Alagille Syndrome (ALGS)

Alagille syndrome (ALGS), also known as Alagille-Watson syndrome, Watson-Miller syndrome, syndromic bile duct paucity, or arteriohepatic dysplasia, is a rare disorder caused by a scarcity of intrahepatic bile ducts related to defects in the Notch signaling pathway.^1,2 The disorder impacts multiple organ systems, including the hepatic, cardiac, renal, ocular, skeletal, and neurological systems. Patients with ALGS typically exhibit characteristic facial abnormalities, including a broad forehead, deep-set eyes, and a triangular face with a pointed chin.^1-4 

Discovery History

Daniel Alagille (1925-2005), a French pediatric hepatologist, simultaneously taught as a professor at the Université Paris-Sud and as a staff clinician and chairman at Bicêtre Hospital where he established the world-renowned Pediatric Hepatology Unit.^5,6 Additionally, he became chief of pediatric liver research at the Institut National de la Santé et de la Recherche in 1964.⁶

In 1969, Alagille and his colleagues published a research paper titled “L’atresie des voies biliaires intrahepatiques avec voies biliaires extrahepatiques permeables chez l’enfant,”⁷ detailing disease characteristics of a syndrome which he termed “syndromic bile duct paucity.”⁴ He described 25 children who presented with specific renal, cardiac, facial, and vertebral abnormalities in addition to hepatic dysfunction. He believed a single etiology explained this combination of characteristics.^8,9 

Several years later in 1973 at the Royal Manchester Children’s Hospital, British physicians Geoffrey H. Watson and V. Miller described 9 infants presenting with both neonatal liver disease and pulmonary arterial stenosis, characteristic of ALGS.^3,10 These neonates belonged to 5 unrelated families, indicating a possible familial inheritance pattern for this novel syndrome.¹⁰ 

In 1975, Alagille followed his first article in 1969 with a second, published in the Journal of Pediatrics. He and his colleagues observed that 15 out of 30 children presenting with chronic cholestasis caused by hepatic ductular hypoplasia also exhibited a combination of characteristic facial features, butterfly-shaped vertebral arch malformations, cardiac murmurs, and delayed physical, mental, and sexual development.¹¹ 

Although the disease is attributed eponymously to Alagille, Watson, and Miller, an American pediatrician, David W. Smith, and his colleagues described 2 siblings who shared symptoms in the first known publication detailing ALGS.⁸ 

The observations documented by Smith, Watson, Miller, and colleagues prompted research into the mode of inheritance for ALGS, which is now established to be an autosomal dominant pattern of inheritance despite variations in disease expression.¹²

In 1986, Byrne and colleagues documented a deletion on chromosome 20 in a female infant with arteriohepatic dysplasia.^13,14 In 1994 and 1997, almost 30 years following the first publications describing ALGS, several genetic research groups independently identified pathogenic variations in the JAGGED1 (or JAG1) gene using fine mapping techniques for chromosome 20p12 in patients with ALGS. ^14-21 

In the 2000s, researchers also identified variants in the NOTCH2 gene in a small number of patients with ALGS.^15,21-24 Together, JAG1 (94% to 96%) and NOTCH2 (1% to 2%) genetic variations are the causative factors accounting for around 97% of ALGS cases.¹ These genetic scientific breakthroughs spurred further research into the molecular etiology of ALGS over the past 20 years to better understand disease mechanisms and develop effective treatments.¹⁴

Treatment History

Due to the substantial number of variations in the JAG1 and NOTCH2 genes that cause ALGS, the development of effective treatments for the disease has been slow. Currently available options focus on relieving symptoms of the disease rather than targeting the root cause. Current therapies include surgical procedures, such as liver transplantation and partial external biliary diversion, and ileal bile acid transporter inhibitors undergoing clinical trials, such as maralixibat and odevixibat. Other potential therapies include adeno-associated virus (AAV) vector-mediated gene therapy with nuclease-based editing or clustered regularly interspaced short palindromic repeats (CRISPR)/Cas gene editing as well as RNA-targeting treatments using antisense oligonucleotides, splice-switching small molecules, or CasRx transcript editing.⁹

References

1. Diaz-Frias J, Kondamudi NP. Alagille syndrome. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Accessed March 14, 2022. 
2. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011.181
3. Scheimann A. Alagille syndrome: practice essentials. Medscape. Updated October 1, 2021. Accessed March 14, 2022.
4. Alagille syndrome. The Childhood Liver Disease Research Network. Accessed March 14, 2022.
5. Alagille syndrome awareness. The Alagille Syndrome Alliance. Accessed March 14, 2022.
6. Daniel Alagille. Whonamedit? Accessed March 14, 2022. 
7. Alagille D, Habib EC, Thomassin N. L’atresie des voies biliaires intrahepatiques avec voies biliaires extrahepatiques permeables chez l’enfant [Intrahepatic bile duct atresia with patent extrahepatic bile ducts in children]. J Par Pediatr. 1969:301;301-318. French.
8. Bissonnette B, Luginbuehl I, Engelhardt T. Alagille syndrome (AS). In: Bissonnette B, Luginbuehl I, Engelhardt T, eds. Syndromes: Rapid Recognition and Perioperative Implications. 2nd ed. New York City: McGraw Hill; 2019.
9. Sanchez P, Farkhondeh A, Pavlinov I, Baumgaertel K, Rodems S, Zheng W. Therapeutics development for Alagille syndrome. Front Pharmacol. 2021;12:704586. doi:10.3389/fphar.2021.704586
10. Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. 1973;48(6):459-466. doi:10.1136/adc.48.6.459
11. Alagille D, Odièvre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975;86(1):63-71. doi:10.1016/s0022-3476(75)80706-2
12. Elmslie FV, Vivian AJ, Gardiner H, Hall C, Mowat AP, Winter RM. Alagille syndrome: family studies. J Med Genet. 1995;32(4):264-268. doi:10.1136/jmg.32.4.264
13. Byrne JL, Harrod MJ, Friedman JM, Howard-Peebles PN. Del(20p) with manifestations of arteriohepatic dysplasia. Am J Med Genet. 1986;24(4):673-678. doi:10.1002/ajmg.1320240411
14. Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. Transl Gastroenterol Hepatol. 2021;6:22. doi:10.21037/tgh-2020-03
15. Gilbert MA, Bauer RC, Rajagopalan R, et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40(12):2197-2220. doi:10.1002/humu.23879
16. Spinner NB, Rand EB, Fortina P, et al. Cytologically balanced t(2;20) in a two-generation family with Alagille syndrome: cytogenetic and molecular studies. Am J Hum Genet. 1994;55(2):238-243.
17. Pollet N, Boccaccio C, Dhorne-Pollet S, et al. Construction of an integrated physical and gene map of human chromosome 20p12 providing candidate genes for Alagille syndrome. Genomics. 1997;42(3):489-498. doi:10.1006/geno.1997.4676
18. Oda T, Elkahloun AG, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet. 1997;16(3):235-242. doi:10.1038/ng0797-235
19. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;16(3):243-251. doi:10.1038/ng0797-243
20. Krantz ID, Rand EB, Genin A, et al. Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet. 1997;70(1):80-86.
21. Alagille syndrome. Children’s Hospital of Philadelphia. Accessed March 14, 2022.
22. McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 2002;129(4):1075-1082. doi:10.1242/dev.129.4.1075
23. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006;79(1):169-173. doi:10.1086/505332
24. Kamath BM, Bauer RC, Loomes KM, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49(2):138-144. doi:10.1136/jmedgenet-2011-100544

Reviewed by Hasan Avcu, MD, on 3/19/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.