Acute/Neurovisceral Porphyria Panel

Porphyrias are a group of metabolic disorders caused by impairment of heme biosynthesis pathway. There are two different forms of porphyria: acute/neurovisceral and chronic/cutaneous. Symptom onset typically occurs in late childhood to adulthood. Acute/neurovisceral porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), ALA dehydratase prophyria (ADP) and hereditary coproporphyria (HCP). These disorders involve episodic nervous system attacks often resulting in abdominal pain, and psychiatric and neurologic effects. In severe cases attacks can be life threatening resulting in peripheral motor neuropathy, seizures, coma, or bulbar paralysis. Pre-symptomatic diagnosis is helpful in preventing acute attacks through avoidance of triggers including alcohol, certain drugs, infections, steroid hormones, and fasting (Bissell et al. 1993). Cutaneous symptoms are present in less than half of HCP patients but may include photosensitivity resulting in skin blistering similar to patients with porphyria cutanea tarda and variegate porphyria (Whatley et al. 2009; Lamoril et al. 2001; www.porphyriafoundation.com).

There are currently four different forms of acute/neurovisceral porphyria caused by specific pathogenic variants in genes involved in heme biosynthesis: ALA dehydratase porphyria (ALAD), acute intermittent porphyria (HMBS), hereditary coproporphyria (CPOX), and variegate porphyria (PPOX). AIP, HCP, and VP forms of porphyria are inherited in an autosomal dominant manner whereas ADP is inherited in an autosomal recessive manner.

See individual gene test descriptions for information on molecular biology of gene products.

In a series of 103 patients where variegate porphyria diagnosis was established by elevated fecal porphyrin measurement, decreased PPOX activity, and elevated plasma porphyrin fluorescence, pathogenic variants were identified in 96% of cases (Whatley et al. 1999). Analytical sensitivity is >95% for detection of pathogenic variants in the PPOX gene (Singal and Anderson 1993).

In two studies with individuals having a clinical and biochemical diagnosis of hereditary coproporphyria, pathogenic variants in the CPOX gene were identified in 29 of 31 and 32 of 32 patients respectively (Whatley et al. 2009; Rosipal et al. 1999). Analytical sensitivity is >95% as gross deletions in the CPOX gene have only been reported in rare cases (Whatley et al. 2009).

In patients with decreased PBG activity indicative of acute intermittent porphyria, underlying pathogenic variants in the HMBS gene were detected in 240 of 252 individuals (Puy et al. 1997). Analytical sensitivity for detection of causative variants in the HMBS gene is >95% as large deletions are present in only a few cases (Whatley et al. 2009).

Analytical sensitivity for the ALAD gene should be high as all pathogenic variants reported are detectable by sequencing. Clinical sensitivity cannot be estimated because of the small number of patients reported to date.

Deletions in the HMBS, PPOX, and CPOX genes have been reported in less than 5% of cases (Singal and Anderson 1993, Whatley et al. 2009). To date no gross deletions have been reported in the ALAD gene.

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).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).