Hyperammonemia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesGene CPT Codes Copy CPT Codes
10407 ACADM81479,81479 Add to Order
ACADS81405,81479
ACADVL81406,81479
ARG181479,81479
ASL81479,81479
ASS181406,81479
CPS181479,81479
CPT1A81479,81479
CPT281404,81479
ETFA81479,81479
ETFB81479,81479
ETFDH81479,81479
GLUD181406,81479
HADHA81406,81479
HADHB81406,81479
HCFC181479,81479
HLCS81406,81479
HMGCS281479,81479
IVD81406,81479
MCCC181406,81479
MCCC281406,81479
MMAA81405,81479
MMAB81405,81479
MMACHC81404,81479
MMADHC81479,81479
MMUT81406,81479
NAGS81479,81479
OAT81479,81479
OTC81405,81479
PCCA81406,81405
PCCB81406,81479
SLC22A581405,81479
SLC25A1381479,81479
SLC25A1581479,81479
SLC25A2081405,81404
SLC7A781479,81479
TMEM7081479,81479
Test Code Test Copy Genes Total Price Panel CPT Code Gene CPT Codes Copy CPT Code STAT
10407 Genes x (37) $890 81479 81404, 81405, 81406, 81479 Add to Order

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Hyperammonemia is the occurrence of elevated levels of ammonia in the plasma. Normal ammonia levels are considered to be <110 μmol/L (190 μg/dL) in newborns and <80 μmol/L (140 μg/dL) in older infants and adults (Nyhan et al. 2017). Ammonia is toxic to the brain and is typically removed quickly from circulation via the action of the urea cycle (Rabier 2016). When this does not occur properly and ammonia levels increase substantially above these cutoffs, a number of clinical symptoms can occur. These include rapid, acute encephalopathy, decreased consciousness, psychiatric symptoms (such as personality changes, agitated and aggressive behavior, and decreased cognition), vomiting, abnormal gait and/or posturing, and seizures (LaBuzetta et al. 2010; Rabier 2016). Hyperammonemia can lead to irreversible brain damage, coma and death if not identified and treated rapidly, and is considered a medical emergency (LaBuzetta et al. 2010; Lachmann and Murphy 2016).

The various conditions that cause hyperammonemia can be classified as either primary or secondary hyperammonemias. Primary hyperammonemia is due to a dysfunction of the urea cycle that leads directly to the build-up of ammonia. Classical urea cycle defects are caused by pathogenic variants in the ARG1, ASL, ASS1, CPS1, NAGS or OTC genes. These genes all encode proteins that play direct roles in the urea cycle, and are only active in the liver (Häberle 2013).

Secondary hyperammonemias occur when the urea cycle is inhibited due to substrate deficiencies or the accumulation of metabolites that inhibit the action of one or more of the urea cycle enzymes (Häberle 2013). In addition, as the urea cycle operates only in the liver, factors that affect liver function can also disrupt the urea cycle and lead to hyperammonemia (Häberle 2013; Monch 2015; Rabier 2016). Genetic causes of secondary hyperammonemias can include the organic acidemias (primarily methylmalonic acidemia, propionic acidemia, and isovaleric acidemia), lysinuric protein intolerance, pyrroline-5-carboxylate synthetase deficiency, glutamine synthase deficiency, disorders that cause a decrease in the availability of acetyl-CoA (such as fatty acid oxidation defects), and defects in the carnitine cycle (Häberle 2013).

Additional, non-genetic causes of hyperammonemia can include infection (particularly urinary tract infections caused by urease-producing bacteria), alcohol and/or drug misuse, hepatic disease, increased protein load, cancer and chemotherapy, and vascular shunts (Häberle 2013; Monch 2015; Rabier 2016).

