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:
ALAD CPOX HMBS PPOX
ALAD CPOX HMBS PPOX
|ALAD||δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP), also known as Doss porphyria|
|CPOX||Hereditary coproporphyria (HCP), also known as coproporphyrinogen deficiency, and harderoporphyria|
|HMBS||Acute intermittent porphyria (AIP), also known as porphobilinogen deaminase deficiency|
|PPOX||Variegate 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 Condition||Gene||Clinical Sensitivity Resources|
|Clinical sensitivity unknown for δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP)||ALAD||N/A|
|>90% of dominant hereditary coproporphyria (HCP)||CPOX||PMID: 9888388, 19460837|
|Clinical sensitivity unknown for recessive harderoporphyria||CPOX||N/A|
|>95% of acute intermittent porphyria (AIP)||HMBS||PMID: 9199558, 19460837|
|>95% of variegate porphyria (VP)||PPOX||PMID: 10486317|
|δ-Aminolevulinic acid dehydratase deficiency porphyria (ADP)||ALAD||Autosomal recessive|
|Hereditary coproporphyria* (HCP)||CPOX||Autosomal dominant|
|Acute intermittent porphyria* (AIP)||HMBS||Autosomal dominant|
|Variegate porphyria* (VP)||PPOX||Autosomal 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:
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).
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|