NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Lysosomal Acid Lipase Deficiency

Synonyms: Acid Lipase Deficiency, LAL Deficiency

, MS, CGC, , ScM, , MS, CGC, and , MD.

Author Information

Initial Posting: ; Last Revision: September 1, 2016.

Estimated reading time: 21 minutes

Summary

Clinical characteristics.

The phenotypic spectrum of lysosomal acid lipase (LAL) deficiency ranges from the infantile-onset form (Wolman disease) to later-onset forms collectively known as cholesterol ester storage disease (CESD).

Wolman disease is characterized by infantile-onset malabsorption that results in malnutrition, storage of cholesterol esters and triglycerides in hepatic macrophages that results in hepatomegaly and liver disease, and adrenal gland calcification that results in adrenal cortical insufficiency. Unless successfully treated with hematopoietic stem cell transplantation (HSCT), infants with classic Wolman disease do not survive beyond age one year.

CESD may present in childhood in a manner similar to Wolman disease or later in life with such findings as serum lipid abnormalities, hepatosplenomegaly, and/or elevated liver enzymes long before a diagnosis is made. The morbidity of late-onset CESD results from atherosclerosis (coronary artery disease, stroke), liver disease (e.g., altered liver function ± jaundice, steatosis, fibrosis, cirrhosis and related complications of esophageal varices, and/or liver failure), complications of secondary hypersplenism (i.e., anemia and/or thrombocytopenia), and/or malabsorption. Individuals with CESD may have a normal life span depending on the severity of disease manifestations.

Diagnosis/testing.

Diagnosis of LAL deficiency is suspected in individuals with characteristic clinical findings such as hepatomegaly, elevated transaminases, and a typical serum lipid profile: high total serum concentrations of cholesterol, low-density lipoprotein, and triglycerides; and low serum concentration of high-density lipoprotein. The diagnosis is confirmed by identification of either biallelic pathogenic variants in LIPA or deficient LAL enzyme activity in peripheral blood leukocytes, fibroblasts, or dried blood spots.

Management.

Treatment of manifestations:

  • Both Wolman disease and CESD: Enzyme replacement therapy (ERT) with sebelipase alfa was recently approved by the FDA and is administered at a dose of 1 mg/kg body weight every other week; this treatment can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have CESD. Consider referral to a liver specialist. Liver transplantation may be indicated when liver disease progresses to cirrhosis and liver failure.
  • Wolman disease: Consultation with a nutrition team to limit malnutrition if possible, including use of parenteral nutrition; corticosteroid and mineralocorticoid replacement in the presence of adrenal insufficiency.
  • CESD: Reduce cholesterol through the use of statins, cholestyramine, and a diet low in cholesterol and triglycerides. Aggressive reduction of additional cardiovascular risk factors and lipophilic vitamins may also be beneficial. Consult with a nutrition team for children with failure to thrive or adults with weight loss.

Prevention of primary manifestations: Successful hematopoietic stem cell transplantation can correct the metabolic defect.

Prevention of secondary complications: Use nonspecific beta-blockers in those with esophageal varices to reduce the risk of bleeding.

Surveillance: No standard guidelines for surveillance of CESD have been developed.

  • For children: Monitor growth and nutritional status; evaluate fasting lipid levels, platelet count, and liver enzymes every six months.
  • For adults: reevaluate every 6-12 months depending on disease severity. Monitor nutritional status. Evaluate fasting lipid levels, platelet count, and liver enzymes routinely. Evaluate those with severe liver disease for esophageal varices by upper endoscopy every three years. Monitor and treat those with hepatosplenomegaly thrombocytopenia to prevent bleeding complications.
  • For children and adults: monitor hepatosplenic volume and screen for hepatocellular carcinoma with serial liver and spleen imaging.

Agents/circumstances to avoid: In the presence of thrombocytopenia avoid use of nonsteroidal anti-inflammatory drugs.

Evaluation of relatives at risk: It is appropriate to evaluate the sibs of a proband in order to identify those who would benefit from early treatment and surveillance.

Genetic counseling.

LAL deficiency is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis of pregnancies at increased risk are possible if the LIPA pathogenic variants in the family have been identified.

GeneReview Scope

Lysosomal Acid Lipase Deficiency: Included Phenotypes 1
  • Cholesterol ester storage disease
  • Wolman disease

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

The phenotypic spectrum of lysosomal acid lipase (LAL) deficiency ranges from infantile-onset form (Wolman disease) to later-onset forms, collectively known as cholesterol ester storage disease (CESD). LAL deficiency cannot be diagnosed on clinical findings alone.