Genetics

This sequencing panel currently includes genes that have been associated with primary or secondary hyperammonemia. The majority of the disorders associated with these genes are inherited in an autosomal recessive manner. The few exceptions are carnitine palmitoyltransferase II deficiency caused by defects in the CPT2 gene (both autosomal dominant and recessive inheritance has been reported), hyperinsulinism-hyperammonemia syndrome caused by defects in the GLUD1 gene (autosomal dominant inheritance), and methylmalonic aciduria and homocystinuria, cblX type and ornithine transcarbamylase deficiency (both of which are X-linked recessive disorders). The most common genetic cause of primary hyperammonemia in adults has been reported to be OTC deficiency in symptomatic, heterozygous female carriers (Rabier 2016).

See the individual gene test descriptions for information on disorder specific clinical features and molecular biology of gene products.

Testing Strategy

This panel typically provides ≥98% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

In addition to the regions described above, this testing includes coverage of the following OTC variants that reside in untranslated or deep intronic regions: c.-366A>G, c.540+265G>A, c.867+1126A>G and c.1005+1091C>G.

This panel does NOT provide coverage for the following variants in untranslated or deep intronic regions: ARG1 c.306-611T>C, ASS1 c.175-1119G>A, CPS1 c.4102-239A>G, HADHB c.442+614A>G, L2HGDH c.906+354G>A, NAGS c.-3064C>A, OAT c.199+313C>G and SLC22A5 c.825-52G>A. Coverage for any these variants can be requested separately via targeted sequencing if desired.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Clinical Sensitivity - Sequencing with CNV

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which these genes have been sequenced together in a patient cohort with hyperammonemia as the primary indication for testing. The clinical sensitivity of sequencing the individual genes is high in patient groups with biochemical and/or enzymatic diagnoses of the relevant disorders; details are available on the individual gene test description pages. Analytical sensitivity is expected to be high as the majority of variants reported in these genes are detectable via direct sequencing.

To date, no large (exonic level, usually multi-exon) deletions or duplications have been documented in the following genes: ACADS, CPT2, GLUD1, NAGS, ETFA, ETFB, MCCC2, MMAB, MMADHC or HCFC1 (Human Gene Mutation Database).

Large deletions or duplications have been documented, but appear to be relatively uncommon, in the following genes: ACADM, ACADVL, ARG1, ASL, CPT1A, HADHA, HADHB, HLCS, HMGCS2, OAT, SLC22A5, SLC25A15, SLC25A20, TMEM70, PCCB, MMUT, ETFDH, MCCC1, MMAA, MMACHC, and IVD (Human Gene Mutation Database).

Large deletions or duplications have been reported as a somewhat more common cause of disease in the ASS1, CPS1, OTC, PCCA, SLC7A7 and SLC25A13 genes. Thus far, 4 gross deletions have been reported in the ASS1 gene, 9 gross deletions in the CPS1 gene, and 2 gross deletions and 4 gross insertions in the SLC25A13 gene (Human Gene Mutation Database).

Deletions and duplications are reported to account for ~5-10% of causative alleles in the OTC gene (Lichter-Knoecki et al. 2016), ~20% of causative alleles in the PCCA gene (Yang et al. 2004; Kaya et al. 2008; Desviat et al. 2009), and ~5-20% of causative SLC7A7 alleles in non-Finnish populations (Kamada et al. 2001; Shoji et al. 2002; Font-Llitjós et al. 2009; Sebastio and Nunes 2011).

Indications for Test

Patients with hyperammonemia are good candidates for this test, especially if other external causes of hyperammonemia (such as infection or hepatic failure) have been ruled out. Adults presenting with encephalopathy are also good candidates for this test.

