Trevisson E, Salviati L, Baldoin MC, Toldo I, Casarin A, Sacconi S, Cesaro L, Basso G, Burlina AB. Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum Mutat. 2007;28:694–702. [PubMed: 17326097]
  • Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML, et al. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008;94:397–402. [PMC free article: PMC2640937] [PubMed: 18562231]
  • Widhalm K, Koch S, Scheibenreiter S, Knoll E, Colombo JP, Bachmann C, Thalhammer O. Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics. 1992;89:1182–4. [PubMed: 1594374]
  • Zielonka M, Garbade SF, Gleich F, Okun JG, Nagamani SCS, Gropman AL, Hoffmann GF, Kolker S, Posset R, et al. From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria. Hum Mutat. 2020;41:946-60. [PMC free article: PMC7428858] [PubMed: 31943503]
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