Suggestive Findings

Wolman disease is suspected in infants with hepatomegaly, vomiting, diarrhea, and failure to thrive. Adrenal calcification on abdominal imaging greatly increases suspicion for Wolman disease [Anderson et al 1999, Boldrini et al 2004].

Cholesterol ester storage disease (CESD) is suspected in individuals (ranging in age from early childhood to adulthood) with signs of increased lipid storage such as hepatomegaly, liver disease, lipid deposition in the intestinal walls, and/or xanthelasma.

Preliminary Testing

Serum concentrations of lipids and lipoproteins are almost always abnormal (Table 1).

  • Total serum concentration of cholesterol is often high, as are serum concentrations of low-density lipoprotein (LDL) and triglycerides.
  • Serum concentration of high-density lipoprotein (HDL) is typically low.

Note: Normal serum lipid levels do not exclude the diagnosis of LAL deficiency [Drebber et al 2005, Chatrath et al 2009, Decarlis et al 2009, Pisciotta et al 2009].

Table 1.

Lipid Values Found in 33 Individuals with LAL Deficiency

Cholesterol 1Triglycerides 2
TotalLDLHDL
Normal<200<130>50<150
In reported casesRange106-428147-2928-8760-443
Average29122830200
% of cases > or < normal range88% > nml100% > nml96% < nml71% > nml

Establishing the Diagnosis

The diagnosis is confirmed by identification of either biallelic pathogenic variants in LIPA or deficient LAL enzyme activity in peripheral blood leukocytes, fibroblasts, or dried blood spots.

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of LIPA is performed first. Consider gene-targeted deletion/duplication analysis if only one pathogenic variant is identified.
  • A multigene panel that includes LIPA and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and sensitivity of multigene panels vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of lysosomal acid lipase deficiency. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Lysosomal Acid Lipase Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method 3
One Variant DetectedTwo Variants Detected
LIPASequence analysis 4Wolman disease
1/7 probands6/7 probands
CESD
2/31 probands29/31 probands
Gene-targeted deletion/duplication analysis 5Unknown 6Unknown, none reported 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.
4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Large deletions appear to be rare, but have been reported [Lee et al 2011].

7.

Examples of homozygosity for exon or whole-gene deletions have not been reported.

Assay of lysosomal acid lipase (LAL) enzyme activity. Residual enzyme activity levels are more significantly decreased in Wolman syndrome (≤5% of controls) compared to a generally less severe but overlapping range of loss of activity in CESD (range 2%-11% of residual activity) [Fasano et al 2012].

Note: (1) Assay of LAL enzyme activity in peripheral blood leukocytes is the confirmatory diagnostic test for LAL deficiency; however, enzyme activity can also be diagnostically measured in hepatocytes, skin fibroblasts, or dried blood spots that have been promptly transported and properly stored [Reiner et al 2014]. (2) The confirmation of significant loss of LAL enzymatic function is recommended when LIPA pathogenic variants identified on genome-wide sequencing (e.g., exome sequencing) first suggest the diagnosis of LAL deficiency.

Liver biopsy. Note: Use of more invasive testing, such as liver biopsy, is not necessary in the diagnostic evaluation of all persons suspected of having LAL deficiency. See Clinical Description, Liver Biopsy.

Clinical Characteristics

Clinical Description

Lysosomal acid lipase (LAL) deficiency, like other diseases caused by enzyme deficiencies, has a wide phenotypic spectrum. Infantile-onset LAL deficiency is known as Wolman disease. All later-onset LAL deficiency, which may present from early childhood to late adulthood (often with subclinical disease), is known as cholesterol ester storage disease (CESD).

Wolman Disease

Infants with Wolman disease may present as early as the first day of life with vomiting, steatorrhea, and abdominal distention [Shome et al 2002]. Other infants may come to medical attention within weeks to months due to failure to thrive [Browne et al 2003].

Hepatomegaly, the result of build-up of cholesterol esters and triglycerides in macrophages of the liver, is common and can be dramatic. Splenomegaly, the result of the same mechanism, may also be present.

Increased lipid deposition along the gastrointestinal tract leads to thickened bowel walls with resultant malnutrition and wasting [Nchimi et al 2003].

Steatosis may progress to liver failure.

Enlarged adrenal glands with calcification, a classic finding in Wolman disease, can lead to adrenal cortical insufficiency.

Infants with Wolman disease do not usually survive beyond the first year of life. Treatment with hematopoietic stem cell transplantation (HSCT) has had mixed results, and requires further study [Gramatges et al 2009]. Death results from a combination of malnutrition, liver disease, and adrenal cortical insufficiency.

