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Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

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Lysosomal Acid Lipase Deficiency

Synonyms: Acid Lipase Deficiency, LAL Deficiency (LAL-D)

, MD, MS and , FRCPCH.

Author Information and Affiliations

Initial Posting: ; Last Update: January 15, 2026.

Estimated reading time: 40 minutes

Summary

Clinical characteristics.

The phenotypic spectrum of lysosomal acid lipase deficiency (LAL-D) ranges from an infantile-onset form (previously known as Wolman disease) to childhood/adult-onset forms (previously known as cholesterol ester storage disease [CESD]). Infantile-onset LAL-D is rapidly progressive and symptoms arise within the first few days to weeks of life, with persistent vomiting, steatorrhea, and abdominal distention escalating (if untreated) to severe liver dysfunction and death within the first three to six months of life. However, with early diagnosis and initiation of treatment, long-term survival has improved significantly, although treated individuals may continue to have suboptimal growth, iron deficiency anemia, and lipid accumulation in the gastrointestinal mucosa. Those with infantile-onset disease who are treated typically experience normal long-term intellectual and neurodevelopmental outcomes.

Individuals with childhood/adult-onset LAL-D typically present with otherwise unexplained transaminitis, organomegaly (splenomegaly and/or hepatomegaly), and liver fibrosis that can progress to cirrhosis and liver failure. Childhood/adult-onset LAL-D does not affect long-term neurodevelopmental outcome. Affected individuals typically have hyperlipidemia, especially hypercholesterolemia. There is evidence to support efficacy of enzyme replacement therapy in stabilizing progression of liver fibrosis, reducing the need for lipid-lowering medications, and potentially lowering the risk of long-term cardiovascular complications.

Diagnosis/testing.

The diagnosis of LAL-D is established in a proband with suggestive findings and biallelic pathogenic variants in LIPA identified by molecular genetic testing and/or deficient lysosomal acid lipase (LAL) enzyme activity in peripheral blood leukocytes or dried blood spots.

Management.

Targeted therapies: For infantile-onset disease, enzyme replacement therapy with intravenous sebelipase alfa (premedication and desensitization protocols may be necessary) and dietary long-chain fat restriction (fat <1 g/kg/day) with supplementation of fat-soluble vitamins and essential fatty acids is recommended; some affected individuals may also benefit from hematopoietic stem cell transplantation. For childhood/adult-onset disease, intravenous administration of sebelipase alfa (1 mg/kg body weight every other week) is recommended; some centers also recommend dietary modification. Liver transplantation has been performed in individuals with adult-onset disease, especially in those with progressive liver fibrosis or cirrhosis, although there is a risk of recurrence of liver disease and it is not considered curative.

Supportive care: Standard treatment for anemia/thrombocytopenia. For childhood/adult-onset disease, lipid-lowering medications for hyperlipidemia; standard treatment for cardiovascular disease, malabsorption/malnutrition, esophageal varices, and anemia/thrombocytopenia.

Surveillance: For infantile-onset disease, measure weight, length/height, and mid-upper arm circumference in infants/children and weight in adults at each visit; assess for chronic diarrhea and monitor liver enzymes, essential fatty acids, and fat-soluble vitamins (A, D, E, and K) levels every six months; obtain a complete blood count every six months in children and every six to 12 months in adults to assess for anemia and thrombocytopenia; monitor anti-drug antibody (ADA) concentration for those on enzyme replacement therapy if the ALT and AST levels are >3 times the normal limit or if there are clinical concerns regarding efficacy of treatment, such as weight loss / poor weight gain, increased stool frequency, or elevated inflammatory markers (i.e., ferritin and LDH); abdominal imaging to assess the liver, spleen, and mesenteric lymph nodes and to evaluate for hepatocellular carcinoma every six to 12 months in those with advanced cirrhosis.

For childhood/adult-onset disease, measure weight and length/height in infants/children and weight in adults at each visit; assess for chronic diarrhea and monitor essential fatty acids and fat-soluble vitamin (A, D, E, and K) levels with consideration of monitoring liver enzymes, chitotriosidase, ferritin, and LDH as clinically indicated; measure liver enzymes every six to 12 months or as clinically indicated based on disease severity; assess for hepatomegaly, hepatic fibrosis, and cirrhosis at every visit, as indicated by clinical/biochemical parameters; monitor anti-drug antibody (ADA) concentration as clinically indicated for those on enzyme replacement therapy; obtain a complete blood count and fasting lipid levels every six months in children and every six to 12 months (or as clinically indicated based on disease severity) in adults; upper endoscopy every three years in those with severe liver disease; abdominal imaging to assess the liver, spleen, and mesenteric lymph nodes and to evaluate for hepatocellular carcinoma as clinically indicated in those with advanced cirrhosis.

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 are not known, assay of LAL enzyme activity can be used to assist in the identification of affected sibs.

Genetic counseling.

LAL-D is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a LIPA pathogenic variant, each sib of an affected individual has at conception 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. If the LIPA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

GeneReview Scope

Lysosomal Acid Lipase Deficiency (LAL-D): Included Phenotypes 1
  • Infantile-onset LAL-D (previously Wolman disease)
  • Childhood/adult-onset LAL-D (previously cholesterol ester storage disease [CESD])

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

Consensus diagnostic and treatment guidelines for lysosomal acid lipase deficiency (LAL-D) are available [Kohli et al 2020, de Las Heras et al 2024]. Rapid diagnosis by biochemical and genetic testing is available. Although newborn screening is possible, it has not yet been implemented in the United States. Once a diagnosis of infantile-onset LAL-D is made, it should be considered a clinical emergency and treatment should be initiated without delay with dietary modification and enzyme replacement therapy (see Management).

Suggestive Findings

Infantile-Onset LAL-D

Infantile-onset LAL-D should be suspected in infants with the following clinical, supportive laboratory, and imaging findings.

