High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor

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*1B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder 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.

Recent advances in the epidemiology and genetics of acute intermittent porphyria

“…Cyp21a1, the homolog of human CYP21A2 or CYP17A1 (-37), is a crucial enzyme in corticosteroid and sex hormone synthesis; Cyp21a1 is downregulated in mice with induced AIP but upregulated in wild-type mice (88,89). A study based on the population in the Spanish region of Murcia revealed parallel findings: the alleles CYP2D6*4 and *5 may prevent acute attacks in patients with AIP while CYP2D6 may constitute a penetrance-modifying gene (26).…”

“…Due to founder effects, the prevalence of AIP was markedly higher in some regions, such as 17.7 per million in southeastern Spain (26) and 23 per million in Sweden (19). In northern Sweden, it was even 192 per million (27).…”

Health impact of acute intermittent porphyria in latent and non-recurrent attacks patients

“…Such is the case with the HMBS pathogenic variant NM_000190.3( HMBS ):c.669_698del30 p.(Glu223_Leu232) in the Region of Murcia, south-east Spain [ 3 ]. As a consequence, AIP prevalence has increased in this part of the country [ 4 ].…”

Current and innovative emerging therapies for porphyrias with hepatic involvement

“…Although precipitating factors can trigger acute attacks, unknown modifying genes and/or epigenetic factors are likely to be largely responsible for the pathological phenotype. 13,14 Common precipitants of acute attacks include medications and other chemicals (see network resources), excess alcohol intake, certain steroid hormones, acute illness, infection, stress, physical exhaustion, caloric deprivation and rapid weight loss. These factors are all linked through the induction of hepatic ALAS1 mRNA expression, either directly or via PGC1a (e.g.…”