Cholesterol Ester Storage Disease (CESD)

Although CESD may present in childhood in a manner similar to Wolman disease with failure to thrive and delayed milestones [Bindu et al 2007], it has also been identified in individuals with atypical phenotypes such as elevated liver enzymes or serum lipid abnormalities identified on routine screening [Drebber et al 2005] and apparent autosomal recessive hypercholesterolemia without mutation of the expected gene [Stitziel et al 2013] (see Differential Diagnosis, Autosomal recessive hypercholesterolemia).

Atherosclerosis due to hyperlipidemia accounts for much of the morbidity associated with late-onset CESD, such as coronary artery disease and catastrophic vascular events including stroke [Elleder et al 1990]. In one family the phenotype resembled autosomal recessive hypercholesterolemia (see Differential Diagnosis) with extremely high total and low-density lipoprotein cholesterol levels, and abnormal hepatic accumulation of cholesterol without other features of CESD [Stitziel et al 2013].

Hepatomegaly with or without splenomegaly is frequently present as a result of cholesterol ester and triglyceride build-up in macrophages. Organomegaly, often among the first findings noted, may be present for years before a diagnosis is reached [Ameis et al 1995, vom Dahl et al 1999]. Individuals with splenomegaly may develop anemia and/or thrombocytopenia due to secondary hypersplenism.

Liver disease is common. It may present as altered liver function with or without jaundice, steatosis, fibrosis, or cirrhosis. Liver disease can lead to esophageal varices, which are associated with risk for hemorrhage and can be life-threatening [Gasche et al 1997]. Some individuals may experience liver failure.

Hepatocellular carcinoma has occurred in the setting of advanced cirrhosis [Riva et al 2008].

Lipid deposition in the wall of the intestinal tract can contribute to diarrhea and weight loss [Anderson et al 1999, Drebber et al 2005].

On occasion, signs of hyperlipidemia (e.g., xanthelasma, particularly of the palpebral area) may be visible [Elleder et al 1990, vom Dahl et al 1999].

Enlarged adrenal glands with punctate calcifications can be present, more often in those with more severe disease [Boldrini et al 2004].

Individuals with CESD may have a normal life span depending on the severity of disease manifestations.

Liver Biopsy

Liver biopsy demonstrates microvesicular steatosis or “fatty liver.” To help distinguish LAL deficiency (both Wolman and CESD) from common diagnoses with overlapping findings (see Differential Diagnosis), the following findings on liver biopsy are used:

  • Presence of additional supportive findings including “sea-blue” histiocytes, large Kupffer cells with increased vacuoles, lipid droplets, and/or cholesterol crystals [Boldrini et al 2004, Drebber et al 2005, Pisciotta et al 2009]
  • Immunohistochemistry including use of the lysosomal markers cathepsin D, lysosomal-associated membrane protein 1 (LAMP1), LAMP2, and lysosomal integral membrane protein 2 [Hůlková & Elleder 2012]
  • Identification of Maltese cross-type birefringence in frozen sections [Hůlková & Elleder 2012]

Genotype-Phenotype Correlations

In general, null allelic variants with no residual enzyme function result in Wolman disease and pathogenic variants that allow for residual LAL enzyme activity result in CESD.

The c.894G>A pathogenic variant, associated with residual enzyme activity, has been identified in European and Hispanic populations and, to a lesser extent, in Asian populations. Although this variant has not been identified in African Americans, it cannot be concluded that this population is not at risk for this condition [Scott et al 2013]. Variant c.894G>A is the most common observed in CESD, accounting for more than 50% of reported pathogenic variants [Bernstein et al 2013]. Nearly all individuals with CESD reported in the published literature are compound heterozygous or homozygous for c.894G>A. Of note, three members of one family homozygous for the c.894G>A variant had an atypical phenotype that resembled autosomal recessive hypercholesterolemia (see Differential Diagnosis) [Stitziel et al 2013].

Among individuals with the same genotype, varying levels of residual enzyme activity have been reported; therefore, the predictive value of genotype is only in distinguishing Wolman disease from CESD.

The level of residual LAL enzyme activity identified on enzyme assay is not useful for predicting disease course, as manifestations of disease vary greatly among individuals with similar levels of enzyme activity.

Nomenclature

Other names used for lysosomal acid lipase (LAL) deficiency in the past that are no longer in use include:

  • Acid cholesterol ester hydrolase deficiency
  • Cholesterol ester hydrolase deficiency storage disease

Cholesterol ester storage disease is also known as cholesteryl ester storage disease.

Prevalence

Due to the rarity and under-recognition of LAL deficiency, precise prevalence rates are not known at this time. Estimates in a German cohort suggested 1:50,000 for CESD and 1:350,000 for Wolman disease; however, LAL deficiency may be found to be more common as milder phenotypes continue to be recognized [Muntoni et al 2007].