Clinical findings

  • Faltering growth / failure to thrive
  • Persistent vomiting
  • Refractory diarrhea, steatorrhea, and malabsorption, including malabsorption of fat-soluble vitamins
  • Abdominal distention with hepatosplenomegaly
  • Acute liver failure with jaundice (see Supportive laboratory findings below)

Supportive laboratory findings

  • Hemophagocytic lymphohistiocytosis (See Familial Hemophagocytic Lymphohistiocytosis.)
  • Anemia and pancytopenia
  • Laboratory evidence of liver dysfunction:
    • Elevated levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)
    • Hypoalbuminemia
    • Hyperbilirubinemia (conjugated, unconjugated, or mixed)
    • Coagulopathy with prolonged prothrombin time
  • Elevated markers of inflammation and macrophage activation:
    • Serum ferritin
    • Serum lactate dehydrogenase (LDH)
    • C-reactive protein (CRP)
  • Low concentrations of fat-soluble vitamins
  • Elevated low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and high triglycerides

Note: Normal serum lipid levels do not exclude the diagnosis of LAL-D.

Imaging findings. The following may be seen on abdominal imaging:

  • Adrenal calcification without concomitant adrenal dysfunction or insufficiency
  • Hepatomegaly and/or steatotic liver
  • Splenomegaly

Childhood/Adult-Onset LAL-D

Childhood/adult-onset LAL-D should be suspected in children and adults with the following clinical, supportive laboratory, imaging, and pathology findings.

Clinical findings

  • Hepatomegaly, splenomegaly, or both
  • Symptoms of liver disease such as jaundice
  • Chronic diarrhea
  • Steatorrhea
  • Symptoms of protein, iron, and fat-soluble vitamin malabsorption (i.e., poor weight gain, reduced muscle mass, periorbital/pedal edema)
  • Coronary artery disease, aneurysm, and/or stroke

Supportive laboratory findings

  • Elevated levels of ALT and/or AST
  • High LDL, low HDL, and elevated triglycerides
  • Anemia

Note: Normal serum lipid levels do not exclude the diagnosis of LAL-D.

Imaging findings

  • Evidence of liver fibrosis/cirrhosis
  • Adrenal calcification (rare)

Pathology findings

  • Liver biopsy demonstrating the following:
    • Microvesicular or mixed micro- and macrovesicular steatosis
    • Bridging fibrosis or cirrhosis
  • Intestinal wall biopsy demonstrating accumulation of lipids in the macrophages

Family History

For both forms of LAL-D, family history is typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of LAL-D is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in LIPA identified by molecular genetic testing (see Table 1) and/or deficient lysosomal acid lipase (LAL) enzyme activity in peripheral blood leukocytes or dried blood spots.

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology 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. In this scenario, a diagnosis of LAL-D can be made with biochemical confirmation of LAL enzyme deficiency.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and supportive laboratory findings suggest the diagnosis of LAL-D, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

  • Single-gene testing. Sequence analysis of LIPA is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes LIPA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. 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. (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.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by increased lipid storage, comprehensive genomic testing may be considered.

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is commonly used; genome sequencing is also possible. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Lysosomal Acid Lipase Deficiency: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
LIPA Sequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 5Rare 6
1.
2.

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

3.

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

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

Large deletions appear to be rare, but have been reported [Lee et al 2011, Stenson et al 2020].

Assay of LAL enzyme activity. Residual enzyme activity levels are more significantly decreased in infantile-onset LAL-D (absent or ≤1% of controls) compared to a generally less severe loss of activity in childhood/adult-onset LAL-D (2%-11% of residual activity) [Witeck et al 2022]. However, the level of residual LAL enzyme activity is not useful for predicting disease course, as manifestations of disease vary greatly among individuals with similar levels of enzyme activity.

Note: (1) Assay of LAL enzyme activity in peripheral blood leukocytes is the confirmatory diagnostic test for LAL-D; 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) Confirmation by deficient LAL enzymatic function in the affected range is recommended when LIPA pathogenic variants identified on multigene panels or exome or genome sequencing first suggest the diagnosis of LAL-D.

Liver biopsy. Use of more invasive testing, such as liver biopsy, is not necessary in the diagnostic evaluation of LAL-D (see Clinical Description, Liver Biopsy).

Clinical Characteristics

Clinical Description

The phenotypic spectrum of lysosomal acid lipase deficiency (LAL-D) ranges from an infantile-onset form (previously known as Wolman disease) to childhood/adult-onset forms (previously known as cholesterol ester storage disease [CESD]). Infantile-onset LAL-D is rapidly progressive and generally symptoms arise in the first days to weeks of life. Childhood/adult-onset LAL-D encompasses a clinical spectrum. As LAL-D is now a treatable condition (see Management), early diagnosis is essential to improved outcomes [Strebinger et al 2019, Selvanathan et al 2023, de Castro Lopez et al 2025].

To date, at least 310 individuals have been identified with biallelic pathogenic variants in LIPA [Witeck et al 2022] (see also LAL-D Registry). The following description of the phenotypic features associated with this condition is based on these reports.

Untreated Infantile-Onset LAL-D

Untreated infantile-onset LAL-D is an early-onset, rapidly progressive storage disorder that invariably leads to death before age six months [Jones et al 2016, Demaret et al 2021, Witeck et al 2022, de Las Heras et al 2024]. Affected infants may have symptoms within the first few days of life with persistent vomiting, steatorrhea, and abdominal distention [de Castro Lopez et al 2025]. Once a diagnosis of infantile-onset LAL-D is made, it should be considered a clinical emergency and treatment should be initiated without delay with dietary modification and enzyme replacement therapy (see Management and Treated Infantile-Onset LAL-D).

Table 2.

Infantile-Onset Lysosomal Acid Lipase Deficiency: Frequency of Select Features in Untreated Individuals

Feature% of Persons w/FeatureComment
Hepatomegaly93%
Splenomegaly77%
Adrenal calcification74%No adrenal insufficiency/dysfunction
Liver synthetic dysfunction (failure) 173%
Faltering growth / failure to thrive66%
Iron deficiency anemia55%Typically secondary to poor iron absorption
Abdominal distention52%
Chronic intractable diarrhea & steatorrhea51%Leads to malnutrition & fat-soluble vitamin deficiency
Persistent vomiting36%
↑ transaminases33%
Thrombocytopenia26%Typically secondary to splenomegaly & inflammation, incl HLH
Hypertriglyceridemia22%
Hemophagocytic lymphohistiocytosis (HLH)16%Most infants have features of systemic inflammation even if it does not meet classic criteria for HLH.
↑ ferritinAt least 12/73 reported (16%)This is underreported & may be present in all untreated affected persons.
Hypercholesterolemia8%
↑ LDHUnknown but likely in all untreated personsIt is expected LDH would be ↑ in all infants w/LAL-D at diagnosis, as it is an indicator of systemic inflammation & macrophage activation.

