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 testing of a pregnancy at increased risk are possible if the LIPA pathogenic variants in the family have been identified.

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.

Establishing the Diagnosis

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

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic LIPA variants of uncertain significance (or of one known LIPA pathogenic variant and one LIPA variant of uncertain significance) does not establish or rule out the diagnosis.

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: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  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.

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 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).

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].

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.

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 under way for enzyme replacement therapy [Valayannopoulos et al 2014].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the LIPA pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Molecular 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.

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.

Revision History

• 1 September 2016 (ma) Revision: enzyme replacement therapy (Management)
• 30 July 2015 (me) Review posted live
• 4 October 2012 (mfm) Original submission

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