Wolman Disease: The Search for a Cheaper Alternative
Summary of Disease
The Wolman Disease or Lysosomal Acid Lipase Deficiency (LAL-D) is an autosomal-recessive genetic disease that affects between 8 to 25 per million people in the world.1 Prior to 2015, very few infants with this disease survived beyond the first year of life.2 The administration of fat-regulating drugs had minimal influence on a patient’s symptoms, and thus, medical care was limited to supportive care.3 This situation was improved when Sebelipase alfa, more commonly known as Kanuma, was approved by the Food and Drug Administration in 2015 and remains the only drug approved for LAL-D.4 Although the LAL-D treatment market is projected to grow to revenues of $954 million by 2025,3 the costs to acquire this drug has become so high that many patients are simply unable to afford them.
Etiology and Pathology
LAL-D is an autosomal recessive genetic disorder.5 This means that an individual must inherit two sets of the abnormal gene (one from each parent) for the disease to progress. Abnormal LIPA genes produce a mutated variant of the lysosomal acid lipase (LAL) enzymes. LAL enzymes are required to break down fats, such as cholesterol and triglycerides, in the human body.6 Without functional LAL enzymes, fat will aggregate in the various organs and tissues, which may cause complications such as anemia (lack of oxygen-delivering red blood cells resulting in fatigue), jaundice (yellowing of the skin and eyes caused by the buildup of bilirubin, a byproduct of red blood cell breakdown which is metabolized by the liver), malabsorption, and inflammation-induced liver dysfunction.5
Symptoms and Diagnosis
“The major issue with this treatment is the immense cost burden on families. With an average cost of $892,000 USD per patient per year, this treatment is inaccessible to many families.”
Symptoms of LAL-D are often present in infants during the first few weeks of life.5 These symptoms include swelling of the stomach, enlargement of the liver and spleen, and fluid accumulation in the abdominal cavity, all of which leads to malabsorption of nutrients and fats. This may cause forceful vomiting, frequent diarrhea and fatty stools. Due to these digestive complications, infants usually fail to grow or gain weight. The symptoms of Wolman Disease get progressively worse, leading to life-threatening complications such as liver failure, severe anemia, and muscle weakness due to the loss of muscle mass.5
LAL-D often remains undiagnosed or misdiagnosed in older children and adults due to the varying symptoms that mimic other disorders like non-alcoholic fatty liver disease, chronic liver diseases,familial hypercholesterolaemia and familial combined hyperlipidaemia.7 The symptoms in adults are the same as those present in infants with increased probability of heart attacks and stroke due to the accumulation of fat on artery walls.8
Nevertheless, LAL-D can be identified based on characteristic symptoms during infancy and confirmed through a clinical evaluation of the patient’s history and through specialized tests for LAL function or genetic testing for mutations in the LIPA gene which provides the genetic information for producing the LAL enzyme.5 Individuals may also have increased liver enzymes and high cholesterol levels that can be detected using blood tests.8
Prognosis and Treatment
In infants, disease symptoms arise in the first weeks of life. Without treatment, these infants die within 6 to 12 months due to multi-organ failure.9 Children with infantile-onset LAL-D often cannot produce LAL while individuals with late-onset LAL-D have impaired LAL production, which hinders the breakdown of fat molecules but not to the degree of impaired cellular function seen in infantile-onset LAL-D.10 As a result, late-onset LAL-D is often less severe. However, since LAL-D is often undiagnosed or misdiagnosed in older children and adults, many of these patients die early from progressive liver or heart failure.11
Currently, the only approved treatment for LAL-D is enzyme replacement therapy. Sebelipase alfa is an enhanced version of the LAL enzyme and works to replace the functions of the missing LAL enzymes in fat metabolism.12 This drug is delivered to the patients’ bloodstream through an intravenous (IV) infusion over the span of 2 hours, once every other week.13 However, beware that infusion reactions, characterized by shortness of breath, swelling and itching, may occur during or after the infusion. In this case, doctors may administer anti-inflammatory medicines, such as antihistamines or corticosteroids, to ease the symptoms.13
Nevertheless, undergoing enzyme replacement therapy has allowed infants to achieve normal growth rates and survive for more than 2 years. Significant improvements in hepatic function have also been observed in adults and older children.4 The major issue with this treatment is the immense cost burden on families. With an average cost of $892,000 USD per patient per year,14 this treatment is inaccessible to many families. With current research focused on enhancing treatments for more well-known diseases, such as cancer and diabetes, it is imperative that we recognize the definition of a viable treatment to be one that patients can afford to access.