HLH = hemophagocytic lymphohistiocytosis; LDH = lactate dehydrogenase

1.

This is a main cause of death in untreated or late-treated infants [Strebinger et al 2019].

Gastrointestinal (GI). In addition to vomiting, diarrhea, abdominal distention, and faltering growth, untreated affected individuals typically develop hepatosplenomegaly as the result of buildup of cholesterol esters and triglycerides in macrophages of the liver.

  • Steatosis rapidly leads to liver dysfunction and liver failure, which is the most frequent cause of death in untreated individuals.
  • Increased lipid deposition along the gastrointestinal tract leads to thickened bowel walls with resultant malnutrition and wasting.

Lymphatics. Splenomegaly is also common in untreated individuals and may be due to the buildup of cholesterol esters and triglycerides in macrophages in the spleen. Abdominal distention with enlarged mesenteric lymph nodes is also seen in untreated individuals with infantile-onset LAL-D in whom long-chain fat has been given against dietary advice or has not been severely restricted as part of dietary modification [de Las Heras et al 2024]. Inflammatory cells lead to fibrosis in mesenteric lymph nodes and matting of lymph nodes, which has led to intestinal obstruction in a few affected children.

Immunologic findings. Abnormal lysosomal lipid accumulation in macrophages is known to trigger an inflammatory cytokine cascade. A presenting sign of infantile-onset LAL-D is unexplained pyrexia with elevated inflammatory markers, such as ferritin and lactate dehydrogenase (LDH).

  • Affected individuals may experience systemic inflammation and may progress to having features that are consistent with hemophagocytic lymphohistiocytosis (HLH) [Baronio et al 2021, Asna Ashari et al 2023, Selvanathan et al 2023].
  • Macrophage dysfunction in babies with infantile-onset LAL-D has also been implicated in frequent occurrence of BCG abscess / axillary lymphadenopathy after vaccination.

Endocrine. Adrenal calcification is present at diagnosis in up to 74% of individuals with infantile-onset LAL-D. It may even be identified on prenatal ultrasound scans in the fetus, leading to diagnosis. Some affected individuals who do not have adrenal calcification at diagnosis may develop adrenal calcification later. However, adrenal calcification is not associated with adrenal dysfunction or insufficiency.

Treated Infantile-Onset LAL-D

With early diagnosis and initiation of treatment with a combination of dietary modification (long-chain fat restriction and preventing malnutrition) and enzyme replacement therapy (sebelipase alfa), long-term survival has improved significantly, with several children surviving into adolescence in good health.

  • Treated individuals may still have suboptimal growth.
  • The GI symptoms usually resolve, although accumulation of lipids in the GI mucosa can continue despite treatment.
  • All babies with infantile-onset LAL-D have liver fibrosis; however, liver function generally normalizes within days to weeks after initiation of treatment and liver fibrosis does not progress. Liver function tests and lipid profile is expected to be normal in treated individuals.
  • Non-adherence to dietary fat restriction leads to recurrence of inflammatory symptoms and increase in blood ferritin and LDH concentrations, which resolve with dietary adherence.
  • Iron deficiency anemia may persist even with successful treatment.
  • Adrenal calcification will be present or become more obvious.

Recurrence of GI symptoms or evidence of progressive GI mucosal lipid accumulation may be an indication for hematopoietic stem cell transplantation (HSCT). Survival following HSCT has improved in affected individuals who were treated following early diagnosis with conservative treatment (enzyme replacement therapy and dietary modification) [Potter et al 2021, Lum et al 2023].

Survivors typically experience normal long-term intellectual and neurodevelopmental outcomes [Witeck et al 2022].

Childhood/Adult-Onset LAL-D

Childhood/adult-onset LAL-D presents any time after age six months through childhood and adulthood.

Table 3.

Childhood/Adult-Onset LAL-D: Frequency of Select Features

Feature% of Persons w/Feature 1Comment
Hypercholesterolemia/hyperlipidemia70%-78%May lead to coronary artery disease, aneurysm, &/or stroke
Hepatomegaly68%-88%
↑ transaminases68%-87%
↑ triglycerides53%
Low HDL50%
Splenomegaly38%-45%
Abdominal pain13.5%
Poor growth / failure to thrive12%
Diarrhea &/or steatorrhea8%
Iron deficiency anemia8%
Liver cirrhosis7%
Adrenal calcification5%Not assoc w/adrenal dysfunction
Jaundice2.2%

HDL = high-density lipoprotein

1.

Derived from Witeck et al [2022] and Balwani et al [2023]. Not every feature was assessed in both publications.

Dyslipidemia/atherosclerosis due to hyperlipidemia accounts for much of the morbidity associated with childhood/adult-onset LAL-D, such as coronary artery disease, aneurysm, and/or stroke.

Blood lipid findings may resemble those of autosomal recessive hypercholesterolemia (see Differential Diagnosis), with extremely high total and low-density lipoprotein cholesterol levels [Sheth et al 2023].

Gastrointestinal/hepatic. Organomegaly, including both hepatomegaly and splenomegaly, may be the first finding noted and may be present for years before a diagnosis is reached. Hepatomegaly is frequently present as a result of cholesterol ester and triglyceride buildup in macrophages. Some affected individuals may experience abdominal pain related to organomegaly, aerophagy, gaseous bloating, intestinal obstruction, and/or mesenteric lymphadenopathy.