LAL deficiency may be more common in individuals of Iranian-Jewish ancestry: one study suggested rates as high as 1:4200 in the Iranian-Jewish population of the Los Angeles area due to a c.260G>T founder variant [Valles-Ayoub et al 2011]. This pathogenic variant has been reported both in individuals with Wolman disease and in those with CESD [Valles-Ayoub et al 2011, Pagani et al 1996].

Differential Diagnosis

Acid sphingomyelinase deficiency (Niemann-Pick disease, types A and B). Overlapping clinical features of lysosomal acid lipase (LAL) deficiency and Niemann-Pick disease types A and B are hepatosplenomegaly, which is common in both, and lipid profiles in Niemann-Pick disease A and B which may be similar to those in LAL deficiency (i.e., low HDL with hyperlipidemia).

In contrast, the interstitial lung disease and ophthalmologic findings common to Niemann-Pick disease are not observed in LAL deficiency.

Biochemical analysis distinguishes between the two disorders [vom Dahl et al 1999]. Mutation of SMPD1 is causative. Inheritance is autosomal recessive.

Gaucher disease (GD). Overlapping clinical features of lysosomal acid lipase (LAL) deficiency and GD are hepatosplenomegaly and thrombocytopenia.

In contrast, the adrenal calcifications typical of Wolman disease (and occasionally CESD) and the abnormal lipid profile typical of LAL deficiency are not seen in GD. The bone manifestations common to GD type 1 are not observed in CESD.

Biochemical analysis can distinguish between the two diseases [vom Dahl et al 1999]. Mutation of GBA is causative. Inheritance is autosomal recessive.

Familial hypercholesterolemia. CESD may initially be confused with familial hypercholesterolemia because of increased serum concentration of total cholesterol and LDL; however, serum concentrations of HDL and triglycerides are usually still in the normal range. Liver disease and organomegaly are not observed in familial hypercholesterolemia. Mutation of LDLR, APOB, or PCSK9 accounts for 60%-80% of familial hypercholesterolemia. Inheritance is autosomal dominant.

Autosomal recessive hypercholesterolemia (ARH) (OMIM 603813). CESD manifesting as extremely high total and low-density lipoprotein cholesterol levels may resemble ARH [Stitziel et al 2013]. Mutation of LDLRAP1 is causative. Inheritance is autosomal recessive.

Hepatosplenomegaly is common to many storage disorders, including other lysosomal storage disorders. Other storage disorders can often be distinguished from LAL deficiency based on associated features:

Biochemical analysis can distinguish between storage disorders.

Liver disease in CESD is commonly misattributed to hepatitis, non-alcoholic fatty liver disease, or cryptogenic cirrhosis. Nonalcoholic fatty liver disease, which is associated with obesity, is a common finding on liver biopsy; therefore, body mass index should be considered along with other signs and symptoms when considering the cause of “fatty liver” disease.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with lysosomal acid lipase (LAL) deficiency, the following evaluations are recommended:

  • Complete blood count
  • Complete fasting lipid profile, if not done at the time of diagnosis
  • Liver function tests
  • Upper endoscopy to evaluate individuals with severe liver disease for the presence of esophageal varices
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Enzyme replacement therapy (ERT) with sebelipase alfa was approved by the FDA in late 2015.

  • Results from a Phase III clinical trial of 66 affected individuals demonstrated that ERT can be life saving for those with severe Wolman syndrome and life improving with prolonged survival in those who have cholesterol ester storage disease [Burton et al 2015].
  • ERT is administered intravenously at a dose of 1 mg/kg body weight every other week.

Wolman Disease

Symptoms should generally be treated in a routine manner, while keeping in mind the limited life expectancy of infants with untreated Wolman disease.

Malabsorption and malnutrition. Consultation with a nutrition team should be provided in an attempt to limit malnutrition to the extent possible. Parenteral nutrition is offered in many instances of intractable malabsorption.

Hepatomegaly and liver disease. Liver transplantation can be considered for individuals who progress to cirrhosis and liver failure.

Adrenal cortical insufficiency. Corticosteroid and mineralocorticoid replacement is indicated in the presence of insufficiency.

Hematopoietic stem cell transplantation (HSCT) has overall had mixed results, and requires further study [Gramatges et al 2009]. While successful engraftment can correct the metabolic defect [Stein et al 2007, Tolar et al 2009], HSCT can be associated with morbidity and mortality [Yanir et al 2013].

Consider discussion of comfort care options.

