Knowledge on rare diseases and orphan drugs

Prevalence in Europe is estimated at about 1/1,000,000.

The disease manifests after puberty, predominantly affecting women. Patients suffer neurovisceral episodes that can persist for several weeks, manifesting severe abdominal pain (85-95% of cases), neurological disorders, and psychological disturbances. Abdominal pain is very often associated with low back pain irradiating to the legs, and with nausea, vomiting and constipation. Several psychological disturbances can be observed: 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 these episodes. In the rare case of cardiac arrhythmia or respiratory paralysis, it can be fatal. Such episodes are most commonly triggered by exogenous factors (porphyrinogenic drugs, alcohol, infections, a low-calorie diet, stress), and/or endogenous factors (hormonal, linked to menstrual cycle). In 30% of cases, patients develop skin lesions as a result of photosensitivity. Lesions predominantly appear on sun-exposed areas (hands, face) and come with more or less painful bullae, usually leaving hyperpigmented scars.

The disease is caused by a deficiency in coproporphyrinogen oxidase (CPOX, the sixth 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 CPOX gene (NM_000088; 3q12) coding for CPOX.

Reddish or brown coloration of urine following exposure to warm light is suggestive of the disease. Diagnosis is based on significantly elevated concentrations of PBG (pathognomonic of acute porphyria attack) and ALA in urine, and defective CPOX enzyme activity in circulating lymphocytes. Identification of a causal mutation of the CPOX gene confirms the diagnosis.

Differential diagnoses include acute intermittent porphyria, porphyria cutanea tarda and, above all, variegate porphyria.

Antenatal diagnosis is possible if a pathogenic variant has been identified in the family. It is offered to families at risk of homozygous form.

Genetic counseling is recommended to patients and families to identify individuals at risk of developing or transmitting the disease. Transmission is autosomal dominant. Affected individuals have a 50% risk of transmitting the disease on to their offspring.

Acute episodes 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 acute attacks (avoidance of triggers, particularly drugs).

With early diagnosis and management, acute episodes are rarely severe. In hereditary coproporphyria, acute episodes are less frequent compared to acute intermittent porphryia, and the disease is rarely progressive if the triggering factors are eliminated.

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

* European Reference Network