  • Lipid deposition in the wall of the intestinal tract can contribute to diarrhea and poor weight gain. Features of malnutrition/malabsorption such as iron deficiency anemia and deficiency of fat-soluble vitamins may be present at diagnosis, mimicking celiac disease.
  • Liver disease is common.
    • Liver disease may manifest as altered liver function with or without jaundice, steatosis, fibrosis, or cirrhosis.
    • Transaminases are usually elevated at diagnosis.
    • Liver disease can lead to esophageal varices, which are associated with risk for hemorrhage and can be life-threatening.
    • Some individuals may experience liver failure, requiring a liver transplant.
    • Hepatocellular carcinoma has occurred in the setting of advanced cirrhosis [Cunha-Silva et al 2022].

Splenomegaly may develop and can lead to anemia and/or thrombocytopenia due to secondary hypersplenism.

Endocrine. Enlarged adrenal glands with calcification may be present, although this is rare. Adrenal calcification is not associated with adrenal dysfunction in childhood/adult-onset LAL-D.

Developmental delay (DD) and intellectual disability (ID). Childhood/adult-onset LAL-D does not affect long-term neurodevelopmental outcome. Affected individuals with late-onset LAL-D would be expected to have normal cognitive development and intellectual function.

Prognosis. The long-term efficacy of enzyme replacement therapy with sebelipase alfa in improving survival and preventing complications in people with childhood/adult-onset LAL-D is nuanced and less clear-cut than in infantile-onset LAL-D. The final results of the sebelipase alfa clinical trial showed no progression of liver disease after five years; however, longer term data is lacking [Burton et al 2022].

Liver Biopsy

Liver biopsy may be required to diagnose and assess severity and progression of hepatic fibrosis in childhood/adult-onset LALD but is not indicated or required for the diagnosis of infantile-onset LAL-D. Liver biopsy demonstrates mostly microvesicular and micronodular steatosis (less frequently, mixed micro- and macrovesicular steatosis) or "fatty liver," fibrosis, and cirrhosis [Witeck et al 2022, Balwani et al 2023, de Las Heras et al 2024].

Genotype-Phenotype Correlations

In general, pathogenic null variants with no residual enzyme function result in infantile-onset LAL-D and pathogenic variants that allow for residual lysosomal acid lipase (LAL) enzyme activity result in childhood/adult-onset LAL-D.

Nomenclature

Other names used previously for LAL-D are:

  • Wolman disease
  • Cholesterol ester storage disease / cholesteryl ester storage disease
  • Acid cholesterol ester hydrolase deficiency
  • Cholesterol ester hydrolase deficiency storage disease

Prevalence

The prevalence of infantile-onset LAL-D is estimated to be ~1:35,0000 live births. The prevalence of childhood/adult-onset LAL-D is estimated to be ~1:300,000 live births. The overall prevalence of LAL-D is thought to be ~1:175,000 [Carter et al 2019]. LAL-D is likely to be an underdiagnosed disorder.

There is an increased prevalence of the c.260G>T (p.Gly87Val) pathogenic variant in the Mizrahi Jewish population, with an estimated prevalence of ~1:900 [Jackson et al 2023].

Differential Diagnosis

Genetic disorders in the differential diagnosis of lysosomal acid lipase deficiency (LAL-D) are listed in Table 4 (infantile-onset LAL-D) and Table 5 (childhood/adult-onset LAL-D).

Table 4.

Infantile-Onset Lysosomal Acid Lipase Deficiency: Differential Diagnosis

Gene(s)DisorderMOIKey Features of Disorder
Overlapping w/untreated LAL-DDistinguishing from untreated LAL-D
>340 genes 1 Primary mitochondrial disorders AD
AR
MT
XL
  • Liver failure
  • Poor weight gain
  • Not assoc w/hepatosplenomegaly
  • Often assoc w/multiorgan involvement (e.g., myopathy, cardiomyopathy, CNS involvement), lactic acidosis, TCA metabolites in urine
>175 genes 2Congenital disorders of N-linked glycosylation & multiple pathway disordersAR
XL
  • Liver failure
  • Diarrhea
  • Malnutrition
  • Dysmorphic facial features
  • Not typically assoc w/abdominal distention
  • Normal ferritin & LDH
ABCB4
ABCB11
ATP8B1
KIF12
LSR
MYO5B
NR1H4
TJP2
USP53 		Primary cholestatic liver disease caused by defects that impair bile acid transport (progressive familial intrahepatic cholestasis) (See Pediatric Genetic Cholestatic Liver Disease Overview.)AR
(AD) 3
  • Conjugated jaundice
  • Cholestasis
  • Steatorrhea
  • Liver failure
  • Not typically assoc w/anemia/thrombocytopenia
  • Normal ferritin & LDH
AGL Glycogen storage disease type III AR
  • Hepatomegaly
  • ↑ hepatic transaminases
  • Absence of GI symptoms such as persistent vomiting & diarrhea
  • Not assoc w/splenomegaly, anemia, thrombocytopenia, or liver failure
  • Cardiac hypertrophy
  • ↑ CK
  • Hypoglycemia
AKR1D1
AMACR
BAAT
CYP27A1
CYP7B1
HSD3B7 		Primary cholestatic liver disease caused by disorders of bile acid synthesis (See Pediatric Genetic Cholestatic Liver Disease Overview & Cerebrotendinous Xanthomatosis.)AR 3
  • Conjugated jaundice
  • Cholestasis
  • Steatorrhea
  • Liver failure
  • Not typically assoc w/anemia or thrombocytopenia
  • Normal ferritin & LDH
FAH Tyrosinemia type I (fumarylacetoacetase deficiency)AR
  • Liver failure, jaundice
  • ↑ risk of sepsis
  • Not assoc w/hepatosplenomegaly
  • GI manifestations such as persistent vomiting & diarrhea are unlikely.
GALT Classic galactosemia AR
  • Liver failure, jaundice
  • ↑ risk of sepsis
  • Not assoc w/hepatosplenomegaly
  • Cataracts
  • GI manifestations such as persistent vomiting & diarrhea are unlikely.
GBA1 Neuropathic Gaucher disease types 2 & 3AR
  • Hepatosplenomegaly
  • Pancytopenia
  • Growth failure
  • Severe early neurologic involvement in Gaucher type 2
  • Liver failure is rare.
  • Not assoc w/diarrhea/steatorrhea
GBE1 Glycogen storage disease type IV (classic [progressive] hepatic subtype)AR
  • Liver failure
  • Rapid progression
  • Hepatosplenomegal
  • Hepatic fibrosis/cirrhosis
  • ↑ chitotriosidase
Absence of GI manifestations such as persistent vomiting & diarrhea
SMPD1 Niemann-Pick disease type A (NPD-A; see Acid Sphingomyelinase Deficiency)AR
  • Hepatosplenomegaly
  • Pancytopenia
  • Growth failure
  • ↑ chitotriosidase
Severe early neurologic involvement in NPD-A
NPC1
NPC2 		Niemann-Pick disease type C (NPC)AR
  • Neurologic manifestations in later infancy in NPC
  • Liver failure in NPC1- & NPC2-related NPC 4
PEX1
PEX2
PEX3
PEX5
PEX6
PEX10
PEX11B
PEX12
PEX13
PEX14
PEX16
PEX19
PEX26 		Zellweger spectrum disorder (peroxisomal biogenesis disorders)AR 5Liver failure
  • Distinctive craniofacial features
  • Congenital malformations (neuronal migration defects assoc w/neonatal-onset seizures, renal cysts, & bony stippling [chondrodysplasia punctata] of patella[e] & long bones)
  • Generalized hypotonia
PHKA2
PHKB
PHKG2 		Liver phosphorylase kinase deficiency causing glycogen storage disease IXAR
XL		Hepatomegaly 6
  • Absence of GI manifestations such as persistent vomiting & diarrhea
  • Fasting ketosis & hypoglycemia
PRF1
STX11
STXBP2
UNC13D 		Familial hemophagocytic lymphohistiocytosis AR
(AD) 7		Indistinguishable (in absence of GI manifestations seen in infantile-onset LAL-D)

AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; CNS = central nervous system; GI = gastrointestinal; LAL-D = lysosomal acid lipase deficiency; LDH = lactate dehydrogenase; MOI = mode of inheritance; MT = mitochondrial; TCA = tricarboxylic acid; XL = X-linked

1.
2.
3.

The vast majority of pediatric genetic primary cholestatic liver diseases are inherited in an autosomal recessive manner. Exceptions include autosomal dominant inheritance (in some individuals) of ABCB4-related liver disease (i.e., PFIC3) (see Pediatric Genetic Cholestatic Liver Disease Overview, Genetic Counseling).

4.

Liver failure in NPC1- and NPC2-related Niemann-Pick disease type C may be indistinguishable from that in infantile-onset LAL-D, except for the faltering growth, recurrent vomiting, and steatorrhea in infantile-onset LAL-D.

5.

Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner. (One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state.)

6.
7.

Familial hemophagocytic lymphohistiocytosis (fHLH) is inherited in an autosomal recessive manner. Autosomal dominant inheritance of STXBP2-related fHLH is suggested by rare reports of symptomatic individuals with heterozygous gain-of-function variants.

Table 5.

Childhood/Adult-Onset Lysosomal Acid Lipase Deficiency: Differential Diagnosis

Gene(s)DisorderMOIKey Features of Disorder
Overlapping w/LAL-DDistinguishing from LAL-D
APOB
LDLR
LDLRAP1
PCSK9 		Familial hypercholesterolemia (FH)AD
(AR) 1
  • Significantly ↑ LDL-C & total cholesterol
  • Persons w/more severe FH, often as a result of biallelic APOB, LDLR, LDLRAP1, or PCSK9 pathogenic variants, can present w/very significant ↑ in LDL-C, early-onset coronary artery disease (as early as childhood in some), & calcific aortic valve disease. Late-onset LAL-D manifesting as extremely high total & LDL-C serum concentrations may resemble severe FH. 2
  • Serum concentrations of HDL-C & triglycerides are usually in the normal range.
  • Absence of liver disease & organomegaly
ABCG5
ABCG8 		Sitosterolemia AR
  • Hyperlipidemia
  • Hypercholesterolemia
  • Tendon xanthomas /xanthelasma
  • Premature atherosclerosis
↑ plasma concentrations of plant sterols
GBA1 Gaucher disease type 1AR
  • Hepatosplenomegaly
  • Thrombocytopenia
  • Normal LDL
  • Bone disease
SMPD1 Niemann-Pick disease type B (See Acid Sphingomyelinase Deficiency.)AR
  • Hepatosplenomegaly (common)
  • Low HDL-C serum concentration w/hyperlipidemia (↑ LDL-C serum concentration & hypertriglyceridemia)
Interstitial lung disease

AD = autosomal dominant; AR = autosomal recessive; HDL-C = high-density lipoprotein cholesterol; LAL-D = lysosomal acid lipase deficiency; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance; XL = X-linked

1.

APOB-, LDLR-, and PCSK9-related familial hypercholesterolemia (FH) are inherited in an autosomal dominant manner. If an individual has biallelic (homozygous or compound heterozygous) pathogenic variants in one of these three genes – a condition referred to as homozygous FH or HoFH – the presentation becomes more severe with earlier onset of features. LDLRAP1-related FH is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner.

2.

Other conditions to consider in the differential diagnosis of childhood/adult-onset LAL-D include the following:

  • Familial combined hyperlipidemia (similar to autosomal dominant familial hypercholesterolemia)
  • Metabolic dysfunction-associated steatotic liver disease (MASLD). Like childhood/adult-onset LAL-D, MASLD is associated with progressive liver fibrosis, cirrhosis, liver dysfunction, and liver failure. Liver biopsy features are also similar except for predominantly macrovesicular steatosis in MASLD, whereas mostly microvesicular steatosis is seen in LAL-D.

Management

Recommendations for the diagnosis and management of infantile-onset lysosomal acid lipase deficiency (LAL-D) have been published [Kohli et al 2020, de Las Heras et al 2024]. Practice and dosing regimens vary between countries/regions. Multinational consensus clinical practice guidelines do not exist.

Evaluations Following Initial Diagnosis

Initial management of infantile-onset LAL-D should be considered a medical emergency (see Targeted Therapies). To establish the extent of disease and needs in an individual diagnosed with infantile-onset LAL-D, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 6.

