Argininosuccinate Lyase Deficiency
Summary
Clinical characteristics.
Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form and a late-onset form:
- The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death.
- In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia.
Manifestations of ASL deficiency (ASLD) that appear to be unrelated to the severity or duration of hyperammonemic episodes:
- Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability)
- Liver disease (hepatitis, cirrhosis)
- Trichorrhexis nodosa (coarse brittle hair that breaks easily)
- Systemic hypertension
Diagnosis/testing.
Elevated plasma ammonia concentration (>100 µmol/L), elevated plasma citrulline concentration (usually 100-300 µmol/L), and elevated argininosuccinic acid in the plasma or urine establish the diagnosis of ASLD. Identification of biallelic pathogenic variants in ASL by molecular genetic testing or – in limited instances – by significantly reduced ASL enzyme activity from skin fibroblasts, red blood cells, or in a flash-frozen sample from a liver biopsy help in confirmation of the diagnosis. Note: All 50 states in the US include ASL deficiency in their newborn screening programs.
Management.
Treatment of manifestations: Treatment involves rapid control of hyperammonemia during metabolic decompensations and long-term management to help prevent episodes of hyperammonemia and long-term complications. During acute hyperammonemic episodes, oral protein intake is discontinued, oral intake is supplemented with intravenous lipids and/or glucose, and intravenous nitrogen-scavenging therapy is used. If ammonia levels do not normalize, hemodialysis is the next step.
Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management; for those not responsive to these measures, oral nitrogen-scavenging therapy can be considered. Orthotopic liver transplantation (OLT) is considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.
Surveillance: Monitoring the concentration of plasma amino acids to identify deficiency of essential amino acids and impending hyperammonemia at intervals depending on age and metabolic status.
Agents/circumstances to avoid: Excess protein intake; less than recommended intake of protein; prolonged fasting or starvation; obvious exposure to communicable diseases; valproic acid; intravenous steroids; hepatotoxic drugs (in those with hepatic involvement).
Evaluation of relatives at risk: Testing of at-risk sibs (either by molecular genetic testing if the family-specific pathogenic variants are known or by biochemical testing) shortly after birth can reduce morbidity by permitting early diagnosis and treatment of those who are affected.
Genetic counseling.
ASL deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk family members and prenatal testing and preimplantation diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
Diagnosis
Argininosuccinate lyase (ASL) is the enzyme that catalyzes the fourth step in the urea cycle, in which argininosuccinic acid is cleaved to produce arginine and fumarate. All 50 states in the US include ASL deficiency in their newborn screening programs.
Suggestive Findings
ASL deficiency (ASLD) should be suspected in infants with a positive newborn screening result and in symptomatic individuals with supportive clinical and laboratory findings.
Positive Newborn Screening (NBS) Result
NBS for ASL deficiency is primarily based on quantification of the analyte citrulline on dried blood spots.
Citrulline values above the cutoff reported by the screening laboratory are considered positive, but elevation of citrulline can also be seen with citrullinemia type 1, citrin deficiency, and pyruvate carboxylase deficiency; hence, confirmation of the diagnosis of ASL deficiency requires follow-up testing to detect elevated plasma or urine concentration of argininosuccinic acid or its anhydride compounds. If testing supports the likelihood of ASL deficiency, additional testing is required to establish the diagnosis (see Establishing the Diagnosis).
Clinical Findings
Individuals with ASLD may present with the following nonspecific supportive clinical features and preliminary laboratory findings that vary by age.
In the neonatal period
- Hyperammonemia can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis.
- The presentation is typically indistinguishable from that of other proximal urea cycle disorders (i.e., carbamoyl-phosphate synthetase I deficiency, ornithine transcarbamylase deficiency, and citrullinemia type I).
In individuals outside the neonatal period
- Episodic hyperammonemia that is triggered by acute infection, stress, or non-compliance with dietary restrictions or medications
- Liver involvement including hepatomegaly, elevated transaminases, liver fibrosis, or cirrhosis
- Neurocognitive deficits such as ADHD, developmental delay, learning disability, and seizures that may be independent of hyperammonemia
- Trichorrhexis nodosa consisting of coarse and brittle hair that breaks easily. See images.
- Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes
- Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium
Laboratory Findings
Plasma ammonia concentration
- In the severe forms of ASL deficiency, the initial plasma ammonia concentration (before treatment) may be greater than 1,000 µmol/L, though typically elevations are in the ranges of few hundred µmol/L.
- In the milder neonatal and late-onset forms of ASL deficiency, the elevations of plasma ammonia concentration may be less pronounced but above the upper limits of normal for age (see Table 1).
Table 1.
Upper Limits of Normal Plasma Ammonia Concentration by Age
| Age | Upper Limits of Normal Ammonia Concentration (µmol/L) 1 |
|---|---|
| 0-7 days | 94 |
| 8-30 days | 80 |
| 1-12 months | 47 |
| 1-15 years | 48 |
| >16 years | 26 |
- 1.
The values depicted are only representative of the normal ranges; the normal reference ranges of individual laboratories should be used for clinical interpretation.
Plasma quantitative amino acid analysis. See Table 2.
The typical range of citrulline at presentation is 100-300 µmol/L [Brusilow & Horwich 2001]. The typical plasma levels of argininosuccinic acid are between 5 and 110 µmol/L [Ficicioglu et al 2009].
Urinary analysis
- Orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed [Gerrits et al 1993, Brosnan & Brosnan 2007].
- Argininosuccinic acid is significantly elevated. Urinary concentration of argininosuccinate is typically greater than 10,000 µmol/g of creatinine on urine amino acid analysis [Ficicioglu et al 2009] (normal range 0-1 µmol/L).
Establishing the Diagnosis
The diagnosis of ASL deficiency is established in a proband with suggestive metabolic/biochemical findings and confirmed by the following set of specific laboratory test findings:
- Elevated plasma ammonia concentration
- Elevated plasma citrulline concentration (usually 100-300 µmol/L)
- Elevated argininosuccinic acid in the plasma or urine
Identification of biallelic pathogenic variants in ASL by molecular genetic testing (Table 3) or – in limited instances – by significantly reduced ASL enzyme activity from skin fibroblasts or red blood cells or in a flash-frozen sample from a liver biopsy help in confirmation of the diagnosis. As the laboratories that can assess enzymatic activity are limited and as molecular genetic testing has become widely available, the latter modality has become the more commonly used confirmatory test for ASL deficiency.
Molecular genetic testing approaches, which depend on the clinical findings, can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (typically exome sequencing and exome array).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Children with the distinctive laboratory findings of ASL deficiency described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas symptomatic individuals with nonspecific supportive clinical and laboratory findings (who have not undergone NBS or who had normal NBS results in the past) in whom the diagnosis of ASL deficiency has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2).
Option 1
When NBS results and other laboratory findings suggest the diagnosis of ASL deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing. Sequence analysis of ASL detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
Note: Single-gene testing is most appropriate when the diagnosis is made based on results of biochemical testing that show elevated levels of argininosuccinic acid in the plasma or urine.
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 at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
Note: A multigene panel test may be considered first when the presentation is with hyperammonemia and confirmatory biochemical diagnosis has not been performed or is unavailable.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When an individual presents with hyperammonemia and confirmatory biochemical diagnosis has not been performed or is unavailable, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 3.
Molecular Genetic Testing Used in Argininosuccinate Lyase Deficiency
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method 3 |
|---|---|---|
| ASL | Sequence analysis 4 | >90% |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Author observation
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
The clinical presentation of argininosuccinate lyase deficiency (ASLD) is variable. The two most common forms are severe neonatal-onset form and late-onset form.
