TY - JOUR
T1 - Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency
AU - Felzen, Antonia
AU - van Wessel, Daan B.E.
AU - the NAtural course and Prognosis of PFIC and Effect of biliary Diversion (NAPPED) Consortium
AU - Gonzales, Emmanuel
AU - Thompson, Richard J.
AU - Jankowska, Irena
AU - Shneider, Benjamin L.
AU - Sokal, Etienne
AU - Grammatikopoulos, Tassos
AU - Kadaristiana, Agustina
AU - Jacquemin, Emmanuel
AU - Spraul, Anne
AU - Lipiński, Patryk
AU - Czubkowski, Piotr
AU - Rock, Nathalie
AU - Shagrani, Mohammad
AU - Broering, Dieter
AU - Nicastro, Emanuele
AU - Kelly, Deirdre
AU - Nebbia, Gabriella
AU - Arnell, Henrik
AU - Fischler, Björn
AU - Hulscher, Jan B.F.
AU - Serranti, Daniele
AU - Arikan, Cigdem
AU - Polat, Esra
AU - Debray, Dominique
AU - Lacaille, Florence
AU - Goncalves, Cristina
AU - Hierro, Loreto
AU - Muñoz Bartolo, Gema
AU - Mozer-Glassberg, Yael
AU - Azaz, Amer
AU - Brecelj, Jernej
AU - Dezsőfi, Antal
AU - Calvo, Pier Luigi
AU - Grabhorn, Enke
AU - Hartleif, Steffen
AU - van der Woerd, Wendy J.
AU - Kamath, Binita M.
AU - Wang, Jian She
AU - Li, Liting
AU - Durmaz, Özlem
AU - Kerkar, Nanda
AU - Jørgensen, Marianne Hørby
AU - Fischer, Ryan
AU - Jimenez-Rivera, Carolina
AU - Alam, Seema
AU - Cananzi, Mara
AU - Laverdure, Noemie
AU - Hansen, Bettina E.
N1 - Funding Information:
1. MD/PhD scholarship from the University of Groningen, Groningen, The Netherlands 2. ESPGHAN Networking Grant 2019 3. ChiLDReN and CTSA National Institutes of Health grants: Ann & Robert H. Lurie Children's Hospital, Chicago: U01DK062436; University of Colorado, Denver: U01DK62453, UL1 TR002535; Baylor college of Medicine, Houston: U01DK103149; Children's Hospital of Philadelphia, Philadelphia: U01DK062481, UL1TR000003; Children's Hospital of Pittsburgh, Pittsburgh: U01DK062466; University of California, San Francisco U01DK062500; University of California, San Francisco CTSI grant UL1TR001872; Riley Hospital for Children, Indianapolis: U01DK084536; Seattle Children’s Hospital, Seattle: DK084575; Children’s Hospital Los Angeles, California: U01DK084538. 4. Unrestrictive research grant from Albireo 5. Unrestrictive research grant from Mirum Pharmaceuticals. 6. C&W de Boer Stichting research grant.
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/2
Y1 - 2023/2
N2 - Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
AB - Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p <0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p <0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.
UR - http://www.scopus.com/inward/record.url?scp=85146218689&partnerID=8YFLogxK
U2 - 10.1016/j.jhepr.2022.100626
DO - 10.1016/j.jhepr.2022.100626
M3 - Article
C2 - 36687469
AN - SCOPUS:85146218689
SN - 2589-5559
VL - 5
JO - JHEP Reports
JF - JHEP Reports
IS - 2
M1 - 100626
ER -