ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes - 23/08/21
, Khurram Lone, MD 1, Muhammed Salman Bashir, MSc 4, Sami Alrashidi, MD 1, Mosa Fagih, MD 5, Alanoud Alanazi, MD 1, Salem AlYaseen, MD 1, Abdulaziz Almayouf, MD 1, Muhanad Alruwaithi, MD 1, Ali Asery, MD 1Abstract |
Objectives |
To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for “genotype–phenotype” correlations.
Study design |
We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease).
Results |
Overall, 27 different mutations were identified (ATP8B1, n = 5; ABCB11, n = 11; ABCB4, n = 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n = 2; ABCB11, n = 4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P < .001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P = .011; P = .0039, respectively).
Conclusions |
We identified genotype–phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.
Il testo completo di questo articolo è disponibile in PDF.Keywords : cholestasis, PFIC, Saudi Arabia
Abbreviations : ALT, BSEP, ESLD, GGT, HCC, HR, INR, PFIC, TSB, UDCA
Mappa
| Supported financially by Prince Abdullah bin Khalid Celiac Disease Research Chair, Vice Deanship of Research Chairs, Department of Pediatrics, Faculty of Medicine, King Saud University. The authors declare no conflicts of interest. |
Vol 236
P. 113 - settembre 2021 Ritorno al numero
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