Rianne Chen
Works Cited:
1. Woodard TJ. Managing Lysosomal Acid Lipase Deficiency. US Pharmacist . May 2017. https://www.uspharmacist.com/article/managing-lysosomal-acid-lipase-deficiency. Accessed February 12, 2021.
2. Demczko M. Cholesteryl Ester Storage Disease and Wolman Disease. Merck Manuals Professional Edition. https://www.merckmanuals.com/en-ca/professional/pediatrics/inherited-disorders-of-metabolism/cholesteryl-ester-storage-disease-and-wolman-disease. Published April 2020. Accessed February 12, 2021.
3. Grand View Research. LAL-D Treatment Market Size Worth $954 Million by 2025 : Grand View Research, Inc. PR Newswire . https://www.prnewswire.com/news-releases/lal-d-treatment-market-size-worth-954-million-by-2025--grand-view-research-inc-300841556.html. Published May 1, 2019. Accessed February 12, 2021.
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5. Wolman Disease. NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/wolman-disease/. Published August 15, 2016. Accessed February 12, 2021.
6. Lysosomal Acid Lipase Deficiency (LAL D) - LAL Deficiency. American Liver Foundation. https://liverfoundation.org/for-patients/about-the-liver/diseases-of-the-liver/lysosomal-acid-lipase-deficiency/. Published February 3, 2021. Accessed February 12, 2021.
7. Cunha-Silva M, Mazo DFC, Corrêa BR, et al. Lysosomal Acid Lipase Deficiency Leading to Liver Cirrhosis: a Case Report of a Rare Variant Mutation. Annals of Hepatology. 2019;18(1):230-235. doi:10.5604/01.3001.0012.7930
8. Lysosomal acid lipase deficiency: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/lysosomal-acid-lipase-deficiency/. Published August 18, 2020. Accessed February 12, 2021.
9. Aslanidis C, Ries S, Fehringer P, Büchler C, Klima H, Schmitz G. Genetic and Biochemical Evidence That CESD and Wolman Disease Are Distinguished by Residual Lysosomal Acid Lipase Activity. Genomics. 1996;33(1):85-93. doi:10.1006/geno.1996.0162
10. Lysosomal Acid Lipase Deficiency: Boston Children's Hospital. Boston Childrens Hospital. https://www.childrenshospital.org/conditions-and-treatments/conditions/l/lysosomal-acid-lipase-deficiency. Accessed February 12, 2021.
11. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. doi:10.1016/j.atherosclerosis.2014.04.003
12. Erwin AL. The role of sebelipase alfa in the treatment of lysosomal acid lipase deficiency. Therapeutic Advances in Gastroenterology. 2017;10(7):553-562. doi:10.1177/1756283x17705775
13. Kanuma. News Medical Life Sciences. https://www.news-medical.net/drugs/Kanuma.aspx. Accessed February 12, 2021.
14. Alexion Pharmaceuticals; 2018. https://www.cadth.ca/sites/default/files/cdr/pharmacoeconomic/SR0544_Kanuma_PE_Report.pdf. Accessed February 12, 2021.
Cite This Article:
Chen R., Chen L., Kord D., Ananthkrishnan O., Chharawala V., Lombo L. Wolman Disease. Illustrated by V. Chharawala. Rare Disease Review. March 2022. DOI:10.13140/RG.2.2.25818.82886.
