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Invitae Acute Hepatic Porphyrias Panel

Test description

The Invitae Acute Hepatic Porphyrias panel analyzes up to 4 genes (ALAD, CPOX, HMBS and PPOX) associated with the following forms of acute hepatic porphyria: delta aminolevulinic acid dehydratase deficiency porphyria (ADP), hereditary coproporphyria (HCP), acute intermittent porphyria (AIP) and variegate porphyria (VP). This panel may be appropriate for individuals with signs and symptoms of an acute hepatic porphyria with or without cutaneous manifestations. Additionally, this panel may be appropriate for those in whom porphyria is suspected due to abnormal porphyrin excretion. Genetic testing of these genes may confirm a diagnosis, help guide treatment and management decisions, identify at-risk family members, and guide enrollment in clinical trials.

Any individual with significantly increased levels of urinary 5-ALA excretion, with or without increased porphobilinogen, should consider genetic analysis for disease confirmation.

The genes within the Invitae Acute Hepatic Porphyrias panel cannot be combined with any other genes or panels at this time. Please contact Client Services with any questions.

Of note, this panel does not currently include testing for the following types of porphyria:

  • X-linked protoporphyria (XLP) associated with variants in ALAS2
  • Erythropoietic protoporphyria (EPP) associated with variants in FECH
  • Erythropoietic protoporphyria 2 (EPP2) associated with variants in CLPX
  • Porphyria cutanea tarda (PCT) associated with variants in UROD
  • Congenital erythropoietic porphyria (CEP) associated with variants in UROS
  • Hepatoerythropoietic porphyria (HEP) associated with variants in UROD

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Primary panel (4 genes)
GeneDisorder
ALADδ-Aminolevulinic acid dehydratase deficiency porphyria (ADP), also known as Doss porphyria
CPOXHereditary coproporphyria (HCP), also known as coproporphyrinogen deficiency, and harderoporphyria
HMBSAcute intermittent porphyria (AIP), also known as porphobilinogen deaminase deficiency
PPOXVariegate porphyria (VP), also known as protoporphyrinogen oxidase deficiency

Acute hepatic porphyrias are a group of diverse disorders associated with altered activity of porphyrin enzymes in the heme biosynthetic pathway, which results in accumulation and excess excretion of pathway intermediates and products. Each type of porphyria has characteristic patterns and levels of excess intermediates, which result in different clinical manifestations. For example, the excess porphyrins seen in individuals with hereditary coproporphyria (HCP) and variegate porphyria (VP) have photosensitive effects, causing cutaneous manifestations such as blistering skin lesions, features which are not typically present in individuals with δ-aminolevulinic acid dehydratase deficiency porphyria (ADP) or acute intermittent porphyria (AIP).

Age of onset varies depending on the type of porphyria, inheritance pattern, and certain environmental factors including certain drugs, steroid hormones, and exposure to heavy metals, which may cause previously asymptomatic individuals to display clinical symptoms of porphyria.

Individuals with acute intermittent porphyria (AIP) typically remain clinically asymptomatic throughout life. If clinical symptoms do manifest, onset is typically in adulthood. Individuals present with acute neurovisceral attacks that may last for several days at a time. Symptoms include abdominal pain, cramps, nausea, tachycardia, muscle pain and weakness, tremors, hyponatremia, hypertension, and excess sweating. Peripheral motor neuropathy, characterized by muscle weakness which begins in the proximal upper extremities, may also develop. δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP) is characterized by adolescent-onset attacks of abdominal pain and neuropathy. Exposure to heavy metals such as lead can cause symptoms in heterozygous carriers who would otherwise be asymptomatic. Hereditary coproporphyria (HCP) and variegate porphyria (VP) are characterized by neurovisceral attacks as well as cutaneous manifestations including blistering or non-blistering skin lesions, which are caused by photosensitivity.

First line laboratory testing for individuals displaying acute neurovisceral symptoms includes urinary 5-aminolevulinic acid (5-ALA), porphobilinogen and total porphyrins. All four acute hepatic porphyrias are associated with significant increases in urinary 5-aminolevulinic acid (5-ALA). AIP, HCP, and VP are also associated with increased urinary excretion of porphobilinogen. For individuals with blistering or non-blistering skin lesions, total plasma porphyrins or erythrocyte porphyrins should be tested.

Treatment for the neurological symptoms of acute hepatic porphyrias most commonly consists of intravenous hemin therapy (typically heme arginate) and avoidance of drugs and other environmental factors which are known to be harmful in individuals with acute porphyrias. Cutaneous symptoms are more difficult to treat and center around protection from sunlight exposure. Currently, there is no officially approved treatment available to prevent recurrent attacks.

