Details

Autor(en) / Beteiligte

• Felzen, Antonia
• van Wessel, Daan B.E.
• Gonzales, Emmanuel
• Thompson, Richard J.
• Jankowska, Irena
• Shneider, Benjamin L.
• Sokal, Etienne
• Grammatikopoulos, Tassos
• Kadaristiana, Agustina
• Jacquemin, Emmanuel
• Spraul, Anne
• Lipiński, Patryk
• Czubkowski, Piotr
• Rock, Nathalie
• Shagrani, Mohammad
• Broering, Dieter
• Nicastro, Emanuele
• Kelly, Deirdre
• Nebbia, Gabriella
• Arnell, Henrik
• Fischler, Björn
• Hulscher, Jan B.F.
• Serranti, Daniele
• Arikan, Cigdem
• Polat, Esra
• Debray, Dominique
• Lacaille, Florence
• Goncalves, Cristina
• Hierro, Loreto
• Muñoz Bartolo, Gema
• Mozer-Glassberg, Yael
• Azaz, Amer
• Brecelj, Jernej
• Dezsőfi, Antal
• Calvo, Pier Luigi
• Grabhorn, Enke
• Hartleif, Steffen
• van der Woerd, Wendy J.
• Kamath, Binita M.
• Wang, Jian-She
• Li, Liting
• Durmaz, Özlem
• Kerkar, Nanda
• Jørgensen, Marianne Hørby
• Fischer, Ryan
• Jimenez-Rivera, Carolina
• Alam, Seema
• Cananzi, Mara
• Laverdure, Noemie
• Ferreira, Cristina Targa
• Guerrero, Felipe Ordoñez
• Wang, Heng
• Sency, Valerie
• Kim, Kyung Mo
• Chen, Huey-Ling
• de Carvalho, Elisa
• Fabre, Alexandre
• Bernabeu, Jesus Quintero
• Zellos, Aglaia
• Alonso, Estella M.
• Sokol, Ronald J.
• Suchy, Frederick J.
• Loomes, Kathleen M.
• McKiernan, Patrick J.
• Rosenthal, Philip
• Turmelle, Yumirle
• Horslen, Simon
• Schwarz, Kathleen
• Bezerra, Jorge A.
• Wang, Kasper
• Hansen, Bettina E.
• Verkade, Henkjan J.

Titel

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Ist Teil von

• JHEP reports, 2023-02, Vol.5 (2), p.100626-100626, Article 100626

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2023

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. 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. 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). 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. 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. [Display omitted] •Homozygous E297G or D482G mutations in ABCB11 are associated with long-term native liver survival.•Native liver survival is poor in those with BSEP deficiency who carry two truncating mutations.•One protein truncating mutation in ABCB11 overrides the phenotypic effect of a concomitant E297G or D482G mutation.•The indicated heterozygous genotype is also associated with a poor response to surgical biliary diversion.•No hepatocellular carcinoma was observed in individuals with a E297G or D482G mutation and a truncating ABCB11 mutation.