Biomedical Scientist, doctorate in Bioengineering. Determined to contribute to a world in which Healthcare and Innovation are accessible to everyone.
Lysosomal acid lipase deficiency (LAL-D) is a very rare inherited progressive metabolic disorder that is caused by genetic mutations in the LIPA gene, which result in the loss of activity of the LAL enzyme.1 LAL-D patients display an uncontrolled lysosomal buildup of lipids, mainly in the form of cholesteryl esters and triglycerides, that continuously accumulate throughout the body, leading to multi-organ damage and dysfunction.1
LAL-D can affect patients of all ages, manifesting from infancy to adulthood, and may present sudden and unpredictable clinical complications, particularly without a prompt diagnosis.1 The disease is divided into two forms based on clinical manifestation: the fulminant infantile-onset Wolman disease (WD) and the progressive child-to-adulthood-onset cholesteryl ester storage disease (CESD).1,2 WD is associated with the most severe mutations in the LIPA gene that result in the near-complete absence (<1%) of LAL activity. CESD is linked to less severe LIPA alterations that lead to a residual (1% to 12%) LAL activity.
The prognosis of WD is very poor, especially in the absence of early diagnosis and treatment.2,3 Disease progression and the impact of clinical manifestations in CESD vary from patient to patient and, because of the paucity of data, detailed elucidation of the overall prognosis and life expectancy is still lacking.2,3 These fluctuate according to disease severity and timely diagnosis. The long-term prognosis with enzyme replacement treatment (ERT) is currently being investigated. What seems to be clear is that the early diagnosis and treatment of LAL-D are imperative for the improvement of disease prognosis.
Prognosis of Wolman Disease
In WD, affected infants typically exhibit signs of the disease within the first days or weeks of life.1 Clinical manifestations are aggressive and severe. Infants experience vomiting, chronic diarrhea or steatorrhea, abdominal distention, severe intestinal malabsorption, hepatic insufficiency, and adrenal calcifications.2,4 Consequently, patients invariably suffer from profound weight loss and failure to thrive, presenting a median life expectancy of 3.7 months.4
A 2016 study from Jones and colleagues, in which the disease progression of 35 WD patients was investigated, reported an overall estimated probability of survival past age 12 months of 0.114 (95% confidence interval: 0.009-0.220).4 However, in the 26 patients exhibiting early growth failure, the same estimated probability was reduced to 0.038 (95% confidence interval: 0.000-0.112). The same study also investigated the outcome of hematopoietic stem cell transplant (HSCT) and liver transplant in 9 and 1 treated patients, respectively. Though transplanted patients survived longer than untreated subjects, the survival prognosis was still meager with a median age at death of 8.6 months.4 A series of HSCT attempts have been undertaken in several patients with WD, having generated mixed results.5 Of note, dietary adjustments do not seem to improve prognosis in WD infants.2,5
Prognosis of CESD
The overall prognosis of CESD is currently unknown, largely due to the heterogeneity in disease severity and onset. Children and adults with CESD may remain undiagnosed or misdiagnosed for long periods of their lives and sometimes until they suffer a sudden cardiovascular or cerebrovascular accident or even liver failure.1–3 The severity of CESD is typically determined by the amount of residual LAL activity (1% to 12%) that remains functional.6,7 Patients often present with hepatomegaly, splenomegaly, abdominal distension, dyslipidemia, liver dysfunction, and gastrointestinal disturbances.1–3,8 Secondary complications may include anemia, thrombocytopenia, liver disease-related hepatocellular carcinoma, and esophageal varices that are highly prone to hemorrhage.9 The abnormal lipid profile may lead to accelerated atherosclerosis, which significantly increases the risk of coronary artery disease, aneurysm, and stroke, thereby constituting the major cause of morbidity related to late-onset CESD.9,10
A comprehensive review by Bernstein and colleagues, reporting the clinical findings in 135 CESD patients, revealed a mean age of onset of 5 years, with disease severity being inversely associated with the age of onset.9 Liver disease and elevated serum transaminases were reported in every subject. Hepatomegaly, splenomegaly, and esophageal varices were exhibited by 99.3%, 74%, and 8.9% of patients, respectively. The main cause of death (73%) was reported to be liver failure, with 50% of deaths occurring before the age of 21 years. Importantly, nearly all patients displayed hypercholesterolemia, suggesting an increased cardiovascular risk.
Prognosis After ERT
The development of enzyme replacement therapy (ERT) has led to significant improvements in the prognosis of LAL-D. The use of recombinant human LAL, sebelipase alfa, has been under clinical trials since 2013.5 Though the long-term clinical benefits of sebelipase alfa are still under investigation, LAL-D patients enrolled in clinical trials, LAL-CL01/LAL-CL04 and LAL-CL03, have had significant improvements in liver function and lipid profiles, with overall decreased levels of serum transaminases, total cholesterol, low-density lipoprotein (LDL) and triglycerides, as well as increased levels of high-density lipoprotein (HDL).11–13
Notably, the majority of patients participating in these trials were children (aged 1 month to 18 years). Remarkably, 5 out of 9 sebelipase alfa-treated WD infants (median age of 3 months at baseline) survived to 24 months of age.13 These children showed weight-for-age improvements along with reduced hepatosplenomegaly, anemia, and gastrointestinal symptoms. Thus, the favorable impacts of ERT on disease course have brought hope to the prognosis of LAL-D, especially in the case of WD.
1. 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
2. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670-679. doi:10.1016/S2468-1253(17)30052-3
3. Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency – early diagnosis is the key. Hepat Med. 2019;11:79-88. doi:10.2147/HMER.S201630
4. Jones SA, Valayannopoulos V, Schneider E, et al. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants. Genet Med. 2016;18(5):452-458. doi:10.1038/gim.2015.108
5. Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic options. Drug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264
6. Saito S, Ohno K, Suzuki T, Sakuraba H. Structural bases of Wolman disease and cholesteryl ester storage disease. Mol Genet Metab. 2012;105(2):244-248. doi:10.1016/j.ymgme.2011.11.004
7. 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
8. Hoffman EP, Barr ML, Giovanni MA, Murray MF. Lysosomal acid lipase deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, eds. GeneReviews® [Internet]. University of Washington, Seattle; 2015. Updated September 1, 2016. Accessed July 11, 2021,
9. Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58(6):1230-1243. doi:10.1016/j.jhep.2013.02.014
10. Elleder M, Ledvinová J, Cieslar P, Kuhn R. Subclinical course of cholesterol ester storage disease (CESD) diagnosed in adulthood. Virchows Arch A. 1990;416(4):357-365. doi:10.1007/BF01605297
11. Balwani M, Breen C, Enns GM, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013;58(3):950-957. doi:10.1002/hep.26289
12. Valayannopoulos V, Malinova V, Honzík T, et al. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014;61(5):1135-1142. doi:10.1016/j.jhep.2014.06.02213.
13. Jones SA, Rojas-Caro S, Quinn AG, et al. Survival in infants treated with sebelipase alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12(1):25. doi:10.1186/s13023-017-0587-3
Reviewed by Michael Sapko, MD, on 7/1/2021.