Mortality in Pedigrees with Acute Intermittent Porphyria

Area of Science:

• Genetics
• Epidemiology
• Medical History

Background:

• Acute intermittent porphyria (AIP) is a genetic disorder with historically high mortality rates.
• The specific mortality risk associated with heterozygosity for hydroxymethylbilane synthase (HMBS) gene variants causing AIP remains largely unknown.

Purpose of the Study:

• To estimate all-cause mortality in individuals with HMBS gene variants causing AIP.
• To compare mortality rates in AIP pedigrees with the general Dutch population.

Main Methods:

• Utilized a family tree mortality ratio method to analyze lifespan data from Dutch AIP pedigrees spanning 1810–2017.
• Calculated standardized mortality ratios (SMRs) for AIP pedigrees against the general Dutch population.

Main Results:

• Overall mortality in HMBS variant heterozygotes was not significantly different from the general population (SMR 1.01).
• A significant excess mortality was observed in women aged 45–64 (SMR 1.99) and men aged 70–74 (SMR 1.55), primarily between 1915 and 1964.
• Since the mid-20th century, individuals with HMBS variant heterozygosity have achieved a normal lifespan.

Conclusions:

• HMBS variant heterozygosity does not confer an increased overall mortality risk compared to the general population.
• Historical excess mortality in specific demographics highlights the impact of AIP management and awareness over time.
• Improved disease management, family counseling, and increased awareness have contributed to normalizing lifespans for AIP patients in recent decades.