Wikipedia

Alagille syndrome

Alagille syndrome(ALGS) is agenetic disorderthat affects primarily theliverand theheart.Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 30,000[1][2]to 1 in every 40,000 live births. It is named after the French pediatricianDaniel Alagille,who first described the condition in 1969.[3][4]Children with Alagille syndrome live to the age of 18 in about 90% of the cases.[5]

Alagille syndrome
Other namesAlagille–Watson syndrome (ALGS), hepatic ductular hypoplasia
Alagille syndrome is inherited in an autosomal dominant manner
SpecialtyMedical genetics,Gastroenterology,Cardiology
Named afterDaniel Alagille

Signs and symptoms

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The severity of the disorder can vary within the same family, with symptoms ranging from so mild as to go unnoticed, to severe heart and/or liver disease that requirestransplantation.[6]It is uncommon, but Alagille syndrome can be a life-threatening disease with a mortality rate of 10%.[7]The majority of deaths from ALGS are typically due to heart complications or chronic liver failure.[8]

Liver

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Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in theskinand the whites of the eyes (jaundice), itching (pruritus), pale stools (acholia), an enlarged liver (hepatomegaly), an enlarged spleen (splenomegaly) and deposits ofcholesterolin the skin (xanthomas).[9]Aliver biopsymay indicate too fewbile ducts(bile duct paucity) or, in some cases, the complete absence of bile ducts (biliary atresia). Bile duct paucity results in the reduced absorption of fat and fat-soluble vitamins (A, D, E and K), which may lead to rickets or afailure to thrive.Cirrhosisand eventualliver failureis fairly common among ALGS patients, and 15% of those with severehepaticmanifestations require a liver transplant.[10]Hepatocellular cancerhas been reported in a small number of cases, but it is extremely rare.[11]

Heart

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Tetralogy of Fallot is a common heart defect experienced in Alagille syndrome patients.

Other

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Other presentations of Alagille's syndrome includebutterfly vertebrae,ophthalmicdefects, and distinct facial structures. Thebutterfly vertebraecan be detected with an x-ray, but there typically are no symptoms from this abnormality. Other skeletal defects common in ALGS patients are spina bifida and the fusion of vertebrae.[10]Most of the ophthalmological defects affect theanterior chamber of the eyeball,includingAxenfeld's anomalyand Rieger anomaly, butretinapigment changes are also common.[10]These anomalies can be beneficial in diagnosing Alagille syndrome. Many people with ALGS have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. While these distinct facial features are often presented in ALGS patients, the features are presumably not due to Alagille syndrome, but they are characteristic of patients with intrahepaticcholestatic liver disease.[12]So while these facial characteristics are extremely common in ALGS patients, it is because many patients experience extreme liver complications or liver failure, but it is not caused by the disease itself. Thekidneysmay also be affected because the mutations inJAG1andNOTCH2often lead torenal dysplasia,deformedproximal tubules,orlipidosiscaused by the hindrance oflipid metabolism.[13]

Genetics

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ALGS is caused by loss of function mutations in eitherJAG1(Jagged1) orNOTCH2(Notch homolog 2).[14][15]In the majority of people with ALGS, the gene mutation occurs in theJAG1gene. TheJAG1mutation is either intragenic and found onchromosome20p12, or it is a deletion of the entireJAG1gene.[16]Mutations inNOTCH2are much less likely to cause Alagille syndrome, but the primary type of ALGS-causing mutation inNOTCH2is amissense mutation.[17]Amissense mutationis apoint mutationthat changes onenucleotide,which results in acodonthat codes for the wrongamino acid.Alagille syndrome is inherited in anautosomal dominantpattern, which means one copy of the altered gene is sufficient to cause the disorder. The "autosomal"aspect of the disease means that the gene mutation occurs in anautosome,which is one of the 44 chromosomes in the human body that is not asex chromosome(chromosome X or Y). Although the majority of cases are due to theautosomal dominantgene, there have been reports of a rare, autosomal recessive version of the disease.[16]In the autosomal recessive case, the ALGS patient must inherit two mutated genes: one from each parent. Although about 40% of the mutations are inherited from affected parents, most cases result from new, acquired mutations. These are caused by environmental factors that mutate one copy of the gene.[17]Environmental factors that can result in gene mutations may include radiation such as ultraviolet rays from the sun, or chemicals such asbenzene,which is found in cigarette smoke.[18]

