Medical Management of Alagille Syndrome

Abstract

Alagille syndrome is a highly variable, autosomal dominant disorder that affects the liver, heart, eyes, face, skeleton, kidneys, and vascular system. Much has been learned about the genetics of this disorder, which is caused primarily by mutations in the Notch signaling pathway ligand JAGGED1; however, the medical management of this condition is complex and continues to generate controversy. The significant variability of organ involvement requires the managing physician to have an understanding of the breadth and interplay of the variable manifestations. Furthermore, the liver disease in particular requires an appreciation of the natural history and evolution of the profound cholestasis.

Novel Heterozygous Mutations in JAG1 and NOTCH2 Genes in a Neonatal Patient with Alagille Syndrome

“…Jaundice with pruritus and xanthomas can occur secondary to this hyperbilirubinemia and hypercholesterolemia [1–3]. Severity of liver disease varies among patients; cholestasis typically worsens until school age and may resolve in some patients [9]. A small fraction of patients (~15%) will have progressive disease leading to cirrhosis and liver failure that requires transplantation [2–4].…”

Developmental abnormalities and liver disease in childhood

“…Patients in the syndromic group have Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, 353 Comprehensive descriptions have been reported by Alagille and colleagues 354,355 and others. [356][357][358] Two distinct genetic mechanisms are known to be responsible for Alagille syndrome. The vast majority of cases (ALGS1) are due to mutations in JAGGED1 (JAG1, encoding the ligand for the Notch 1 receptor) on chromosome 20p12 359,360 and may be associated with a macroscopic deletion of the short arm of chromosome 20 in some patients or microdeletions of 20p in others.…”

“…Treatments for the pruritus include cholestyramine, rifampicin or surgical diversion of bile flow. 358,395 In general, the prognosis is good for children whose jaundice resolves; however, approximately 25% of patients succumb in childhood to severe cardiac disease or progressive liver disease. The outcome in 92 patients in the series of Emerick et al 357 was as follows: the 20-year predicted life expectancy was 75% for all patients, 80% for those not requiring liver transplantation, and 60% for those who required transplantation.…”

Molekulare Diagnostik bei genetischen Lebererkrankungen

“…Mittlerweile konnte die genetische Grundlage mehrerer Erkrankungen, die mit einer Cholestase einhergehen, entschlüsselt werden. Das Alagille-Syndrom ist gekennzeichnet durch eine chronische Cholestase sowie Fehlbildungen der Lungengefäße und dysmorphe Gesichtszüge [1]. Es ist meistens durch eine Mutation im JAG-1-Gen verursacht.…”

“…luläre Verteilungsstörung von Kupfer gekennzeichnet ist.Abb 1. 9 Diagnostik bei Verdacht auf Hämochroma-tose.…”