Infantile-Onset Lysosomal Acid Lipase Deficiency: Recommended Evaluations at Initial Diagnosis

System/ConcernEvaluationComment
Biochemical Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietitian 1
  • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
  • Initiation of treatment (see Table 8) is required as soon as diagnosis is made.
  • Consider hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
Gastroenterology/
Hepatology
  • Liver enzymes (AST/ALT)
  • Albumin, GGT, & alkaline phosphatase
  • Total & conjugated bilirubin levels
  • LDH level
  • Nutritional baseline profile including fat-soluble vitamins, essential fatty acids, magnesium, & selenium
  • Electrolytes
  • To assess for liver failure & nutritional status
  • Consider consultation w/hepatology if liver failure is present.
Gastroenterology / nutrition / feeding team eval for malabsorption & malnutritionConsider referral to gastroenterologist.
Constitutional Measurement of growth parameters
  • To evaluate for evidence of poor growth
  • Incl weight, length, & mid-upper arm circumference & the best anthropometric measurements of nutritional status
Hematology CBC, ferritin, & coagulation profileTo assess for thrombocytopaenia, anemia, pancytopaenia, & evidence of HLH
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families regarding nature, MOI, & implications of LAL-D to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; GGT = gamma-glutamyl transferase; HLH = hemophagocytic lymphohistiocytosis; LAL-D = lysosomal acid lipase deficiency; LDH = lactate dehydrogenase; MOI = mode of inheritance

1.

After a new diagnosis of infantile-onset LAL-D in an infant, the closest hospital and local pediatrician should also be informed.

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

To establish the extent of disease and needs in an individual diagnosed with childhood/adult-onset LAL-D, the evaluations summarized in Table 7 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 7.

Childhood/Adult-Onset Lysosomal Acid Lipase Deficiency: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Constitutional Measurement of growth parametersTo evaluate for evidence of poor growth
Gastrointestinal/
Hepatology
  • Gastroenterology / nutrition / feeding team eval for malabsorption & malnutrition
  • Incl levels of fat-soluble vitamins, essential fatty acids, magnesium, & selenium
  • To incl eval of nutritional status
  • Consider referral to gastroenterologist.
Physical exam for hepatomegaly
  • Albumin
  • AST, ALT, & GGT
  • ALP
  • Ferritin
  • Coagulation profile
  • To assess for liver dysfunction
  • Consider referral to hepatologist & screening for coexistent conditions leading to liver enzyme elevations.
Consider upper endoscopy to assess for esophageal varices.In those w/severe liver disease
Consider transient elastography (FibroScan®) & liver biopsy to assess for evidence of cirrhosis or hepatocellular carcinoma.In adults who have ↑ transaminases & signs of liver cirrhosis/failure
Lipids/
Cardiovascular 		Complete fasting lipid profileTo assess for hyperlipidemia
Consider assessment for cardiovascular disease incl echocardiogram, stress test, &/or carotid duplex, depending on age.Consider referral to cardiologist in those who have hyperlipidemia.
Hematologic/
Lymphatic 		Physical exam for splenomegaly
CBCTo assess for anemia &/or thrombocytopenia
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of LAL-D to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; GGT = gamma-glutamyl transferase; LAL-D = lysosomal acid lipase deficiency

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Infantile-onset LAL-D. While there is no cure for infantile-onset LAL-D, enzyme replacement therapy (ERT) in combination with dietary substrate (long-chain fat) reduction is the current standard of care. ERT is effective in improving the long-term survival in infantile-onset LAL-D but does not seem to be as effective in reducing gastrointestinal lipid deposition and gastrointestinal symptoms [Demaret et al 2021, Vijay et al 2021, de Las Heras et al 2024]. However, the long-term benefits, outcomes, and complications are still emerging [Lum et al 2023]. Hematopoietic stem cell transplantation (HSCT) has been successfully performed in some children who have already been treated with ERT for specific indications such as hemophagocytic lymphohistiocytosis (HLH), poor clinical response to ERT secondary to anti-drug antibodies, or progressive gastrointestinal mucosal lipid accumulation leading to malnutrition with faltering growth or difficult-to-manage infusion-associated reactions. Further long-term evidence for the safety and efficacy is required before HSCT can be considered a definitive treatment for infantile-onset LAL-D.

Table 8.

Infantile-Onset Lysosomal Acid Lipase Deficiency: Targeted Therapies

TypeTreatmentDosage / Dietary Considerations / IndicationOther Considerations
Enzyme replacement therapy (ERT) 1 Sebelipase alfa (Kanuma®)
  • Sebelipase alfa is administered intravenously 2
  • In US, licensed/approved dose is 1 mg/kg/week
  • In Europe, licensed starting dose is 3 mg/kg/week 3, 4
  • Immunomodulation w/bortezomib/rituximab may be required in cases where there are features of severe systemic inflammation.
  • Premedication according to local ERT protocols
  • Desensitization protocols 5
  • Monitor anti-drug antibody concentration (see Table 12).
Dietary substrate reduction (DSR) 6, 7
  • Long-chain fat restriction (fat <1 g/kg/day)
  • Supplementation w/: fat-soluble vitamins; essential fatty acids; protein (up to 4 mg/kg/day); carbohydrates (20% of energy requirements)
  • Total parenteral nutrition is likely to be required at diagnosis, particularly in symptomatic persons.
  • MCT-rich intravenous lipid such as long-chain fat-free lipid (e.g., SMOF or SMOFlipid®) should be substituted for conventional intravenous lipid preparations, in addition to fat restriction (total fat <1 mg/g/day)
  • Protein as amino acids (up to 4 gm/kg/day)
  • Carbohydrates as glucose (12-25 mg/kg/day)
  • Sebelipase alfa ERT w/DSR to optimize health & nutrition by treating underlying disease aggressively is a prerequisite for successful HSCT.
  • Non-adherence w/DSR & any increase in dietary fat intake can lead to complications such as mesenteric lymphadenopathy, recurrence of GI symptoms, & deterioration in liver function & inflammatory markers (ferritin & LDH)
  • When enteral feeds can be commenced, long-chain fat restriction should be continued. 8
  • Add more dietary protein as amino acids.
  • Limit supplementation of MCTs & glucose until infant's condition is stabilized.
  • Once stabilized, infant can be switched to low-fat MCT-based formula feed (e.g., Monogen®) under strict dietary & clinical supervision. 9
  • Formula feed should be introduced very gradually over several weeks to months. 10
Transplant HSCTIn infantile-onset LAL-D w/HLH, intensive conditioning & high-dose ERT prior to HSCT is likely to be beneficial. 11The outcome of HSCT following stabilization of disease activity w/combination of treatment w/sebelipase alfa & dietary fat restriction seems promising.

