Alnylam Act^® Acute Hepatic Porphyria Sponsored Testing Program

Porphyria is a family of rare, genetic diseases characterized by potentially life-threatening attacks and, for some patients, chronic debilitating symptoms that negatively impact daily functioning and quality of life. Porphyria includes several subtypes, and each has unique manifestations, making an accurate diagnosis even more challenging.

The four types of acute hepatic porphyria (AHP) are acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALAD-deficiency porphyria (ADP). These four types result from a genetic defect leading to a deficiency in one of the enzymes of the heme biosynthesis pathway in the liver.

There are currently eight different forms of porphyria caused by specific pathogenic variants in genes involved in heme biosynthesis: ALA dehydratase porphyria (ALAD), acute intermittent porphyria (HMBS), hereditary coproporphyria (CPOX), variegate porphyria (PPOX), porphyria cutanea tarda/hepatoerythropoietic porphyria (UROD), congenital erythropoietic protoporphyria (UROS), erythropoietic protoporphyria (FECH), and X-linked protoporphyria (ALAS2).

Autosomal dominant forms of porphyria include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and porphyria cutanea tarda. Autosomal recessive forms include ALA dehydratase porphyria, hepatoerythropoietic porphyria, congenital erythropoietic protoporphyria and erythropoietic protoporphyria. Only pathogenic variants in the ALAS2 gene are involved in an X-linked recessive form of porphyria (Karim et al. 2015; Besur et al. 2014).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary. This panel provides 100% 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. PGnome^® panels typically provide slightly increased coverage over the PGxome^® equivalent. PGnome^® sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Random (spot) urine for aminolevulinic acid (ALA), porphobilinogen (PBG), porphyrins is the primary test used to diagnosis AHP. A genetic test can be used to determine which AHP type a patient has and can be useful for at-risk family screening.

To learn more about our test methods and limitations, please CLICK HERE.

To be eligible for the Alnylam Act Acute Hepatic Porphyrias Testing Program, patients in the US and Canada must be pubescent or older and meet at least one of the following criteria:

Family history of acute hepatic porphyria.

OR

Elevated (> upper limit of normal) urinary porphobilinogen (PBG) or aminolevulinic acid (ALA) levels.

OR

Unexplained recurrent (more than one), prolonged (>24 hours) episodes of severe, diffuse (poorly localized) abdominal pain.
And at least TWO of the following:

• Red to brownish urine
• Blistering skin lesions on sun-exposed areas
• Peripheral nervous system manifestations occurring around the time of abdominal pain (for example, motor neuropathy (paresis), sensory neuropathy (numbness, tingling, limb pain))
• Central nervous system manifestations occurring around the time of abdominal pain (for example, confusion, anxiety, seizures, hallucinations)
• Autonomic nervous system manifestations occurring around the time of abdominal pain (for example, hyponatremia (Na in the blood < lower limit of normal, tachycardia, hypertension, nausea and vomiting, constipation))

Individuals in the US and Canada tested through the Alnylam Act^® program are eligible for optional pre- and post-test genetic counseling to help them understand their test results. This service is provided through GenomeMedical, a third-party genetic counseling service, and is made available by Alnylam at no charge as part of the program.

Pre-test genetic counseling is intended to help the patient learn more about what to expect during the genetic testing process. If the patient receives a negative test result, Genome Medical will provide an educational video explaining the results.

Patients can access genetic counseling by having their healthcare provider complete the pre- and/or post-test genetic counseling section of the PreventionGenetics test requisition form.

Patients will be contacted by GenomeMedical to schedule an appointment, generally within 24-48 hours of receipt of the faxed referral form.

SPECIMEN REQUIREMENTS

Whole Blood

Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube).

Saliva

Oragene™ or GeneFiX™ Saliva Collection kit used according to manufacturer instructions. DNA from saliva specimens is invariably contaminated with microbial and food DNA, which can impact specimen quality and may result in delayed testing and/or the need for a second specimen.

OCD-100 Swab

OCD-100 Buccal Swab used according to manufacturer instructions.

Buccal

Specimens may be shipped at room temperature.

Specimen collection kits: Buccal specimen collection kits, which contain the TRF and the shipping label, may be requested through the kit order form or via the online order form.

SHIPPING AND HANDLING INSTRUCTIONS

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.