Lysosomal Acid Lipase Deficiency (LAL-D)

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Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare inherited pan-ethnic metabolic disorder caused by inborn genetic mutations in the LIPA gene that result in abnormal LAL enzymatic activity and subsequent widespread lysosomal accumulation of body lipids.1 

LAL-D has a wide spectrum of clinical manifestations, which ranges from the fulminant infantile-onset Wolman disease (WD) to the progressive child-to-adulthood-onset cholesteryl ester storage disease (CESD).

Being an autosomal recessive disease, the family pedigree of a proband can be assessed in order to identify carriers and evaluate the risk of disease inheritance.2

An early diagnosis of LAL-D is fundamental to ensure a proper patient management and reduce the risk of complications associated with disease progression, namely premature atherosclerotic disease.1

Amount of Residual LAL Activity

The severity of LAL-D appears to be directly proportional to the magnitude of tissue build-up of cholesteryl esters and triglycerides. This seems to be directly correlated with the amount of residual LAL activity that remains functional, which is determined by the nature of the underlying mutation variant.3,4 The most severe alterations in the LIPA gene result in complete or near complete absence (<1%) of LAL activity and are associated with WD detected in infants, which is normally fatal within the first months of life.3–5 In turn, less severe mutations lead to a residual (1% to 12%) LAL activity and occur in children and adults with CESD. Thus, the risk of a poor prognosis is inversely proportional to the amount of residual LAL activity.

Age and Gender

LAL-D can be manifested in patients of all ages, from infancy to adulthood, though disease severity seems to be inversely proportional to the age of onset.1 Gender does not seem to be a risk factor in LAL-D as males and females are affected in about equal numbers.6

Genetics

Several kinds of different loss-of-function mutation variants in the LIPA gene have been identified.7,8 The most common inherited defect in the LIPA gene is a splice site mutation in exon 8 (E8SJM; c.894G>A).6,7 This variant has been found in approximately 50% of CESD patients and results in the deletion of the exon 8 in the mRNA.

After the disease-causing LIPA pathogenic variants in the family are identified, carrier testing for at-risk relatives may be performed in order to identify those who would benefit from early institution of treatment and surveillance.2 The parents of a LAL-D proband are obligate heterozygotes and carry one LIPA pathogenic variant. Each sib of a LAL-D individual has a 25% risk of manifesting the disease, while having 50% chance of being an asymptomatic carrier and a 25% chance of being unaffected and not a carrier.2 The offspring of an affected individual will be obligate heterozygote carriers.

Ethnicity

Though the prevalence and incidence of LAL-D are not precisely known, studies have been conducted in multi-racial and multi-ethnic cohorts of individuals who were screened for heterozygous E8SJM (c.894G>A) mutations in view of estimating these parameters across multiple populations.9 The c.894G>A pathogenic variant has been identified in European and Hispanic populations and, to a lesser extent, in Asian populations. The analysis of the combined results revealed c.894G>A allele frequencies ranging from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of approximately 1:1,000 to 1:300, respectively. This particular variant was not detected in African Americans. This does not mean that this population is not at risk for manifesting LAL-D but it suggests that the c.894G>A mutation might not be the most common alteration in this group. Based on the carrier frequencies, the prevalence of CESD has been predicted at about 1:125,000 for Caucasians and Hispanics and 1:1,000,000 for Asians.

Another study described the global prevalence of LAL-D using 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.10 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 different ethnicities established a lower risk of LAL-D in the East Asian, Finnish, South Asian, and Ashkenazi populations, as compared to that of non-Finnish European ancestry.

Diet and Lifestyle

Due to the abnormally high lipid profile of LAL-D patients, the implementation of a diet low in cholesterol and triglycerides is advised to reduce the risk of atherosclerotic disease.2

LAL-D patients should also adapt their lifestyle in order to manage their disease. Patients manifesting liver fibrosis or cirrhosis should partially or completely avoid alcohol intake, respectively.2,11,12 Smoking should also be avoided to lower the risk of vascular disease progression.11

Complications and Associated Risks

Liver disease can lead to hemorrhages and life-threatening esophageal varices.7,13 It is suggested that the use of non-specific beta-blockers in patients with esophageal varices may reduce the risk of bleeding.2

The typical dyslipidemia present in LAL-D is characterized by upregulated levels of serum transaminases, total cholesterol, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) cholesterols, as well as downregulated levels of high-density lipoprotein (HDL) cholesterols.14–16 As a result, patients, especially those with late-onset CESD, display an accelerated atherosclerotic profile and increased risk of both cardiovascular disease, cerebrovascular accidents and, consequently, premature death.7,17 In CESD patients, cardiovascular manifestations predominantly involve coronary artery disease, aneurysm and stroke.7

References

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:https://doi.org/10.1016/j.atherosclerosis.2014.04.003

2. Hoffman EP, Barr ML, Giovanni MA, Murray MF. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [updated 2016 Sep 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.

3. 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:https://doi.org/10.1016/j.ymgme.2011.11.004

4. 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:https://doi.org/10.1006/geno.1996.0162

5. 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

6. Muntoni S, Wiebusch H, Jansen-Rust M, et al. Prevalence of Cholesteryl Ester Storage Disease. Arterioscler Thromb Vasc Biol. 2007;27(8):1866-1868. doi:10.1161/ATVBAHA.107.146639

7. 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:https://doi.org/10.1016/j.jhep.2013.02.014

8. 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 <em>LIPA</em> pathogenic variants. Atherosclerosis. 2017;265:124-132. doi:10.1016/j.atherosclerosis.2017.08.021

9. 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

10. Carter A, Brackley SM, Gao J, Mann JP. The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD. J Hepatol. 2019;70(1):142-150. doi:10.1016/j.jhep.2018.09.028

11. Kohli R, Ratziu V, Fiel MI, Waldmann E, Wilson DP, Balwani M. Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in  children and adults: Consensus recommendations from an international collaborative working group. Mol Genet Metab. 2020;129(2):59-66. doi:10.1016/j.ymgme.2019.11.004

12. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51(1):307-328. doi:10.1002/hep.23258

13. Gasche C, Aslanidis C, Kain R, et al. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease  associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997;27(4):744-750. doi:10.1016/s0168-8278(97)80092-x

14. Brown MS, Dana SE, Goldstein JL. Receptor-dependent hydrolysis of cholesteryl esters contained in plasma low density lipoprotein. Proc Natl Acad Sci U S A. 1975;72(8):2925-2929. doi:10.1073/pnas.72.8.2925

15. Goldstein JL, Dana SE, Faust JR, Beaudet AL, Brown MS. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein.  Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem. 1975; 250(21):8487-8495.

16. Kostner GM, Hadorn B, Roscher A, Zechner R. Plasma lipids and lipoproteins of a patient with cholesteryl ester storage disease. J Inherit Metab Dis. 1985;8(1):9-12. doi:10.1007/BF0180547517.

17. 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

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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