Lysosomal acid lipase deficiency (LAL-D) is a very rare inherited autosomal recessive disease that results in abnormal lysosomal storage of cholesteryl esters and triglycerides throughout the body.1 It is characterized by systemic dyslipidemia and progressive atherosclerosis, as well as liver, splenic, and gastrointestinal dysfunction.
Clinically, LAL-D is divided into 2 entities, depending on the amount of residual LAL enzymatic activity: neonatal onset fulminant infantile Wolman disease (WD) and child-to-adulthood onset progressive cholesteryl ester storage disease (CESD).1–3 WD patients present a near complete absence (<1%) of LAL activity, while a residual (1% to 12%) LAL activity is found in children and adults with CESD.4–6
Infants with WD have extensive accumulation of cholesteryl esters and triglycerides in the liver, spleen, adrenals, bone marrow, and lymph nodes, displaying massive hepatosplenomegaly, adrenal calcifications, vomiting, diarrhea, malabsorption-associated malnutrition, and weight loss, which typically lead to death within the first 3 to 12 months of life.1,3,7,8 In turn, the accumulation of cholesteryl esters and triglycerides in CESD patients is progressive and may also lead to liver pathology, besides chronic hyperlipidemia. Premature death of CESD patients is usually attributed to liver failure and/or accelerated atherosclerotic disease.3,6,9
LAL-D Genetics and Inheritance
WD and CESD are both caused by mutations in the LIPA gene, which encodes for LAL and is localized to chromosome 10q23.2-q23.3.10 It is the level of residual activity of the mutant LAL that distinguishes them.5 So far, over 120 types of mutations in the LIPA gene have been identified for WD and CESD phenotypes.11–13 Homozygous and compound heterozygous pathogenic variants of this gene (eg, nonsense mutations, deletions, and frameshift defects) are typically associated with WD.4,11 On the other hand, less severe mutations are usually associated with CESD. Being an autosomal recessive disease, both progenitors must be carriers for the offspring to have a 25% chance of developing LAL-D. Approximately half of LAL-D patients exhibit a splice junction mutation in exon 8 (E8SJM; c.894G>A), making it the most frequent inherited defect in the LIPA gene.14,15
A small fraction of the mRNA is still spliced correctly, which influences the percentage of residual LAL activity. Saito and colleagues have reported that, even though there are some exceptions, WD mutations lead to amino acid substitutions that affect the active site of LAL, while CESD mutations entail amino acid substitutions that cause mild conformational changes on the surface of LAL.4 Previous investigation has shown that missense mutations generate heterogeneous phenotypes between WD and CESD, but CESD mutations are dominant over the LAL-D phenotype, as patients who are heterozygous for a WD mutation and a CESD mutation exhibit CESD instead of WD.16
Prevalence and Incidence of LAL-D
LAL-D is a pan-ethnic disease for which prevalence and incidence are not precisely known. This is due not only to the rarity of the disease but also and mainly to its under-recognition. Between 1980 and 1996, a study was conducted in Australia in view of identifying the prevalence of several types of lysosomal storage disorders upon birth.17 Data from this study suggested an Australian prevalence and incidence of WD of 1:528,000 and 1:704,000, respectively.
Later in 2011, the incidence of WD in Iranian-Jewish children was projected to be as high as 1:4200.18 However, the acknowledgment of milder forms of LAL-D has led to the conclusion that it may actually represent a significant proportion of patients previously diagnosed with other dyslipidemia-associated disorders that share overlapping symptoms, such as nonalcoholic fatty liver disease (NAFLD).1,19 Therefore, most of the existing estimates for LAL-D prevalence result from population screening for heterozygous E8SJM (c.894G>A) mutations and are based on its frequency.14,20
In 2007, a study involving three geographically different cohorts of a total of 2023 German individuals identified 10 heterozygous E8SJM carriers with an allele frequency of 0.0025, which translates into a carrier frequency of approximately 1:200.14 The homozygote frequency was estimated as 25 per million. In 2013, Scott et al. published a study of the frequency of the c.894G>A mutation on two different cohorts of multiracial and ethnic groups.20
The first cohort comprised 10,000 healthy individuals from the greater New York metropolitan area of African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish origins, whereas the second encompassed the genotyping of 6,578 LIPA alleles of African-American, Caucasian, and Hispanic individuals from Dallas County, Texas. The combined results from the analysis of the 2 cohorts revealed c.894G>A allele frequencies ranging from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of approximately 1:1000 to 1:300, respectively. Ashkenazi Jews displayed a carrier frequency of 1:500, while no heterozygotes were detected in the Africa-American population, which suggests that the c.894G>A mutation might not be the most common alteration in this group. Based on these frequencies, the prevalence of CESD has been predicted to be about 1:125,000 for Caucasians and Hispanics, 1:333,333 for Ashkenazi Jews, and 1:1,000,000 for Asians.
A more recent publication from Carter and colleagues described a comprehensive genetic epidemiological meta-analysis of the combination of all previously reported disease variants with unreported major functional variants among a multi-ancestry population.13 The heterozygous carrier rate and disease prevalence at birth were respectively estimated as 1:627 and 1:393,630 for WD, 1:435 and 1:183,543 for CESD, and 1:421 and 1:177,452 for LAL-D (WD + CESD). Differential analysis by ethnicity established a lower prevalence of LAL-D in the East Asian, Finnish, South Asian, and Ashkenazi populations, as compared to that of non-Finnish European ancestry (1:103,286). These values currently represent the most reliable available data on the prevalence of LAL-D across multiple populations, confirming its classification as an ultra-rare disease.
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7. 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
8. Abramov A, Schorr S, Wolman M. Generalized xanthomatosis with calcified adrenals. AMA J Dis Child. 1956;91(3):282-286. doi:10.1001/archpedi.1956.02060020284010
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10. Anderson RA, Rao N, Byrum RS, et al. In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) deficient in Wolman disease to chromosome 10q23.2-q23.3. Genomics. 1993;15(1):245-247. doi:https://doi.org/10.1006/geno.1993.1052
11. Pisciotta L, Tozzi G, Travaglini L, et al. Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. Atherosclerosis. 2017;265:124-132. doi:10.1016/j.atherosclerosis.2017.08.021
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15. Lohse P, Maas S, Lohse P, et al. Compound heterozygosity for a wolman mutation is frequent among patients with cholesteryl ester storage disease. J Lipid Res. 2000;41(1):23-31.
16. Pagani F, Pariyarath R, Garcia R, et al. New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease. J Lipid Res. 1998;39(7):1382-1388.
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18. Valles-Ayoub Y, Esfandiarifard S, No D, et al. Wolman disease (LIPA p.G87V) genotype frequency in people of iranian-jewish ancestry. Genet Test Mol Biomarkers. 2011;15(6):395-398. doi:10.1089/gtmb.2010.0203
19. Hůlková H, Elleder M. Distinctive histopathological features that support a diagnosis of cholesterol ester storage disease in liver biopsy specimens. Histopathology. 2012;60(7):1107-1113. doi:https://doi.org/10.1111/j.1365-2559.2011.04164.x20.
20. Scott SA, Liu B, Nazarenko I, et al. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology. 2013;58(3):958-965. doi:10.1002/hep.26327
Reviewed by Michael Sapko, MD, on 7/1/2021.