Pathophysiology

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JAG1andNOTCH2encode for proteins that are crucial to thenotch gene–signaling cascade.Specifically,JAG1encodes for a surface-binding ligand that regulates the notch signaling pathway. It plays a crucial role in cell signaling during embryonic development. If the pathway is disrupted due to mutations, an infant will not develop properly.[6]Alagille syndrome causes bile duct paucity, which is characterized by narrow and malformed bile ducts. Bile duct paucity causes bile to build up in the liver, resulting in scarring of the liver which hinders the liver's normal functions, like blood filtration and drug metabolism.[6]

Diagnosis

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Alagille syndrome can be extremely difficult to diagnose. While people are born with ALGS, it is almost always diagnosed later during childhood. The diagnosis can be difficult because the severity of the disease varies widely among patients.[19]Some common clinical tests that are run in order to diagnose the disease include vertebral x-rays, heart exams to detect any defects such as aheart murmur,and aliver biopsyto detect liver disease or any precursors. If a patient presents with multiple symptoms such asjaundice,heart murmur,and the characteristic facial features discussed above (deep set eyes, broad brow, etc.), they are likely to be diagnosed with Alagille syndrome.[19]A more calculated and specific diagnosis can be done withgenetic testing.Next-generation sequencingcan be utilized to detectsingle nucleotide polymorphisms(SNPs) in the affected gene(s).Multiplex ligation-dependent probe amplification(MLPA) can detect large deletions and/or insertions and microarray comparative genomic hybridization is used to improve the accuracy of MLPA.[20]

It is important to distinguish Alagille syndrome frombiliary atresiabecause the latter benefits from aKasai procedurein the early postnatal period, whereas this operation would make Alagille syndrome worse. Indirect features on ultrasound of biliary atresia include abnormal and diminutive gallbladder shape, the triangular cord sign, andhepatic arteryenlargement, though these can overlap with Alagille syndrome.[21]

Treatment

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Early treatment is possible once the disease is diagnosed. Treatments of Alagille syndrome typically involve medications, therapies, and/or surgical procedures. All treatments aim to improvebileexcretion from the liver, reduce pain caused by the disease, and help improve nutritional deficiencies.[22]Diet can also be a crucial factor in improving quality of life when living with ALGS.[23]

Medication

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Several medications are used to improve bile flow, includingursodiol(Actigall or Urso).[22]These medications differ in their rates of success. Certain drugs may be used to reduce itching (pruritus), such ascholestyramineandrifampin.While these medications can reducepruritus,the itching often is reduced when bile flow is improved viaursodiolorliver transplant.[22]

Many patients with Alagille syndrome have nutritional and/ormalabsorptionissues which often hinders normal growth. Patients benefit fromvitamin A,D, E, and K supplements because the reduced bile flow makes it difficult to absorb and utilize these vitamins. A high-calorie diet is very important, and often requires agastrostomytube to maintain the high caloric intake.[2]

Maralixibat(Livmarli) was approved for medical use in the United States in September 2021.[24][25]

Surgery

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Surgery is common in more severe cases on Alagille syndrome, especially for patients with liver disease or end-stage liver failure.Liver transplantscan either be a complete liver transplant from a deceased organ donor, or a partial transplant from a living donor.[26][27]

Partial biliary diversion has been used to significantly reducepruritus,jaundice,andxanthomacaused by poor bile flow in patients with bile duct paucity. A portion of the bile produced by the liver is directed through a surgically createdstomainto a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile. Patients withbiliary atresiamay require aKasai procedureto improve bile drainage; however, later liver transplantation is still often necessary.[28]