Severe neonatal-onset form. The clinical presentation of the severe neonatal-onset form, which is indistinguishable from that of other urea cycle disorders, is characterized by hyperammonemia within the first few days after birth. Newborns typically appear healthy for the first 24 hours but within the next few days develop vomiting, lethargy, and refusal to accept feeds [Brusilow & Horwich 2001]. Tachypnea and respiratory alkalosis are early findings. 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 (coarse and friable hair) at this early stage are the only clinical findings that may suggest the diagnosis of ASL deficiency [Brusilow & Horwich 2001].
Late-onset form. In contrast to the neonatal-onset form, the manifestations of the late-onset form range from episodic hyperammonemia (triggered by acute infection, stress, or non-compliance with 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].
Whereas manifestations secondary to hyperammonemia are common to all urea cycle disorders, many individuals with ASL deficiency can present with a complex clinical phenotype. The incidence of (1) neurocognitive deficiencies; (2) hepatitis, cirrhosis; (3) trichorrhexis nodosa; and (4) systemic hypertension are overrepresented in individuals with ASL deficiency [Nagamani et al 2012a, Kölker et al 2015, Kho et al 2018]. 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].
Complications of ASL Deficiency
Neurocognitive deficiencies. In a cross-sectional study of individuals with a urea cycle disorder (UCD), it was observed that persons with ASL deficiency had a higher incidence of developmental delay and neurologic abnormalities than did individuals with OTC deficiency [Tuchman et al 2008].
Individuals with ASL deficiency also had an increased incidence of attention-deficit/hyperactivity disorder (ADHD), developmental delay (intellectual disability, behavioral abnormalities, and/or learning disability), and seizures compared to persons with all other UCDs [Tuchman et al 2008]. In a recent retrospective study, developmental delay and epilepsy were observed in 92% (48/52) and 42% (22/52) of individuals, respectively [Baruteau et al 2017]. Though neurocognitive deficits are common in ASL deficiency, they are not universally present; many individuals with ASL deficiency who are treated with protein restriction and supplemental arginine have normal cognition and development [Widhalm et al 1992, Ficicioglu et al 2009].
The increasing reliance on newborn screening programs for early diagnosis of ASL deficiency allows the evaluation of early treatment on disease progression, especially in the late-onset form:
- Ficicioglu et al [2009] reported the long-term outcome of 13 infants diagnosed between age four and six weeks by newborn screening programs. All had low ASL enzyme activity; in spite of optimal therapy with protein restriction and arginine supplementation, four of 13 had learning disability, three had mild developmental delay, three had seizures, and six had an abnormal EEG including abnormal sharp irregular background activity, frequent bilateral paroxysms, and increased slow wave activity.
- In a separate cohort of 17 individuals with ASL deficiency diagnosed by newborn screening 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]. The overall favorable outcomes in persons in this cohort may be attributable not only to early dietary and therapeutic interventions but also to the high proportion of persons with very mild disease.
Liver disease in individuals with ASL deficiency also appears to be independent of the defect in ureagenesis. The spectrum of hepatic involvement ranges from hepatomegaly to elevations of liver enzymes to severe liver fibrosis [Billmeier et al 1974, Mori et al 2002, Tuchman et al 2008]. Liver involvement has been noted even in individuals treated with protein restriction and arginine supplementation who had not experienced significant hyperammonemia [Mori et al 2002, Mercimek-Mahmutoglu et al 2010]. In a recent retrospective study, hepatomegaly and elevated alanine aminotransferase (ALT) were observed in nearly half of individuals with ASL deficiency [Baruteau et al 2017]. At present no biochemical or molecular features help predict liver dysfunction in people with ASL deficiency. Given the potential direct toxicity of argininosuccinate on hepatocytes, lowering of the argininosuccinate levels in plasma (a reflection of its production by the liver) may have potential benefit [Nagamani et al 2012c].
Trichorrhexis nodosa (see images) is characterized by nodular swellings of the hair shaft accompanied by frayed fibers and loss of cuticle. About half of individuals with ASL deficiency have an abnormality of the hair manifest as dull, brittle hair surrounded by areas of partial alopecia [Fichtel et al 2007]. Normal hair contains 10.5% arginine by weight; hair that is deficient in arginine as a result of ASL deficiency is weak and tends to break. Thus, this clinical feature responds to arginine treatment.
