Porphyrias

The porphyrias are rare hereditary disorders of haem biosynthesis. Deficiency of a specific enzymatic step leads to accumulation of upstream haem precursors and porphyrins, with downstream effects on multiple organ systems. Clinical presentation follows two broad patterns: acute neurovisceral attacks and cutaneous photosensitivity. The age of onset varies across the spectrum and depends on the specific subtype, with acute hepatic porphyrias typically presenting after puberty and erythropoietic forms often presenting in childhood.

Acute attacks typically feature severe abdominal pain, generalised or localised and not accompanied by muscle guarding, alongside gastrointestinal symptoms (nausea, vomiting, constipation, and ileus), autonomic features (tachycardia and hypertension), peripheral neuropathy, neuropsychiatric manifestations, and occasionally fever, sweating, and tremor. Cutaneous presentations range from blistering photodistributed skin fragility in the chronic hepatic forms to painful acute non-blistering photosensitivity in the erythropoietic forms. Some entities, notably variegate porphyria and hereditary coproporphyria, may show combined acute and cutaneous features.

The estimated symptomatic prevalence of overt acute intermittent porphyria, the most common acute hepatic porphyria, is 5.4 per 1,000,000 in European cohorts; the prevalence of pathogenic variant carriers is substantially higher, reflecting low clinical penetrance. Yearly incidence is estimated to be 0.12 per 1,000,000. Regional founder effects raise local prevalence severalfold in Sweden and parts of Spain; German registry data document spectrum heterogeneity.

The hereditary porphyrias are caused by pathogenic variants in eight core genes encoding enzymes of the haem biosynthesis pathway. The genetic forms can be grouped into acute hepatic porphyrias and cutaneous porphyrias. Frequently identified causes include the following examples: acute intermittent porphyria (HMBS, most common acute hepatic), familial porphyria cutanea tarda (UROD), the inherited form of the most common cutaneous porphyria, and erythropoietic protoporphyria (FECH, painful acute non-blistering photosensitivity).

The genetic conditions associated with porphyria follow heterogeneous inheritance patterns. Acute intermittent porphyria (HMBS), variegate porphyria (PPOX), and hereditary coproporphyria (CPOX) are autosomal dominant with low penetrance (often <10% of carriers developing symptoms); ALA-dehydratase deficiency porphyria (ALAD) and congenital erythropoietic porphyria (UROS) are autosomal recessive; erythropoietic protoporphyria (FECH) typically follows an autosomal recessive pseudo-dominant pattern with a hypomorphic trans allele; X-linked protoporphyria (ALAS2) is X-linked.

• Where a hereditary porphyria is suspected, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity supports diagnosis and informs individualised clinical management, with therapeutic decisions made by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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