Sensitivity by Clinical ConditionGeneClinical Sensitivity Resources
Clinical sensitivity unknown for δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP)ALADN/A
>90% of dominant hereditary coproporphyria (HCP)CPOXPMID: 9888388, 19460837
Clinical sensitivity unknown for recessive harderoporphyriaCPOXN/A
>95% of acute intermittent porphyria (AIP)HMBSPMID: 9199558, 19460837
>95% of variegate porphyria (VP)PPOXPMID: 10486317
DisorderGeneInheritance
δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP)ALADAutosomal recessive
Hereditary coproporphyria* (HCP)CPOXAutosomal dominant
HarderoporphyriaCPOXAutosomal recessive
Acute intermittent porphyria* (AIP)HMBSAutosomal dominant
Variegate porphyria* (VP)PPOXAutosomal dominant

*Incomplete penetrance has been reported in all of the autosomal dominant acute hepatic porphyrias.

Acute intermittent porphyria (AIP) is the most common acute hepatic porphyria, with an estimated prevalence of 5.9 per 1,000,000 individuals in Europe (PMID: 23114748). Variegate porphyria (VP) has an estimated prevalence of approximately 0.5 per 100,000 individuals in Europe and the United States and 3 per 1,000 individuals in South Africa, where VP is particularly common (PMID: 23409300, 8673113). Hereditary coproporphyria (HCP) and δ-aminolevulinic acid dehydratase deficiency porphyria (ADP) are both rare conditions, and prevalence is unknown.

Clinicians may consider ordering the Invitae Acute Hepatic Porphyria panel for individuals with an indication of:

  • Elevated urinary porphobilinogen (PBG) or aminolevulinic acid (ALA) levels
  • Recurrent, prolonged (>24 h) episodes of severe abdominal pain
  • Neurological symptoms that occurred around the time of severe abdominal pain (i.e. muscle weakness, sensory loss, confusion, hallucinations, seizures)
  • Gastrointestinal manifestations that occurred around the time of severe abdominal pain (i.e. nausea/vomiting, diarrhea, constipation)
  • Hyponatremia around the time of severe abdominal pain
  • Red to brownish urine on exposure to light
  • Chronic blistering lesions on sun-exposed areas
  1. Pischik, E, Kauppinen, R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015; 8:201-14. PMID: 26366103
  2. Anderson, KE, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann. Intern. Med. 2005; 142(6):439-50. PMID: 15767622
  3. Sarkany, RP. Making sense of the porphyrias. Photodermatol Photoimmunol Photomed. 2008; 24(2):102-8. PMID: 18353093
  4. Bonkovsky, HL, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am. J. Med. 2014; 127(12):1233-41. PMID: 25016127
  5. Pischik, E, Kauppinen, R. Neurological manifestations of acute intermittent porphyria. Cell. Mol. Biol. (Noisy-le-grand). 2009; 55(1):72-83. PMID: 19268005
  6. Whatley, SD, et al. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin. Chem. 2009; 55(7):1406-14. PMID: 19460837
  7. Chen, B, et al. Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease. Hum. Mutat. 2016; 37(11):1215-1222. PMID: 27539938
  8. Meissner, P, et al. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria. J. Clin. Invest. 1993; 91(4):1436-44. PMID: 7682572
  9. Akagi, R, et al. delta-Aminolevulinate dehydratase (ALAD) porphyria: the first case in North America with two novel ALAD mutations. Mol. Genet. Metab. 2006; 87(4):329-36. PMID: 16343966
  10. Solis, C, et al. Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch. Neurol. 2004; 61(11):1764-70. PMID: 15534187
  11. Meissner, PN, et al. A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria. Nat. Genet. 1996; 13(1):95-7. PMID: 8673113
  12. Singal, AK, Anderson, KE. Variegate Porphyria. 2013 Feb 14. In: Adam, MP, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 23409300
  13. Elder, G, et al. The incidence of inherited porphyrias in Europe. J. Inherit. Metab. Dis. 2013; 36(5):849-57. PMID: 23114748
  14. Balwani, M et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017 Oct; 66(4):1314-1322. doi: 10.1002/hep.29313. PMID: 28605040

For management guidelines, please refer to:
Balwani, M et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. Hepatology. 2017 Oct; 66(4):1314-1322 (PMID: 28605040).
Pischik, E, Kauppinen, R. An update of clinical management of acute intermittent porphyria. Appl Clin Genet. 2015; 8:201-14 (PMID: 26366103).

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALAD NM_000031.5
CPOX NM_000097.5
HMBS NM_000190.3
PPOX NM_000309.3