Lysosomal acid lipase deficiency (Wolman disease and CESD)

Recommended panel testing at Breda Genetics for this condition:

Lysosomal acid lipase deficiency (Wolman/CESD) and its differential diagnosis (LIPA, SMPD1, GBA, LDLR, APOB, PCSK9, LDLRAP1).

clue cell with yellow content


Lysosomal acid lipase deficiency is caused by homozygous or compound heterozygous mutation in the LIPA gene. Lysosomal acid lipase deficiency is predominantly a pediatric disease, although milder forms of the disease with possibility of a normal life-span are also possible.

Detailed clinical description

Wolman disease

Deficiency of lysosomal acid lipase causes two distinct phenotypes in humans: Wolman disease and cholesteryl ester storage disease (CESD). Wolman disease is an early-onset fulminant disorder of infancy with massive xanthomatous infiltration in the liver, adrenal, spleen, lymph nodes, bone marrow, small intestine, lungs, and thymus, and slight changes in the skin, retina, and central nervous system. These organs appear to be infiltrated by macrophages filled with cholesteryl esters and triglycerides (foam cell infiltration). Adrenals gland may soon appear with diffuse punctate calcification, likely as consequence of early extensive necrosis, leading to adrenal cortical insufficiency. Death, which usually occurs within the first months of life, may be caused by by nutritional failure due to intenstinal malabsorption. Lipids in blood may be normal or just moderately elevated. Nonspecific clinical signs include poor weight gain, vomiting, diarrhea, increasing hepatosplenomegaly with abdominal protuberance.

Wolman disease is very rare, with a stimated incidence of less than one in 100,000 live births.

Cholesteryl Ester Storage Disease

Cholesteryl Ester Storage Disease (CESD) is at the milder end of disease variability, it is later-onset and presents with primary hepatic involvement by foam cells (macrophages engorged with cholesteryl esters). The disorder is slowly progressive and show a wide clinical variability, ranging from early onset involvement with severe cirrhosis to later onset manifestations with more slowly progressive hepatic disease and survival into adulthood. Although CESD is relatively benign in contrast to Wolman disease, death may occur as consequence of acute hepatic failure. Accumulation of neutral fats and cholesterol esters in the arteries predispose affected persons to atherosclerosis and cardiovascular events such as infarction and stroke. Hypercholesterolemia is common. Massive hepatomegaly and hepatic fibrosis may lead to esophageal varices. Patients with CESD may be at risk of developing pulmonary hypertension. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed, and thus the possibility of CESD should be considered in patients with hepatosplenomegaly and dyslipidemia.


The diagnosis of CESD and Wolman disease is suspected on a clinical and biochemical basis (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) and must be confirmed either biochemically (by enzyme dosage analysis) or genetically by molecular testing (sequencing and deletion/duplication testing of the LIPA gene). Skin biopsy may show cytoplasmic accumulations.


In 2015 the results of a phase 3 trial with sebelipase, a recombinant human lysosomal acid lipase, resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. Subsequently Sebelipase alfa (Kanuma™), administered by intravenous infusion once weekly or once every other week, received its first global approval, in the EU, in August 2015 for long-term enzyme replacement therapy in patients of all ages with lysosomal acid lipase deficiency deficiency. Regulatory submissions have also been filed in the USA, Mexico and Japan for use in this indication.

Genetic testing

Several type of mutations have been so far described in the LIPA gene (nonsense mutations, small frame shifting insertions and deletions, splice mutations, missense mutations, intragenic deletions). The difference between Wolman-related and CESD-related mutations is seemingly in that the first ones completely abolish the protein synthesis leading to undetectable LIPA activity, whereas the latter allow some sort of residual enzimatic activity. The most common CESD mutation is c.894G>A in exon 8: this variant impacts the splicing process leaving though at least 3%-5% of transcripts correctly spliced.

Differential diagnosis

In Wolman disease foam cells are found in bone marrow and vacuolated lymphocytes in peripheral blood, as in Niemann-Pick disease type A and B (acid sphingomyelinase deficiency, SMPD1 gene mutations). Overlapping clinical features are also seen between Wolman disease and Niemann-Pick disease type A and B.

Gaucher disease (GBA mutations): overlapping clinical features of lysosomal acid lipase deficiency and Gaucher disease are hepatosplenomegaly and thrombocytopenia.

CESD may initially be confused with familial hypercholesterolemia because of increased serum concentration of total cholesterol and LDL; mutation of LDLR, APOB, or PCSK9 accounts for 60%-80% of familial hypercholesterolemia.

CESD manifesting as extremely high total and low-density lipoprotein cholesterol levels may resemble autosomal recessive hypercholesterolemia. Mutations in the LDLRAP1 gene are causative in autosomal recessive hypercholesterolemia.

Liver disease in CESD may be misattributed to hepatitis, non-alcoholic fatty liver disease, or cryptogenic cirrhosis. As nonalcoholic fatty liver disease is associated with obesity, body mass index should be taken into account when considering the cause of fatty liver disease.

Recommended testing workflow

Recommended panel testing at Breda Genetics for this condition:

Lysosomal acid lipase deficiency (Wolman/CESD) and its differential diagnosis (LIPA, SMPD1, GBA, LDLR, APOB, PCSK9, LDLRAP1).


OMIM: 278000

Lysosomal Acid Lipase Deficiency. Hoffman EP, Barr ML, Giovanni MA, Murray MF. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2015 Jul 30 [updated 2016 Sep 1]. PMID: 26225414

Cholesterol ester storage disease with a novel LIPA mutation (L264P) that presented massive hepatomegaly: A case report. Kuranobu N, Murakami J, Okamoto K, Nishimura R, Murayama K, Takamura A, Umeda T, Eto 3, Kanzaki S. Hepatol Res. 2016 Mar;46(5):477-82.PMID: 26385844

Clinical Features of Lysosomal Acid Lipase Deficiency. Burton BK, Deegan PB, Enns GM, Guardamagna O, Horslen S, Hovingh GK, Lobritto SJ, Malinova V, McLin VA, Raiman J, Di Rocco M, Santra S, Sharma R, Sykut-Cegielska J, Whitley CB, Eckert S, Valayannopoulos V, Quinn AG. J Pediatr Gastroenterol Nutr. 2015 Dec;61(6):619-25. PMID: 26252914

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. 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. N Engl J Med. 2015 Sep 10;373(11):1010-20. PMID: 26352813

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