Diseases

Name Inheritance OMIM ID
3 Methylcrotonyl-CoA Carboxylase 1 Deficiency AR 210200
3-Methylcrotonyl CoA Carboxylase 2 Deficiency AR 210210
Arginase Deficiency AR 207800
Argininosuccinate Lyase Deficiency AR 207900
Carnitine Palmitoyltransferase I Deficiency AR 255120
Carnitine Palmitoyltransferase II Deficiency, Infantile AR 600649
Carnitine Palmitoyltransferase II Deficiency, Late-Onset AD,AR 255110
Carnitine Palmitoyltransferase II Deficiency, Lethal Neonatal AR 608836
Carnitine-Acylcarnitine Translocase Deficiency AR 212138
Citrin Deficiency AR 605814
Citrullinemia Type I AR 215700
Citrullinemia Type II AR 603471
Congenital Hyperammonemia, Type I AR 237300
Deficiency Of Butyryl-CoA Dehydrogenase AR 201470
Encephalopathy, Acute, Infection-Induced, 4, Susceptibility To AD,AR 614212
Glutaric Aciduria, Type 2 AR 231680
Gyrate Atrophy of Choroid and Retina with or without Ornithinemia AR 258870
Hyperammonemia, Type III AR 237310
Hyperinsulinemic Hypoglycemia, Familial 6 AD 606762
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome AR 238970
Isovaleryl-CoA Dehydrogenase Deficiency AR 243500
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency AR 609016
Lysinuric Protein Intolerance AR 222700
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency AR 201450
Mental Retardation, X-Linked 3 (Methylmalonic Acidemia and Homocysteinemia, cblX Type) XL 309541
Methylmalonic Aciduria and Homocystinuria, cblC Type AR 277400
Methylmalonic Aciduria and Homocystinuria, cblD Type AR 277410
Methylmalonic Aciduria Cbla Type AR 251100
Methylmalonic Aciduria Cblb Type AR 251110
Methylmalonic Aciduria Due To Methylmalonyl-CoA Mutase Deficiency AR 251000
Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency AR 605911
Mitochondrial Complex V (ATP Synthase) Deficiency, Nuclear Type 2 AR 614052
Multiple Carboxylase Defiency, Early Onset AR 253270
Ornithine Carbamoyltransferase Deficiency XL 311250
Propionic Acidemia AR 606054
Systemic Carnitine Deficiency AR 212140
Trifunctional Protein Deficiency AR 609015
Very Long Chain Acyl-CoA Dehydrogenase Deficiency AR 201475

Related Test

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PGxome®

Citations

  • Desviat et al. 2009. PubMed ID: 19157943
  • Font-Llitjós M. et al. 2009. European Journal of Human Genetics. 17: 71-9. PubMed ID: 18716612
  • Häberle J. 2013. Archives of Biochemistry and Biophysics. 536: 101-8. PubMed ID: 23628343
  • Human Gene Mutation Database (Bio-base).
  • Kamada Y. et al. 2001. The Journal of Clinical Investigation. 108: 717-24. PubMed ID: 11544277
  • Kaya et al. 2008. PubMed ID: 18790721
  • LaBuzetta J.N. et al. 2010. The American Journal of Medicine. 123: 885-91. PubMed ID: 20920686
  • Lachmann R.H. and Murphy E. 2016. Emergencies. In: Hollak C.E.M. and Lachmann R.H., editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 541-551.
  • Lichter-Konecki U. et al. 2016. Ornithine Transcarbamylase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 24006547
  • Monch E. 2015. Deficiencies of the Urea Cycle - Clinical Significance and Therapy. Bremen: UNI-MED. 91 p.
  • Nyhan et al. 2017. Work-Up of the Patient with Hyperammonemia. In: Hoffmann G.F., Nyhan W.L. and Zschocke J., editors. Inherited Metabolic Diseases: A Clinical Approach. Berlin: Springer, p 113-117.
  • Rabier D. 2016. Hyperammonemia. In: Hollak C.E.M. and Lachmann R.H., editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 541-551.
  • Sebastio G. and Nunes V. 2011. Lysinuric Protein Intolerance. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301535
  • Shoji Y. et al. 2002. Human Mutation. 20: 375-81. PubMed ID: 12402335
  • Yang et al. 2004. PubMed ID: 15059621

Ordering/Specimens

Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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