Hypertension. Whereas there have only been anecdotal reports of hypertension in ASL deficiency, preclinical data and systematic analysis of blood pressures from one controlled clinical trial have shown that ASL deficiency 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 ASL in the vascular endothelium.
Electrolyte imbalances. Some individuals develop electrolyte imbalances such as hypokalemia. The hypokalemia is observed even in individuals who are not treated with sodium phenylbutyrate. The etiology is unclear; increased renal wasting has been suggested.
Genotype-Phenotype Correlations
Data are insufficient to infer any genotype-phenotype correlations.
Prevalence
The estimated prevalence is 1:70,000 to 1:218,000 live births [Brusilow & Horwich 2001, NORD]. However, ASL deficiency is very likely underdiagnosed, making it difficult to assess the true frequency in the general population.
Differential Diagnosis
The severe neonatal-onset form of ASL deficiency shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway (see Urea Cycle Disorders Overview).
The late-onset form of ASL deficiency shares a later onset with other disorders such as late-onset ornithine transcarbamylase (OTC) deficiency, and late-onset citrullinemia type 1. However, the elevation of argininosuccinate is characteristic and differentiates ASL deficiency from other urea cycle disorders.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual with argininosuccinate lyase (ASL) deficiency following diagnosis, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis of ASL Deficiency
| Evaluation | Comment |
|---|---|
| Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian 1 |
|
| Neurocognitive assessment | Consider referral to a developmental pediatrician, psychologist, &/or neurologist. |
| Baseline evaluation for evidence of hepatic involvement incl hepatomegaly, hepatitis, & signs of liver failure |
|
| Plotting of systolic & diastolic blood pressure on centile charts based on age & stature | |
| Consultation w/clinical geneticist &/or genetic counselor |
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; PT = prothrombin time
- 1.
After a new diagnosis of ASL deficiency in a child, the closest hospital and local pediatrician should also be informed.
Treatment of Manifestations
Treatment involves rapid control of hyperammonemia during metabolic decompensations and long-term management to help prevent episodes of hyperammonemia and long-term complications.
During acute hyperammonemic episodes severe enough to cause neurologic symptoms, the treatment includes the following [Ahrens et al 2001] (full text) (see Table 5).
Table 5.
Acute Inpatient Treatment in Individuals with ASL Deficiency
| Manifestation/ Concern | Treatment | Consideration/Other |
|---|---|---|
| Acute hyperammonemic episodes | Discontinue oral protein intake. | |
| Supplement oral intake w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism. | ||
| IV nitrogen-scavenging therapy. A loading dose of 600 mg/kg L-arginine-HCL & 250 mg/kg each of sodium benzoate & sodium phenylacetate in 25-35 mL/kg of 10% dextrose solution given intravenously over a 90-min period is recommended, followed by a sustained IV infusion of 600 mg/kg L-arginine-HCL & 250 mg/kg each of sodium benzoate & sodium phenylacetate over a 24-hr period. | When available, plasma concentrations of ammonia-scavenging drugs should be monitored to avoid toxicity. 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. | |
| Failure to decrease ammonia levels w/medical therapy | Prompt institution of hemodialysis |
|
HCL = hydrochloride; IV = intravenous
Inpatient emergency treatment should: (a) take place at the closest medical facility equipped to treat individuals with metabolic disorders, (b) be started without delay, and (c) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
Long-term management. Dietary restriction of protein and dietary supplementation with arginine are the mainstays of long-term management as detailed in Table 6.
Table 6.