See also

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References

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  1. ^Mitchell E, Gilbert M, Loomes KM (November 2018). "Alagille Syndrome".Clinics in Liver Disease.22(4):625–641.doi:10.1016/j.cld.2018.06.001.PMID30266153.
  2. ^abAyoub MD, Kamath BM (August 2022). "Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management".Clinics in Liver Disease.26(3):355–370.doi:10.1016/j.cld.2022.03.002.PMID35868679.
  3. ^synd/729atWhonamedit?
  4. ^Alagille D, Odièvre M, Gautier M, Dommergues JP (January 1975). "Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur".The Journal of Pediatrics.86(1):63–71.doi:10.1016/S0022-3476(75)80706-2.PMID803282.
  5. ^Ayoub MD, Bakhsh AA, Vandriel SM, Keitel V, Kamath BM (October 2023)."Management of adults with Alagille syndrome".Hepatology International.17(5):1098–1112.doi:10.1007/s12072-023-10578-x.PMC10522532.PMID37584849.
  6. ^abc"Alagille syndrome".Genetics Home Reference.U.S. National Library of Medicine.Retrieved31 October2016.
  7. ^Diaz-Frias J, Kondamudi NP (2019)."Alagille Syndrome".StatPearls [Internet].Treasure Island (FL): StatPearls Publishing.PMID29939604.
  8. ^Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N (August 2018)."Systematic Review: The Epidemiology, Natural History, and Burden of Alagille Syndrome".Journal of Pediatric Gastroenterology and Nutrition.67(2). J Pediatr Gastroenterol Nutr:148–156.doi:10.1097/MPG.0000000000001958.PMC6110620.PMID29543694.
  9. ^"Symptoms & Causes for Alagille Syndrome".National Institute of Diabetes and Digestive and Kidney Diseases.
  10. ^abcKrantz ID, Piccoli DA, Spinner NB (February 1997)."Alagille syndrome".Journal of Medical Genetics.34(2):152–157.doi:10.1136/jmg.34.2.152.PMC1050871.PMID9039994.
  11. ^Sijmons RH (February 2008)."Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndrome".Hereditary Cancer in Clinical Practice.6(1):22–57.doi:10.1186/1897-4287-6-1-22.PMC2735164.PMID19706204.
  12. ^Sokol RJ, Heubi JE, Balistreri WF (August 1983). "Intrahepatic" cholestasis facies ": is it specific for Alagille syndrome?".The Journal of Pediatrics.103(2):205–208.doi:10.1016/s0022-3476(83)80345-x.PMID6875709.
  13. ^Bissonnette ML, Lane JC, Chang A (May 2017)."Extreme Renal Pathology in Alagille Syndrome".Kidney International Reports.2(3):493–497.doi:10.1016/j.ekir.2016.11.002.PMC5720621.PMID29318215.
  14. ^Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, et al. (July 1997)."Mutations in the human Jagged1 gene are responsible for Alagille syndrome".Nature Genetics.16(3):235–242.doi:10.1038/ng0797-235.PMID9207787.S2CID5775213.
  15. ^Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, et al. (February 2012)."NOTCH2 mutations in Alagille syndrome".Journal of Medical Genetics.49(2):138–144.doi:10.1136/jmedgenet-2011-100544.PMC3682659.PMID22209762.
  16. ^abVajro P, Ferrante L, Paolella G (June 2012). "Alagille syndrome: an overview".Clinics and Research in Hepatology and Gastroenterology.36(3):275–277.doi:10.1016/j.clinre.2012.03.019.PMID22521120.
  17. ^abMitchell E, Gilbert M, Loomes KM (November 2018). "Alagille Syndrome".Clinics in Liver Disease.22(4). Springer:625–641.doi:10.1016/j.cld.2018.06.001.PMID30266153.S2CID52883591.
  18. ^"What is a gene mutation and how do mutations occur?".Genetics Home Reference.U.S. National Library of Medicine.
  19. ^ab"Alagille Syndrome - Diagnosis & Treatment".Boston Children's Hospital.
  20. ^Ohashi K, Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, et al. (November 2017). "Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome".Acta Paediatrica.106(11):1817–1824.doi:10.1111/apa.13981.PMID28695677.S2CID24604635.
  21. ^Abdel Razek A, Abdalla A, Elfar R, Ashmalla GA, Ali K, Barakat T (December 2020)."Assessment of Diffusion Tensor Imaging Parameters of Hepatic Parenchyma for Differentiation of Biliary Atresia from Alagille Syndrome".Korean journal of radiology.21(12):1367–1373.doi:10.3348/kjr.2019.0824.PMC7689146.PMID32729270.
  22. ^abc"Alagille Syndrome".Department of Surgery.University of California - San Francisco.Retrieved2019-10-08.
  23. ^Jesina D (2017-11-01)."Alagille Syndrome: An Overview".Neonatal Network.36(6):343–347.doi:10.1891/0730-0832.36.6.343.ISSN1539-2880.PMID29185945.
  24. ^"Highlights of prescribing information: LIVMARLITM (maralixibat) oral solution"(PDF).Mirum Pharmaceuticals, Inc.U.S. Food and Drug Administration.
  25. ^"Maralixibat: FDA-Approved Drugs".U.S.Food and Drug Administration(FDA).Retrieved29 September2021.
  26. ^Doria C (2016). Doria C (ed.).Contemporary Liver Transplantation: The Successful Liver Transplant Program.Springer.ISBN9783319055435.OCLC1111825084.
  27. ^"Donor Requirements & Evaluation - Live Liver Transplant".Lahey Hospital & Medical Center, Burlington & Peabody.Retrieved2019-10-08.
  28. ^Turnpenny PD, Ellard S (March 2012)."Alagille syndrome: pathogenesis, diagnosis and management".European Journal of Human Genetics.20(3):251–257.doi:10.1038/ejhg.2011.181.ISSN1476-5438.PMC3283172.PMID21934706.
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