GI = gastrointestinal; HSCT = hematopoietic stem cell transplant; LDH = lactate dehydrogenase; MCT = medium-chain triglyceride; SMOF = soy, medium-chain triglyceride, olive, and fish oil

1.

Combination treatment with dietary substrate reduction is recommended.

2.

Infusion-associated reactions and anti-drug antibodies may require desensitization with serial dilutions and prolonged infusion times.

3.

There is an increasing body of evidence for enhanced efficacy of short-term dosing with higher starting doses, such as 5 mg/kg/week or 5 mg/kg twice weekly, if the clinical presentation is very severe or if there is inadequate clinical response to 3 mg/kg/week.

4.

The dose can be reduced to 3 mg/kg/week once the disease activity (levels of transaminases, ferritin, and lactate dehydrogenase (LDH); weight; need for transfusion) improve and normalize [de Castro et al 2024, de Las Heras et al 2024].

5.
6.

Dietary substrate reduction (DSR) therapy should be started at diagnosis and continued indefinitely until the affected individual is on concurrent enzyme replacement therapy.

7.

DSR should be administered under the supervision of an experienced pediatric dietitian.

8.

Nasogastric tube feeding is likely to be required when transitioning from total parenteral nutrition to enteral feeds.

9.

It is expected that oral feeding will eventually be achieved in the vast majority of affected infants.

10.

Stool frequency, growth, and mid-upper arm circumference should be measured frequently. Blood tests for liver function, ferritin, LDH, fat-soluble vitamins, and essential fatty acids will be required at frequent intervals (see Table 12).

11.

Childhood/adult-onset LAL-D. While there is no cure for childhood/adult-onset LAL-D, ERT is available. Dietary substrate reduction is not required, although some centers do recommend it.

Table 9.

Childhood/Adult-Onset Lysosomal Acid Lipase Deficiency: Targeted Therapies

TypeTreatmentDosage/IndicationConsiderations
Enzyme replacement therapy (ERT) Sebelipase alfaAdministered intravenously at a dose of 1 mg/kg body weight every other weekDSR is not required in treatment of childhood/adult-onset LAL-D, although some centers still recommend it.
Transplant Liver transplantationLiver transplantation has been successful in those w/liver failure secondary to progressive liver fibrosis & cirrhosis. 1Liver transplantation does not prevent progression of liver disease or recurrence, since pathophysiology is mediated by bone marrow macrophages.

DSR = dietary substrate reduction

1.

Daily/Supportive Care by Phenotype

Daily/supportive treatment for infantile-onset LAL-D is summarized in Table 10.

Table 10.

Infantile-Onset Lysosomal Acid Lipase: Supportive Care

Manifestation/ConcernDaily TreatmentConsiderations/Other
Malabsorption/
Malnutrition
  • Long-chain fat restriction (fat <1 g/kg/day)
  • Supplementation w/: fat-soluble vitamins; essential fatty acids; protein (up to 4 mg/kg/day); carbohydrates (20% of energy requirements)
See Table 12 for surveillance.
Anemia/
Thrombocytopenia 		Standard treatment per hematologist
  • Platelet & packed red blood cell transfusions as indicated
  • Intramuscular iron injections to treat iron deficiency anemia, as it is refractory to oral therapy/supplementation
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider discussion of comfort care options.

In childhood/adult-onset LAL-D, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 11).

Table 11.

Childhood/Adult-Onset Lysosomal Acid Lipase Deficiency: Supportive Care

Manifestation/ConcernTreatmentConsiderations/Other
Hyperlipidemia
  • Standard treatment w/lipid-lowering medications, incl use of statins, cholestyramine, & ezetimibe
  • Diet low in cholesterol & triglycerides
Combination therapy may be indicated.
Cardiovascular disease Standard treatment per cardiologistAggressive reduction of additional cardiovascular disease risk factors should be encouraged.
Malabsorption/
Malnutrition 		Standard treatment by gastroenterologist & nutritionistDietary modification or dietary long-chain fat restriction is not indicated in childhood/adult-onset LAL-D, although some centers still recommend it.
Esophageal varices Standard treatment per gastroenterologist
  • Consider nonspecific beta-blockers to ↓ risk of bleeding.
  • Beta-blockers have not been shown to prevent formation of esophageal varices.
Anemia/
Thrombocytopenia 		Standard treatment per hematologist
  • Platelet & packed red blood cell transfusions as indicated
  • Intramuscular iron injections to treat iron deficiency anemia, as it is refractory to oral therapy/supplementation
Family/Community Ensure appropriate social work involvement to connect families w/local resources, respite, & support.

Surveillance

To monitor existing manifestations, the individual's response to targeted therapy, and the emergence of new manifestations, the evaluations in Table 12 (infantile-onset LAL-D) and Table 13 (childhood/adult-onset LAL-D) are recommended.

Table 12.

