The phenotype of compound heterozygous BSEP deficiency patients is determined by the combined residual function of the two ABCB11 mutations: results from the NAPPED consortium

The spectrum of Progressive Familial Intrahepatic Cholestasis diseases: Update on pathophysiology and emerging treatments

“…On the other hand, a genotype with two predicted protein truncating mutations (PPTMs) has been associated with a more severe phenotype. It has been hypothesized that the amount of residual bile acid transport activity of the two mutated alleles determines the phenotype and the responsiveness to therapeutic interventions (van Wessel et al, 2020;Strautnieks et al, 2008;Felzen et al, 2020). However, the large amount of different ABCB11 mutations, who have only partly been characterized towards functional Patients with severe BSEP deficiency commonly have jaundice, pruritus, high serum bile acids (sBA) and high transaminases, and present in early childhood.…”

“…The amount of residual function conferred by missense mutations is difficult to predict, and adding to this, most patients are compound heterozygotes, what further complicates assessment of residual activity at the level of individual patients. Even patients with one PPTM and one of the common mutations p.D482G or p.E297G are not always responsive to SBD (Felzen et al, 2020). SBD aims to partially interrupt the enterohepatic circulation, thereby decreasing the amount of bile acids available for reuptake in the terminal ileum and reducing the bile acid accumulation in the body.…”