Alagille Syndrome (ALGS)


Alagille syndrome (ALGS) is a rare, heritable disease affecting several bodily organs and tissues. Most cases are caused by mutations in the Jagged 1 (JAG1) gene, while less than 1% are caused by mutations in the Notch 2 (NOTCH2) gene. Roughly 50% of cases of Alagille syndrome occur as a result of novel mutations, meaning the mutation was not inherited from either parent.1

The proteins encoded by the NOTCH2 and JAG1 genes are key components of the Notch signaling pathway, which plays a crucial role in cell differentiation and organogenesis.2 The disruption of this pathway in ALGS has profound consequences on development and impacts nearly every system in the body.1

The average life expectancy for patients with ALGS is reduced in many cases, with the primary causes of death being cardiac disease, liver disease, and intracranial bleeding. However, many studies do not include long-term follow-up, so the lifespan of patients with the disease is not reported.3

ALGS Features Affecting Mortality

The symptoms displayed by ALGS patients vary in severity and can change as the disease progresses. A study of 92 patients with ALGS demonstrated that the 20-year life expectancy of patients was 75%. The 20-year life expectancy was higher (80%) for patients who did not require a liver transplant, and lower (60%) for patients who did require a liver transplant.4

Congenital heart problems are associated with early mortality in Alagille syndrome, while severe liver dysfunction is associated with mortality later in life.5

A major cause of mortality in ALGS is intracranial bleeding. ALGS patients are also at higher risk of stroke due to weakening and narrowing of the blood vessels in the brain.6

Read more about ALGS Symptoms.

One of the key features of ALGS is the paucity of bile ducts in the liver. The scarcity of these ducts means that the liver cannot transport bile acids and salts to the intestine to aid in digestion. Without transport, these bile acids accumulate in the liver, which can lead to cirrhosis and portal hypertension, as well as increase the patients’ risk of developing liver cancer. In severe cases, liver failure can result.7

However, it must be noted that measures of hepatic function in patient infancy are not predictive of life expectancy. Hepatic function must be monitored throughout the patient’s lifetime so that interventions can be provided promptly when they are required.8

Insufficient bile secretion in patients results in decreased fat absorption from the diet in many cases. Decreased fat absorption means that, in addition to malnutrition, patients also have difficulty absorbing fat-soluble vitamins from their diet. Vitamin levels should be assessed regularly, and supplements should be provided when necessary.9

Another cause of malnutrition may be pancreatic insufficiency. Pancreatic insufficiency has been reported in up to 40% of ALGS patients; however, assessing pancreatic insufficiency can be challenging due to the paucity of bile ducts. Some patients develop insulin-dependent diabetes mellitus, which may indicate that the endocrine function of the pancreas is also affected. Pancreatic insufficiency could also play a role in life expectancy.5

Cardiac congenital heart disease may be the most significant indicator of early mortality in Alagille syndrome. More than 90% of cases include cardiovascular anomalies, with peripheral pulmonary stenosis (PPS) occurring in at least two-thirds of cases. Other cardiac anomalies present in ALGS include tetralogy of Fallot, septal defects, and aortic stenosis. Some congenital heart defects can be treated with surgery, which also has risks that affect life expectancy.5

Renal anomalies are present in both Alagille type 1 and type 2, but these anomalies may occur more frequently in type 2 (those cases caused by mutations in NOTCH2). Structural defects such as small, echogenic kidneys, cysts, and ureteropelvic obstruction have been reported. Renal function is also affected in some cases, with renal tubular acidosis occurring in up to 74% of cases.5

Osteoporosis, “butterfly vertebrae,” and craniofacial abnormalities are also caused by Alagille syndrome. Osteoporosis and brittle bones are thought to be secondary to liver malfunction and malnutrition, but Notch signaling is critical to bone development. Fractures can be frequent and severe, which may affect life expectancy.10

Other Factors Affecting Life Expectancy

The impact of ALGS on patients’ quality of life has not been rigorously assessed. The economic impact of ALGS on patients and their families may also impact life expectancy, but it has not been well studied.11

References

  1. 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
  2. Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;97(4):1235-1294. doi:10.1152/physrev.00005.2017
  3. Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, eds. GeneReviews. University of Washington, Seattle; 2000. Updated December 19, 2019. Accessed June 24, 2019.
  4. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829. doi:10.1002/hep.510290331
  5. 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
  6. Emerick KM, Krantz ID, Kamath BM, et al. Intracranial vascular abnormalities in patients with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2005;41(1):99-107. doi:10.1097/01.mpg.0000162776.67758.2f
  7. Symptoms & causes for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 18, 2021.
  8. Mouzaki M, Bass LM, Sokol RJ, et al. Early life predictive markers of liver disease outcome in an international, multicentre cohort of children with Alagille syndrome. Liver Int. 2016;36(5):755-760. doi:10.1111/liv.12920
  9. Shen YM, Wu JF, Hsu HY, et al. Oral absorbable fat-soluble vitamin formulation in pediatric patients with cholestasis. J Pediatr Gastroenterol Nutr. 2012;55(5):587-591. doi:10.1097/MPG.0b013e31825c9732
  10. Zanotti S, Canalis E. Notch signaling in skeletal health and disease. Eur J Endocrinol. 2013;168(6):R95-103. doi:10.1530/EJE-13-0115
  11. Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148-156. doi:10.1097/MPG.0000000000001958

Reviewed by Eleni Fitsiou, on 6/18/2021.

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