Gene:
ASL
argininosuccinate lyase

PharmGKB contains no dosing guidelines for this . To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.


Annotated Labels

  1. FDA Label for valproic acid and ABL2,ASL,ASS1,CPS1,NAGS,OTC,POLG
  2. FDA Label for phenylacetic acid,sodium benzoate and ARG1,ASL,ASS1,CPS1,NAGS,OTC

last updated 03/21/2016

1. FDA Label for valproic acid and ABL2,ASL,ASS1,CPS1,NAGS,OTC,POLG

Actionable PGx

Summary

Valproic acid is used to treat patients with various types of seizures. The FDA-approved drug label for valproic acid notes that it is contraindicated in patients with known urea cycle disorders (UCDs), a group of uncommon genetic abnormalities, since these patients can sometimes experience fatal hyperammonemic encephalopathy following initiation of treatment. It is also contraindicated in patients with POLG mutations. However, the label does not explicitly mention testing for genetic mutations leading to UCDs or POLG mutations prior to valproic acid treatment.

Annotation

UCDs result from mutations in one of several genes, such as ornithine transcarbamylase (OTC) or carbamoyl-phosphate synthetase 1 (CPS1).

Excerpt from the valproic acid (Depakene) drug label:

Valproic acid is contraindicated in patients with known urea cycle disorders.

Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low blood urea nitrogen (BUN), or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD.

Valproic acid is also contraindicated in patients with POLG mutations. POLG is a mitochondrial DNA polymerase and mutations in this gene are associated with hereditary neurometabolic syndromes such as Alpers Huttenlocher Syndrome. These patients are at an increased risk of liver failure and death.

POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the valproic acid drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Bipolar Disorder
    • Indications & usage section, Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Congenital Abnormalities
    • Warnings section
    • source: PHONT
  • Epilepsy
    • Indications & usage section, Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Headache
    • Indications & usage section, Adverse reactions section
    • source: PHONT
  • Leukemia, Myeloid, Acute
    • Warnings section, Precautions section
    • source: PHONT
  • Migraine without Aura
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Neoplasms
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Pancreatitis
    • Boxed warning section, Adverse reactions section, Warnings and precautions section
    • source: U.S. Food and Drug Administration
  • Seizures
    • Indications & usage section, Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • Spinal Dysraphism
    • Warnings section
    • source: PHONT
  • Toxic liver disease
    • Warnings section, Adverse reactions section, Precautions section
    • source: PHONT
  • OTC
    • toxicity, Contraindications section, Warnings and precautions section
    • source: U.S. Food and Drug Administration
  • POLG
    • toxicity, Boxed warning section, Contraindications section, Warnings and precautions section
    • source: U.S. Food and Drug Administration

last updated 06/20/2016

2. FDA Label for phenylacetic acid,sodium benzoate and ARG1,ASL,ASS1,CPS1,NAGS,OTC

Genetic testing required

Summary

Sodium Phenylacetate and Sodium Benzoate provides an alternate vehicle to urea for waste nitrogen excretion in patients with urea cycle disorders. Urea cycle disorders may be caused by mutations in the genes NAGS, CPS1, OTC, ASS1, ASL and ARG1. This drug-biomarker pair was previously in the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" but has subsequently been removed.

Annotation

Sodium Phenylacetate and Sodium Benzoate provides an alternate vehicle to urea for waste nitrogen excretion in patients with urea cycle disorders. Urea cycle disorders may be caused by mutations in the genes NAGS, CPS1, OTC, ASS1, ASL and ARG1. This drug-biomarker pair was previously in the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" but has subsequently been removed.

Excerpt from the Sodium Phenylacetate and Sodium Benzoate (Ammonul) drug label:

AMMONUL is a nitrogen binding agent indicated as adjunctive therapy for the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.

Urea cycle disorders can result from decreased activity of any of the following enzymes: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL), or arginase (ARG).

Sodium phenylacetate and sodium benzoate are metabolically active compounds that can serve as alternatives to urea for the excretion of waste nitrogen. Figure 2 is a schematic illustrating how the components of AMMONUL, phenylacetate and benzoate, provide an alternative pathway for nitrogen disposal in patients without a fully functioning urea cycle.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the sodium Phenylacetate and Sodium Benzoate (Ammonul) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • ARG1
    • other, Clinical pharmacology section
    • source: U.S. Food and Drug Administration
  • ASL
    • other, Clinical pharmacology section
    • source: U.S. Food and Drug Administration
  • ASS1
    • other, Clinical pharmacology section
    • source: U.S. Food and Drug Administration
  • CPS1
    • other, Clinical pharmacology section
    • source: U.S. Food and Drug Administration
  • NAGS
    • other, Clinical pharmacology section
    • source: U.S. Food and Drug Administration
  • OTC
    • other, Clinical pharmacology section
    • source: U.S. Food and Drug Administration

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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Overview

Alternate Names:  None
Alternate Symbols:  None
PharmGKB Accession Id: PA25046

Details

Cytogenetic Location: chr7 : q11.21 - q11.21
GP mRNA Boundary: chr7 : 65540776 - 65558330
GP Gene Boundary: chr7 : 65530776 - 65561330
Strand: plus

Visualization

UCSC has a Genome Browser that you can use to view PharmGKB annotations for this gene in context with many other sources of information.

View on UCSC Browser
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.
No related genes are available

Curated Information ?

Curated Information ?

Publications related to ASL: 3

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Human mutation. 2009. Mitchell Sabrina, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The consensus coding sequences of human breast and colorectal cancers. Science (New York, N.Y.). 2006. Sjöblom Tobias, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. American journal of human genetics. 2006. Merla Giuseppe, et al. PubMed

LinkOuts

UniProtKB:
ARLY_HUMAN (P04424)
Ensembl:
ENSG00000126522
GenAtlas:
ASL
GeneCard:
ASL
MutDB:
ASL
ALFRED:
LO093529C
HuGE:
ASL
Comparative Toxicogenomics Database:
435
ModBase:
P04424
HumanCyc Gene:
HS10034
HGNC:
746

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