Routine Daily Treatment in Individuals with ASL Deficiency
| Principle/ Manifestation | Treatment | Consideration/Other |
|---|---|---|
| Dietary restriction of protein | Lifelong dietary management is necessary & requires the services of a metabolic nutritionist. 1 |
|
| Arginine base supplementation | The doses of arginine base routinely recommended are 400-700 mg/kg/day in persons weighing ˂20 kg & 8.8-15.4 g/m2/day in those weighing >20 kg. The authors prefer to use a lower dose of arginine whenever possible, in the range of 100-250 mg/kg/day. |
|
| Oral nitrogen-scavenging therapy (an alternative pathway therapy in which sodium benzoate & phenyl butyrate stimulate the excretion of nitrogen in the form of hippuric acid & phenylacety-lglutamine, respectively) | The typical dose ranges 2 for the medications:
| Individuals who have had frequent metabolic decompensations or episodes of ↑ ammonia despite being on a protein-restricted diet & arginine base supplementation are candidates for oral nitrogen-scavenging therapy. |
| Orthotopic liver transplantation (OLT) | Recommended only in those w/recurrent hyperammonemia or metabolic decompensations that are resistant to conventional medical therapy, or in those who develop cirrhosis w/associated metabolic decompensations [Author, personal observations] | OLT does not correct the arginine deficiency or elevation of argininosuccinic acid at the tissue level, two abnormalities thought to account for the long-term complications of ASL deficiency. |
| Hypertension |
| |
| Hypokalemia | Electrolyte (potassium) supplementation is appropriate when indicated. | |
| Neurocognitive delay | Special educational services & therapies as needed |
RDA = recommended daily allowance
- 1.
Some of the correlations between compliance with the prescribed diet and outcome are contradictory. Although in some patients dietary therapy along with arginine supplementation have been shown to reverse the abnormalities of hair, to improve cognitive outcome, and to reverse abnormalities on EEG [Coryell et al 1964, Kvedar et al 1991, Ficicioglu et al 2009], in many 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.
The dose ranges depicted are those typically used in individuals with ASLD. The safety and efficacy of phenylbutyrate doses >20 g/day are not known. The dose of glycerol phenylbutyrate depicted is the recommended initial dose in phenylbutyrate-naïve patients. When switching from sodium phenylbutyrate, the total daily dosage of glycerol phenylbutyrate (mL) = total daily dosage of sodium phenylbutyrate (g) x 0.86. The maximal daily dose for benzoate is 12 grams. When prescribing doses in the upper ranges of the recommended dosing, toxicity should be monitored.
Surveillance
Table 7.
Recommended Surveillance for Individuals with Argininosuccinate Lyase Deficiency
| Manifestation/ Concern | Evaluation | Frequency/Comment |
|---|---|---|
| Management of the disorder | Follow up in a metabolic clinic w/a qualified metabolic dietician & clinical biochemical geneticist | Laboratory & clinical monitoring frequency should depend on metabolic status of the individual. In general:
|
| Abnormal amino acid levels | Analysis of plasma amino acids to identify deficiency of essential amino acids as well as impending hyperammonemia 1 | |
| Hypertension | Measurement of blood pressure using the appropriate-sized cuff & plotting the centile values for age & stature | At each clinic visit |
| Abnormal liver function | Liver function tests (ALT, AST) | Every 6-12 mos as required |
| Abnormal electrolytes | Serum electrolyte analysis | Every 1-2 yrs as required |
ALT = alanine aminotransferase; AST = aspartate aminotransferase
- 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.
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
- Obvious exposure to communicable diseases
- Valproic acid
- Intravenous steroids
- Hepatotoxic drugs in individuals with hepatic involvement
Evaluation of Relatives at Risk
Evaluation of at-risk sibs shortly after birth can reduce morbidity by permitting early diagnosis and treatment of those who are affected. Evaluations can include:
- Molecular genetic testing if the pathogenic variant in the family is known;
- Plasma amino acids to specifically assess for argininosuccinic acid in a newborn at risk prior to molecular genetic testing or while waiting for molecular genetic testing results.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Nitrite and nitrate supplementation is being evaluated as potential therapy for hypertension and vascular dysfunction in ASL deficiency [NCT02252770, NCT03064048, Nagamani et al 2012b].
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.