CESD

Hyperlipidemia. Attempts should be made to reduce cholesterol through the use of statins, cholestyramine, ezetimibe, and a diet low in cholesterol and triglycerides [Gasche et al 1997, Dalgiç et al 2006, Chatrath et al 2009, Abello et al 2010].

Lipophilic vitamin supplementation may also be beneficial.

Aggressive reduction of additional cardiovascular disease risk factors should be encouraged.

Nutrition. Consultation with a nutrition team should be provided to children experiencing failure to thrive and to adults experiencing weight loss. Additionally, a nutrition team can assist individuals in the implementation of a diet low in cholesterol and triglycerides.

Liver transplantation can be considered for individuals who progress to cirrhosis and liver failure. At least four case reports of successful liver transplantation for CESD have been reported, with post-operative improvement of lipid profiles and successful transplant out to five years in one individual [Ambler et al 2013].

Prevention of Secondary Complications

Individuals found to have esophageal varices should be placed on nonspecific beta-blockers to reduce the risk of bleeding; beta-blockers have not been shown to prevent the formation of esophageal varices.

Surveillance

No standard guidelines for the surveillance of individuals with LAL deficiency have been developed. The following screening practices can be considered to monitor for the most common symptoms associated with CESD.

Children

  • Special attention should be paid to growth and nutritional status. Chronic diarrhea or failure to thrive could indicate malabsorption.
  • Consider monitoring fasting lipid levels, platelet count, and liver enzymes every six months.

Adults with CESD should be evaluated every six to 12 months depending on disease severity.

  • Special attention should be paid to nutritional status. Chronic diarrhea or weight loss could indicate malabsorption.
  • Monitor routinely fasting lipid levels, platelet count, and liver enzymes.
  • Individuals with severe liver disease should be evaluated for esophageal varices by upper endoscopy every three years.
  • Individuals with hepatosplenomegaly should be monitored and treated for thrombocytopenia to prevent bleeding complications.

Both children and adults. Obtain serial liver and spleen imaging to monitor for hepatosplenic volume and to screen for hepatocellular carcinoma which has arisen in the setting of advanced cirrhosis [Riva et al 2008]. Consensus on optimal screening protocols has not been published.

Agents/Circumstances to Avoid

Those with thrombocytopenia should avoid use of nonsteroidal anti-inflammatory drugs.

Evaluation of Relatives at Risk

It is appropriate to evaluate the sibs of a proband in order to identify those who would benefit from early institution of treatment.

  • If the LIPA pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the LIPA pathogenic variants in the family are not known, assay of lysosomal acid lipase (LAL) enzyme activity can be used to assist in the identification of affected sibs.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Clinical trials are underway for enzyme replacement therapy [Valayannopoulos et al 2014].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Lysosomal acid lipase (LAL) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one LIPA pathogenic variant).
  • Heterozygotes(carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an individual with lysosomal acid lipase deficiency are obligate heterozygotes (carriers of a LIPA pathogenic variant).
  • The risk that offspring will inherit a second LIPA pathogenic variant depends on the reproductive partner's carrier status. LIPA molecular genetic testing should be offered to the reproductive partner of an affected individual to determine carrier status.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a LIPA pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the LIPA pathogenic variants in the family.

Note: Because of the overlap of lysosomal acid lipase (LAL) enzymatic activity between carriers and non-carriers, assay of LAL enzyme activity is not an appropriate method to determine carrier status.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the LIPA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Lysosomal Acid Lipase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
LIPA10q23​.31Lysosomal acid lipase/cholesteryl ester hydrolaseLIPA databaseLIPALIPA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Lysosomal Acid Lipase Deficiency (View All in OMIM)

278000LYSOSOMAL ACID LIPASE DEFICIENCY
613497LIPASE A, LYSOSOMAL ACID; LIPA

Molecular Genetic Pathogenesis

In the normal state, the enzyme lysosomal acid lipase (LAL) degrades LDL cholesterol esters and triglycerides in lysosomes. The intracellular free cholesterol that results from the degradation of these molecules is transferred to the endoplasmic reticulum, where it interacts with transcription factors that suppress:

  • HMG-CoA reductase activity, which reduces the cellular synthesis of cholesterol;
  • LDL receptor gene transcription, which results in reduced intracellular uptake of LDL.

In the disease state, deficient LAL enzyme activity leads to accumulation of cholesterol esters and triglycerides within lysosomes. Less free intracellular cholesterol results in heightened synthesis of endogenous cholesterol and endocytosis via LDL receptors. The relationship between the disease state and LDL receptor gene expression and activity is not entirely understood [Reiner et al 2014]. However, the overall result of decreased LAL enzyme activity is lysosomal accumulation of cholesterol esters and triglycerides and increased levels of plasma cholesterol.

