Knowledge on rare diseases and orphan drugs

Its prevalence is around 1/330,000 in European countries. Due to a founder effect, it is much higher in South Africa.

The disease generally manifests after puberty, predominantly affecting women. In 60 % of cases, patients' only symptoms are skin lesions due to photosensitivity (bullous photodermatitis). Lesions predominantly appear on sun-exposed areas (hands, face) and are characterized by the presence of more or less painful bullae, which usually leave hyperpigmented scars. In 20% of cases, patients present with both skin lesions and neurovisceral attacks. Finally, 20% of patients experience only neurovisceral attacks. Neurovisceral attacks can last several weeks and manifest as severe abdominal pain, neurological disorders and psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, with nausea, vomiting and severe constipation. Psychological disturbances are variable: irritability, emotional sensitivity, depressive disorder, anxiety and, more rarely, auditory or visual hallucinations, disorientation, and mental confusion. Neurological manifestations can affect both the central and peripheral nervous systems (myalgia, paresis, ascending flaccid paralysis of the limbs or convulsions), and can lead to severe complications such as motor paralysis. Tachycardia and hyponatremia are common during attacks. The attacks are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low caloric diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle).

Variegate Porphyria (VP) is caused by a deficiency in coproporphyrinogen oxidase (PPOX, the penultimate enzyme in the heme biosynthesis pathway), which leads to an accumulation of porphyrins and their precursors (delta aminolevulinic acid, ALA, and porphobilinogen, PBG) in the liver. The enzyme deficiency is due to mutations of the PPOX gene (NM_000309.5) coding for PPOX.

Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria attacks) and ALA in urine, and defective PPOX enzyme activity in circulating lymphocytes. Identification of a causal mutation of the PPOX gene confirms the diagnosis.

Differential diagnoses include acute intermittent porphyria and, particularly, porphyria cutanea tarda. The presence of a fluorometric peak (626-628 nm) in plasma is pathognomonic and allows a definitive diagnosis of variegate porphyria rather than porphyria cutanea tarda.

Antenatal diagnosis may be offered to families at risk of homozygous porphyria variegata.

Transmission is autosomal dominant and penetrance is incomplete. Genetic counseling is offered to patients and their families, informing them that there is a 50% risk of transmitting the disease at each pregnancy.

Acute attacks must be considered as medical emergencies and treated by injection of human hemin and/or perfusion of carbohydrates. Management includes elimination of one or more triggers, relief of pain (opioids), vomiting, and anxiety, and prevention of episodes (avoidance of triggers, particularly drugs). Phlebotomy and chloroquine are not effective in treating cutaneous signs. Micro-bleeds are beneficial in some patients. Protecting the skin from light is key. In the case of symptomatic iron-deficiency anemia, iron supplementation is likely to cause a skin flare-up and should preferably be administered intravenously.

Thanks to early diagnosis and management, fatal outcomes from acute attacks are rare. The disease is rarely progressive. On the other hand, VP is a risk factor for the long-term development of hepatocellular carcinoma and chronic renal failure. Annual monitoring is proposed to detect these chronic complications.

Last update: March 2024 - Expert reviewer(s): Dr Neila TALBI | MetabERN*

* European Reference Network