Infantile-Onset Lysosomal Acid Lipase Deficiency: Recommended Surveillance

System/ConcernEvaluationFrequency
Growth
  • Measure weight, length/height, & mid-upper arm circumference in infants & children to assess for poor growth.
  • Measure weight in adults to assess for weight loss.
At each visit
Gastrointestinal
(in children)
  • Assess for chronic diarrhea, incl using stool frequency charts.
  • Monitor liver enzymes, essential fatty acids, & fat-soluble vitamin (A, D, E, & K) levels.
Every 6 mos
For those on ERT Monitor anti-drug antibody concentration. 1
  • If ALT/AST is >3 times normal limit or if there are clinical concerns re efficacy of treatment, such as weight loss / poor weight gain, ↑ stool frequency, ↑ inflammatory markers (i.e., ferritin & LDH)
  • In cases of anaphylaxis / severe infusion-associated reactions
Lymphatic/
Hematologic 		CBC to assess for anemia & thrombocytopenia
  • Children: every 6 mos
  • Adults: every 6-12 mos or as clinically indicated based on disease severity
Abdominal imaging to assess liver, spleen, & mesenteric lymph nodes & evaluate for hepatocellular carcinoma in those w/advanced cirrhosisOptimal timing of imaging has not been established, but every 6-12 mos is reasonable.
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

ALT = alanine transaminase; AST = aspartate transaminase; CBC = complete blood count; ERT = enzyme replacement therapy; LDH = lactate dehydrogenase

1.

Very few labs around the world have validated processes for anti-drug antibody analysis and reporting.

Table 13.

Childhood/Adult-Onset Lysosomal Acid Lipase Deficiency: Recommended Surveillance

System/ConcernEvaluationFrequency
Growth /
Nutritional status
  • Measure weight & length/height in infants & children to assess for poor growth.
  • Measure weight in adults to assess for weight loss.
At each visit
Gastrointestinal
(in children)
  • Assess for chronic diarrhea, incl using stool frequency charts.
  • Monitor essential fatty acids and fat-soluble vitamin (A, D, E, & K) levels.
  • Consider monitoring liver enzymes, chitotriosidase ferritin, & LDH.
As clinically indicated
Gastrointestinal
(in adults)		Measure liver enzymes.Every 6-12 mos, or as clinically indicated based on disease severity
Assess for hepatomegaly, hepatic fibrosis, & cirrhosis.At every visit, or as indicated by clinical/biochemical parameters
Upper endoscopy in those w/severe liver diseaseEvery 3 yrs
For those on ERT Monitor anti-drug antibody concentration. 1As clinically indicated, such as in those w/infusion-associated reactions & suboptimal clinical response
Lymphatic/
Hematologic 		CBC to assess for anemia & thrombocytopenia
  • Children: every 6 mos
  • Adults: every 6-12 mos or as clinically indicated based on disease severity
Abdominal imaging to assess liver, spleen, & mesenteric lymph nodes & evaluate for hepatocellular carcinoma in those w/advanced cirrhosisAs clinically indicated
Cardiovascular Fasting lipid levels
  • Children: every 6 mos
  • Adults: every 6-12 mos or as clinically indicated based on disease severity
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

CBC = complete blood count; ERT = enzyme replacement therapy; LDH = lactate dehydrogenase

1.

Very few labs around the world have validated processes for anti-drug antibody analysis and reporting.

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. As LAL-D is a treatable condition, early diagnosis is essential to improved outcomes [Strebinger et al 2019, Selvanathan et al 2023, de Castro Lopez et al 2025].

  • 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

It is clear that early treatment results in better outcome [de Castro Lopez et al 2025]. A clinical trial is currently recruiting affected individuals to study the safety and efficacy of in utero ERT in lysosomal storage diseases, including LAL-D (NCT04532047).

Preclinical trials of gene therapy are also promising [Lam et al 2022].

See Author Notes for information about an international LAL-D registry.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are presumed to be heterozygous for a LIPA pathogenic variant.
  • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a LIPA pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for a LIPA pathogenic variant, each sib of an affected individual has at conception 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 and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has LAL-D or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in LIPA.

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 sibs for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk 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.
  • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with LAL-D, particularly if both partners are of the same ancestry. A proposed founder variant has been identified in the Mizrahi Jewish population (see Table 14).

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

High-risk pregnancy. If the LIPA pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

In a fetus not known to be at increased risk, infantile-onset LAL-D may be diagnosed incidentally by the identification of adrenal calcification in the fetus on prenatal ultrasonography.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

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)

278000CHOLESTERYL ESTER STORAGE DISEASE; CESD
613497LIPASE A, LYSOSOMAL ACID; LIPA
620151WOLMAN DISEASE; WOLD

Molecular Pathogenesis

LIPA encodes the enzyme lysosomal acid lipase / cholesteryl ester hydrolase (LAL; also called lysosomal acid lipase A), which is expressed in lysosomes and is responsible for the hydrolysis of cholesterol esters and triacylglycerols. 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:

  • 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, which reduces the cellular synthesis of cholesterol;
  • Low-density lipoprotein (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.

Mechanism of disease causation. Loss of function

Table 14.

LIPA Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_000235​.4
NP_000226​.2 		c.260G>Tp.Gly87ValProposed founder variant in Mizrahi Jewish population [Jackson et al 2023] (See Prevalence.)

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

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

Chapter Notes

Author Notes

Dr Suresh Vijay (ten.shn@1yajiv.hserus), Dr Simon Jones (ku.shn.tfm@senoj.nomis), and Dr Javier de las Heras Montero (sue.aztedikaso@oretnomsarehsaled.oflodareivaj) are actively involved in clinical research regarding individuals with infantile-onset lysosomal acid lipase deficiency (LAL-D). They would be happy to communicate with people who have any questions regarding diagnosis of infantile-onset LAL-D or other considerations.

There is an international LAL-D registry (laldeficiencyregistry.com) that collects prospective data on both infantile-onset and childhood/adult-onset LAL-D (NCT01633489).

Acknowledgments

We would like to acknowledge the LAL-D registry for increasing knowledge, education, and awareness on LAL-D and the study sites that contribute data.

Author History

Manisha Balwani, MD, MS (2026-present)
Marci L Barr, ScM; Geisinger Health System (2015-2026)Monica A Giovanni, MS, CGC; Geisinger Health System (2015-2026)
Erin P Hoffman, MS, CGC; Littleton Adventist Hospital (2015-2026)
Michael F Murray, MD; Geisinger Health System (2015-2026)
Suresh Vijay, FRCPCH (2026-present)

Revision History

  • 15 January 2026 (ma) Comprehensive update posted live
  • 30 July 2015 (me) Review posted live
  • 4 October 2012 (mfm) Original submission

References

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  • 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]
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