Phenotyping acute Porphyrias

Acute hepatic porphyrias are rare metabolic disorders caused by disruptions in heme synthesis, an essential component of hemoglobin. The most common form is acute intermittent porphyria (AIP), resulting from a genetic defect in the HMBS gene. Only a small proportion of carriers develop acute attacks with severe abdominal pain, nerve damage, and psychiatric symptoms. This thesis describes and investigates various manifestations of acute hepatic porphyrias. Using data from Dutch AIP patients, three groups were compared: individuals with frequent attacks, those with few attacks, and asymptomatic carriers. Patients with frequent attacks experienced more symptoms and long-term complications, were hospitalized more often, leading to higher healthcare costs, were more frequently unemployed, and had a higher mortality related to the disease. Secondly, mortality in Dutch AIP families between 1810 and 2017 was compared with that of the general population. Since the 1960s, carriers have shown a similar life expectancy, likely due to improved diagnosis, education, and treatment. Furthermore, two very rare manifestations are described: a slowly progressive neurological disorder in individuals with two HMBS mutations, and a porphyria variant in which the bone marrow appears to play a role. Finally, the recovery of a patient with another metabolic disease, tyrosinemia type 1, after treatment with heme which is commonly used for acute hepatic porphyrias is reported.