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Test ID: PCGP Porphyria Comprehensive Gene Panel, Varies


Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated


Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing (Spanish) (T826)

2. Molecular Genetics: Biochemical Disorders Patient Information (T527) in Special Instructions

Useful For

Follow up for abnormal biochemical results suggestive of porphyria

 

Establishing a molecular diagnosis for patients with porphyria

 

Identifying variants within genes known to be associated with porphyria, allowing for predictive testing of at-risk family members

Testing Algorithm

The following algorithms are available in Special Instructions:

-Porphyria (Acute) Testing Algorithm

-Porphyria (Cutaneous) Testing Algorithm

Method Name

Custom Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing

Reporting Name

Porphyria Comprehensive Gene Panel

Specimen Type

Varies

Specimen Minimum Volume

See Specimen Required

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

The porphyrias are a group of inherited disorders resulting from enzyme defects in the heme biosynthetic pathway. Depending on the specific enzyme involved, various porphyrins and their precursors accumulate in different specimen types. The patterns of porphyrin accumulation in erythrocytes and plasma and excretion of the heme precursors in urine and feces allow for the detection and differentiation of the porphyrias.

 

The porphyrias are typically classified as erythropoietic or hepatic based upon the primary site of the enzyme defect. In addition, hepatic porphyrias can be further classified as acute hepatic or chronic cutaneous, based on their clinical presentation.

 

The primary acute hepatic porphyrias: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), are associated with neurovisceral symptoms that typically onset during puberty or later. Common symptoms include severe abdominal pain, peripheral neuropathy, and psychiatric symptoms. A broad range of medications (including barbiturates and sulfa drugs), alcohol, infection, starvation, heavy metals, and hormonal changes may precipitate crises. Photosensitivity is not associated with AIP, but may be present in HCP and VP. Aminolevulinic acid dehydratase deficiency porphyria (ADP) is a rare, autosomal recessive porphyria that has a variable age at presentation.

 

Clinical manifestations of acute porphyria include attacks of neurologic dysfunction, commonly characterized as abdominal pain. However, these acute attacks are variable and can include vomiting, diarrhea, constipation, urinary retention, acute episodes of neuropathic symptoms, psychiatric symptoms, seizures, respiratory paralysis, tachycardia, and hypertension. Respiratory paralysis can progress to coma and death.

 

HCP and VP are also associated with cutaneous manifestations, including edema, sun-induced erythema, acute painful photodermatitis, and urticaria. In some cases, patients present with isolated photosensitivity.

 

Acute attacks may be prevented by avoiding both endogenous and exogenous triggers. These triggers include porphyrogenic drugs, hormonal contraceptives, fasting, alcohol, tobacco, and cannabis.

 

Acute hepatic porphyrias are caused by autosomal dominant variants in 1 of 3 genes: HMBS, associated with AIP; CPOX, associated with HCP; and PPOX, associated with VP. Variants in these genes show incomplete penetrance, and patients with a confirmed deleterious variant may be asymptomatic. ADP is inherited in an autosomal recessive manner, due to two pathogenic variants in ALAD.

 

The recommended first-tier tests to screen for acute hepatic porphyria are quantitative urinary porphyrins analysis (PQNRU/ Porphyrins, Quantitative, Random, Urine) and fecal porphyrins analysis (FQPPS / Porphyrins, Feces)

 

Cutaneous photosensitivity is associated with the chronic porphyrias: porphyria cutanea tarda (PCT) and the erythropoietic porphyrias; erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), and congenital erythropoietic porphyria (CEP). Although genetic in nature, environmental factors may exacerbate symptoms, significantly impacting the severity and course of disease.

 

CEP is an erythropoietic porphyria caused by uroporphyrinogen III synthase deficiency. Symptoms typically present in early infancy with red-brown staining of diapers, severe cutaneous photosensitivity with fluid-filled bullae and vesicles. Other common symptoms may include thickening of the skin, hypo- and hyperpigmentation, hypertrichosis, cutaneous scarring, and deformities of the fingers, eyelids, lips, nose, and ears. A few milder adult-onset cases have been documented as well as cases that are secondary to myeloid malignancies (sometimes referred to as erythropoietic uroporphyria).

 

PCT is the most common form of porphyria and is most commonly sporadic (acquired), but approximately 25% of cases are inherited in an autosomal dominant manner. The most prominent clinical characteristics are cutaneous photosensitivity and scarring on sun-exposed surfaces. Patients experience chronic blistering lesions resulting from mild trauma to sun-exposed areas. These fluid-filled vesicles rupture easily, become crusted, and heal slowly. Secondary infections can cause areas of hypo- or hyperpigmentation or sclerodermatous changes and may result in the development of alopecia at sites of repeated skin damage. Liver disease is common in patients with PCT as evidenced by abnormal liver function tests and with 30% to 40% of patients developing cirrhosis. In addition, there is an increased risk of hepatocellular carcinoma.

 

Hepatoerythropoietic porphyria (HEP) is observed when an individual inherits PCT from both parents. Patients exhibit a similar clinical presentation to what is seen in CEP.

 

The clinical presentation of EPP and XLP is identical with onset of symptoms typically occurring in childhood. Cutaneous photosensitivity in sun-exposed areas of the skin generally worsens in the spring and summer months. Common symptoms may include itching, edema, erythema, stinging or burning sensations, and occasionally scarring of the skin in sun-exposed areas.

 

Chronic porphyrias are caused by autosomal dominant pathogenic variants in UROD that are associated with inherited PCT or autosomal recessive variants in UROD that are associated with HEP. They are also due to autosomal recessive pathogenic variants in UROS or X-linked variants in GATA1 that are associated with CEP, or autosomal recessive variants in FECH that are associated with EPP. In addition, autosomal dominant variants in CLPX, associated with EPP2, and X-linked variants in ALAS2, associated with XLP, are also causes of chronic porphyrias.

 

A comprehensive gene panel is a helpful tool to establish a targeted diagnosis for patients with suggestive clinical and biochemical features of porphyria.

 

The recommended first-tier biochemical testing for patients with a suspected porphyria is most effective when following a stepwise approach. For more information see Porphyria (Acute) Testing Algorithm and Porphyria (Cutaneous) Testing Algorithm in Special Instructions.

Reference Values

An interpretive report will be provided.

Interpretation

All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Clinical Reference

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424

2. Siegesmund M, van Tuyll van Serooskerken AM, Poblete-Gutierrez P, Frank J: The acute hepatic porphyrias: current status and future challenges. Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):593-605

3. Tortorelli S, White A, Raymond K: Disorders of porphyrin metabolism. In: Dietzen DJ, Wong ECC, Bennett MJ, Haymond S, eds. Biochemical and Molecular Basis of Pediatric Disease. 5th ed. AACC Press; 2020:chap 15

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

81405

81406 x 2

81479

LOINC Code Information

Test ID Test Order Name Order LOINC Value
PCGP Porphyria Comprehensive Gene Panel In Process

 

Result ID Test Result Name Result LOINC Value
608680 Test Description 62364-5
608681 Specimen 31208-2
608682 Source 31208-2
608683 Result Summary 50397-9
608684 Result 82939-0
608685 Interpretation 69047-9
608686 Resources In Process
608687 Additional Information 48767-8
608688 Method 85069-3
608689 Genes Analyzed 48018-6
608690 Disclaimer 62364-5
608691 Released By 18771-6

Day(s) Performed

Varies

Report Available

3 to 4 weeks