Gene structure. LIPA comprises ten exons spread across 36 kb. See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. A variety of pathogenic variants have been reported to cause LAL deficiency, including missense variants, nonsense variants, single- and double-nucleotide insertions and deletions, complex insertion/deletions, and splice site variants [Ameis et al 1995, Seedorf et al 1995, Anderson et al 1999, Hooper et al 2008, Pisciotta et al 2009].

The most common pathogenic variant resulting in CESD, c.894G>A, involves a G-to-A transition at the last base of exon 8 disrupting the normal donor splice consensus sequence (Table 3). Typically, this results in alternative splicing and subsequent skipping of exon 8. In the presence of this pathogenic variant approximately 3%-5% of transcripts are correctly spliced, allowing for residual enzyme activity.

Table 3.

Selected LIPA Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
c.260G>T 2p.Gly87Val
(Gly66Val)
NM_001127605​.1
NP_001121077​.1
c.894G>A
(934G>A)
(E8SJ)
See footnote 3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Founder variant; see Prevalence.

3.

At splice donor site of exon 8, resulting in alternative splicing and subsequent skipping of exon 8

Normal gene product. The enzyme lysosomal acid lipase A is expressed in lysosomes and is responsible for the hydrolysis of cholesterol esters and triacylglycerols. It is a member of a family of highly conserved acid lipases, which also includes human gastric lipase, rat lingual lipase, and bovine pregastric lipase [Zschenker et al 2001].

The catalytic active site of LAL is composed of amino acid residues Ser153, Asp324, and His353. The active-site serine is part of a lipase consensus sequence connecting a β-strand to an α-helix, known as the nucleophilic elbow, which facilitates interaction between the nucleophile and the histidine and ester carbon in the appropriately oriented complex [Lohse et al 1997].

Abnormal gene product. Disease results from loss of function of LAL caused by LIPA pathogenic variants that generate truncated proteins or proteins with altered conformations or reduced activity.

