High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor | Orphanet Journal of Rare Diseases | Full Text

High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor | Orphanet Journal of Rare Diseases | Full Text



Orphanet Journal of Rare Diseases

High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6genotype as a susceptibility factor

• María Barreda-SánchezEmail author,
• Juan Buendía-Martínez,
• Guillermo Glover-López,
• Carmen Carazo-Díaz,
• María Juliana Ballesta-Martínez,
• Vanesa López-González,
• María José Sánchez-Soler,
• Lidya Rodriguez-Peña,
• Ana Teresa Serrano-Antón,
• Remedios Gil-Ferrer,
• Maria del Carmen Martínez-Romero,
• Pablo Carbonell-Meseguer and
• Encarna Guillén-NavarroEmail author

Orphanet Journal of Rare Diseases201914:59

https://doi.org/10.1186/s13023-019-1031-7

©  The Author(s). 2019

• Received: 27 October 2018
• Accepted: 10 February 2019
• Published: 26 February 2019

Abstract

Background

Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress.

Although AIP penetrance is traditionally considered to be around 10–20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown.

Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks.

Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C9*2, *3; CYP2C19*2; CYP2D6*4, *5; CYP3A4*1Band CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBSfounder mutation c.669_698del30.

Results

AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers (p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype.

Conclusions

AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future.

Keywords

• Acute intermittent porphyria
• Founder mutation
• Penetrance
• CYP2D6
• Susceptibility factor
• Acute attacks
• Personalized medicine
• Genomic medicine