References

Literature Cited

  • Abello F, Guardamagna O, Baracco V, Bonardi R. The treatment of colesteryl storage disease (CESD) by ezetimibe monotherapy. Atheroscler Suppl. 2010;11:28.
  • Ambler GK, Hoare M, Brais R, Shaw A, Butler A, Flynn P, Deegan P, Griffiths WJ. Orthotopic liver transplantation in an adult with cholesterol ester storage disease. JIMD Rep. 2013;8:41–6. [PMC free article: PMC3565644] [PubMed: 23430518]
  • Ameis D, Brockmann G, Knoblich R, Merkel M, Ostlund RE, Yang JW, Coates PM, Cortner JA, Feinman SV, Greten H. A 5’ splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesterol ester storage disease. J Lipid Res. 1995;36:241–50. [PubMed: 7751811]
  • Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999;68:333–45. [PubMed: 10562460]
  • Bernstein DL, Hůlková H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58:1230–43. [PubMed: 23485521]
  • Bindu PS, Taly AB, Christopher R, Bharatkumar PV, Panda S, Netravathi M, Ravishankar S, Mahadevan A, Yasha TC, Gayathri N. Cholesterol ester storage disease with unusual neurological manifestations in two siblings: A report from South India. J Child Neurol. 2007;22:1401–4. [PubMed: 18174560]
  • Boldrini R, Devito R, Biselli R, Filocamo M, Bosman C. Wolman disease and cholesteryl ester storage disease diagnosed by histological and ultrastructural examination of intestinal and liver biopsy. Pathol Res Pract. 2004;200:231–40. [PubMed: 15200275]
  • Browne M, Somers G, Savoia H, Kukuruzovic R. Wolman’s disease in an infant. Br J Haematol. 2003;122:522. [PubMed: 12899707]
  • Burton BK, Balwani M, Feillet F, Barić I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sánchez A, Deegan P, Di Rocco M, Enns GM, Erbe R, Ezgu F, Ficicioglu C, Furuya KN, Kane J, Laukaitis C, Mengel E, Neilan EG, Nightingale S, Peters H, Scarpa M, Schwab KO, Smolka V, Valayannopoulos V, Wood M, Goodman Z, Yang Y, Eckert S, Rojas-Caro S, Quinn AG. A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N Engl J Med. 2015;373:1010–20. [PubMed: 26352813]
  • Chatrath H, Keilin S, Attar BM. Cholesterol ester storage disease (CESD) diagnosed in an asymptomatic adult. Dig Dis Sci. 2009;54:168–73. [PubMed: 18478331]
  • Dalgiç B, Sari S, Gündüz M, Ezgü F, Tümer L, Hasanoğlu A, Akyol G. Cholesteryl ester storage disease in a young child presenting as isolated hepatomegaly treated with simvastatin. Turk J Pediatr. 2006;48:148–51. [PubMed: 16848116]
  • Decarlis S, Agostoni C, Ferrante F, Scarlino S, Riva E, Giovannini M. Combined hyperlipidaemia as a presenting sign of cholesteryl ester storage disase. J Inherit Metab Dis. 2009;2009;32 Suppl 1:S11–3. [PubMed: 19214773]
  • Drebber U, Andersen M, Kasper HU, Lohse P, Stolte M, Dienes HP. Severe chronic diarrhea and weight loss in cholesteryl ester storage disease: A case report. World J Gastroenterol. 2005;11:2364–6. [PMC free article: PMC4305829] [PubMed: 15818756]
  • Elleder M, Ledvinova J, Cieslar P, Kuhn R, (1990) Subclinical course of cholesterol ester storage disease (CESD) diagnosed in adulthood. Virchow Archiv A Pathol Anat 416:357-65. [PubMed: 2106753]
  • Fasano T, Pisciotta L, Bocchi L, Guardamagna O, Assandro P, Rabacchi C, Zanoni P, Filocamo M, Bertolini S, Calandra S. Lysosomal lipase deficiency: Molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. Mol Genet Metab. 2012;105:450–6. [PubMed: 22227072]
  • Gasche C, Aslanidis C, Kain R, Exner M, Helbich T, Dejaco C, Schmitz G, Ferenci P. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997;27:744–50. [PubMed: 9365051]
  • Gramatges MM, Dvorak C, Regula D, Enns G, Weinberg K, Agarwal R. Pathological evidence of Wolman’s disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity. Bone Marrow Transplant. 2009;44:449–50. [PubMed: 19308038]
  • Hooper AJ, Tran HA, Formby MR, Burnett JR. A novel missense LIPA gene mutation, N98S, in a patient with cholesteryl ester storage disease. Clin Chim Acta. 2008 Dec;398(1-2):152–4. [PubMed: 18775687]
  • Hůlková H, Elleder M. Distinctive histopathological features that support a diagnosis of cholesterol ester storage disease in liver biopsy specimens. Histopathology. 2012;60:1107–13. [PubMed: 22621222]
  • Klima H, Ullrich K, Aslanidis C, Fehringer P, Lackner KJ, Schmitz G. A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease. J Clin Invest. 1993;92:2713–8. [PMC free article: PMC288469] [PubMed: 8254026]
  • Lee TM, Welsh M, Benhamed S, Chung WK. Intragenic deletion as a novel type of mutation in Wolman disease. Mol Genet Metab. 2011;104:703–5. [PMC free article: PMC3781170] [PubMed: 21963785]
  • Lohse P, Charhrokh-Zadeh S, Lohse P, Seidel D. Human lysosomal acid lipase/cholesteryl ester hydrolase and human gastric lipase: identification of the catalytically active serine, aspartic acid, and histidine residues. J Lipid Res. 1997;38:892–903. [PubMed: 9186907]
  • Lohse P, Maas S, Elleder M, Kirk JM, Besley GTN, Seidel D. Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease. J Lipid Res. 2000;41:23–31. [PubMed: 10627498]
  • Muntoni S, Wiebusch H, Funke H, Ros E, Seedorf U, Assmann G. Homozygosity for a splice junction mutation in exon 8 of the gene encoding lysosomal acid lipase in a Spanish kindred with cholesterol ester storage disease (CESD). Hum Genet. 1995;95:491–4. [PubMed: 7759067]
  • Muntoni S, Wiebusch H, Jansen-Rust M, Rust S, Seedorf U, Schulte H, Berger K, Funke H, Assmann G. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol. 2007;27:1866–8. [PubMed: 17634524]
  • Nchimi A, Rausin L, Khamis J. Ultrasound appearance of bowel wall in Wolman’s disease. Pediatr Radiol. 2003;33:284–5. [PubMed: 12709765]
  • Pagani F, Garcia R, Pariyarath R, Stuani C, Gridelli B, Paone G, Baralle FE. Expression of lysosomal acid lipase mutants detected in three patients with cholesteryl ester storage disease. Hum Mol Genet. 1996 Oct;5(10):1611–7. [PubMed: 8894696]
  • Pisciotta L, Fresa R, Bellocchio A, Pino E, Guido V, Cantafora A, Di Rocco M, Calandra S, Bertolini S. Cholesteryl ester storage disease (CESD) due to novel mutations in the LIPA gene. Mol Genet Metab. 2009;97:143–8. [PubMed: 19307143]
  • Reiner Ž, Guardamagna O, Nair D, Soran H, Hovingh K, Bertolini S, Jones S, Ćorić M, Calandra S, Hamilton J, Eagleton T, Ros E. Lysosomal acid lipase deficiency–An under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235:21–30. [PubMed: 24792990]
  • Riva S, Spada M, Sciveres M, Minervini M, Cintorino D, Maggiore G, Gridelli B. Hepatocarcinoma in a child with cholesterol ester storage disease. Dig Liver Dis. 2008;40:784. [PubMed: 18339594]
  • Scott SA, Liu B, Nazarenko I, Martis S, Kozlitina J, Yang Y, Ramirez C, Kasai Y, Hyatt T, Peter I, Desnick RJ. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology. 2013;58:958–65. [PMC free article: PMC3690149] [PubMed: 23424026]
  • Seedorf U, Wiebusch H, Muntoni S, Christensen NC, Skovby F, Nickel V, Roskos M, Funke H, Ose L, Assmann G. A novel variant of lysosomal acid lipase (Leu336Pro) associated with acid lipase deficiency and cholesterol ester storage disease. Arterioscler Thromb Vasc Biol. 1995;15:773–8. [PubMed: 7773732]
  • Shome DK, Al-Jishi E, Greally JF, Malik N, Zainaldeen HA, Das NS. The Middle-East connection of Wolman Disease. Saudi Med J. 2002;23:597–601. [PubMed: 12070591]
  • Stein J, Garty BZ, Dror Y, Fenig E, Zeigler M, Yaniv I. Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation. Eur J Pediatr. 2007;166:663–6. [PubMed: 17033804]
  • Stitziel NO, Fouchier SW, Sjouke B, Peloso GM, Moscoso AM, Auer PL, Goel A, Gigante B, Barnes TA, Melander O, Orho-Melander M, Duga S, Sivapalaratnam S, Nikpay M, Martinelli N, Girelli D, Jackson RD, Kooperberg C, Lange LA, Ardissino D, McPherson R, Farrall M, Watkins H, Reilly MP, Rader DJ, de Faire U, Schunkert H, Erdmann J, Samani NJ, Charnas L, Altshuler D, Gabriel S, Kastelein JJ, Defesche JC, Nederveen AJ, Kathiresan S, Hovingh GK. National Heart, Lung, and Blood Institute GO Exome Sequencing Project. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2013;33:2909–14. [PMC free article: PMC4002172] [PubMed: 24072694]
  • Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA. Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease. Lipids Health Dis. 2005;4:26. [PMC free article: PMC1291391] [PubMed: 16255772]
  • Tolar J, Petryk A, Khan K, Bjoraker KJ, Jessurun J, Dolan M, Kivisto T, Charnas L, Shapiro EG, Orchard PJ. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease. Bone Marrow Transplant. 2009;43:21–7. [PubMed: 18776925]
  • Valayannopoulos V, Malinova V, Honzík T, Balwani M, Breen C, Deegan P, Enns G, Jones S, Kane J, Stock E, Tripuraneni R, Eckert S, Schneider E, Hamilton G, Middleton M, Sirlin C, Kessler B, Bourdon C, Boyadjiev S, Sharma R, Twelves C, Whitley C, Quinn A. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014;61:1135–42. [PMC free article: PMC4203712] [PubMed: 24993530]
  • Valles-Ayoub Y, Esfandiarifard S, No D, Sinai P, Khokher Z, Kohan M, Kahen T, Darvish D. Wolman disease (LIPA p.G87V) genotype frequency in people of Iranian-Jewish ancestry. Genet Test Mol Biomarkers. 2011;15:395–8. [PubMed: 21291321]
  • vom Dahl S, Harzer K, Rolfs A, Albrecht B, Niederau C, Vogt C, van Weely S, Aerts J, Müller G, Häussinger D. Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitoriosidase activity and a homozymous lysosomal acid lipase -1 exon 8 splice junction mutation. J Hepatol. 1999;31:741–6. [PubMed: 10551400]
  • Yanir A, Allatif MA, Weintraub M, Stepensky P. Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications. Mol Genet Metab. 2013;109:224–6. [PubMed: 23583223]
  • Zschenker O, Jung N, Rethmeier J, Trautwein S, Hertel S, Zeigler M, Ameis D. Characterization of lysosomal acid lipase mutations in the signal peptide and mature polypeptide region causing Wolman disease. J Lipid Res. 2001;42:1033–40. [PubMed: 11441129]

Chapter Notes

Revision History

  • 1 September 2016 (ma) Revision: enzyme replacement therapy (Management)
  • 30 July 2015 (me) Review posted live
  • 4 October 2012 (mfm) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK305870PMID: 26225414

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...