Alternative titles; symbols
SNOMEDCT: 82500001; ICD10CM: E75.5; DO: 14497;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q23.31 | Wolman disease | 620151 | Autosomal recessive | 3 | LIPA | 613497 |
A number sign (#) is used with this entry because Wolman disease (WOLD) is caused by homozygous or compound heterozygous mutation in the LIPA gene (613497) on chromosome 10q23.
Cholesteryl ester storage disease (CESD; 278000), a milder lysosomal acid lipase deficiency, is also caused by mutation in the LIPA gene.
Deficiency of lysosomal acid lipase causes 2 distinct phenotypes in humans: Wolman disease (WOLD) and cholesteryl ester storage disease (CESD; 278000). WOLD is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides. Death occurs early in life. CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters. This slowly progressive visceral disease has a wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood (summary by Du et al., 2001).
Wolman et al. (1961) described 3 sibs, born of Persian Jewish cousins, in whom involvement of the viscera was an important feature and death occurred at the age of about 3 months. Xanthomatous changes were observed in the liver, adrenal, spleen, lymph nodes, bone marrow, small intestine, lungs, and thymus, and slight changes were found in the skin, retina, and central nervous system. The adrenals were calcified. Death was thought to be due to intestinal malabsorption resulting from involvement of the gut. The parents, Persian Jews, were cousins. Lipids in the plasma were normal or moderately elevated. Several features suggested that the entity is distinct from hypercholesterolemia and the hyperlipidemias.
Three cases, the first from the United States, were reported by Crocker et al. (1965), who gave no information on ethnicity. They noted that the relatively nonspecific clinical picture includes poor weight gain, vomiting, diarrhea, increasing hepatosplenomegaly with abdominal protuberance, and death by nutritional failure by 2 to 4 months of age. Foam cells are found in bone marrow and vacuolated lymphocytes in peripheral blood, as in Niemann-Pick disease (257200). Diffuse punctate calcification of the adrenals is typical. Disseminated foam cell infiltration is found in many organs. Great increases in cholesterol are found in the organs.
Konno et al. (1966) reported a Japanese family with 3 affected sibs. Spiegel-Adolf et al. (1966) reported 3 affected sibs in an American family.
Lough et al. (1970) described an affected infant of Greek ancestry in whom calcified adrenals were demonstrated on the fifth day of life.
Eto and Kitagawa (1970) described a 9-month-old girl with characteristic features of Wolman disease accompanied by malabsorption of lipid, hypolipoproteinemia, and acanthocytosis. Lipid analysis of various tissues revealed excessive accumulation of triglyceride within liver cells, with involvement of spleen, central nervous tissue, and other organs.
Roytta et al. (1992) reported the case of an affected 1-month-old girl on the Aland Islands, the first published Scandinavian example of Wolman disease. Skin biopsy showed cytoplasmic accumulations identical to those noted in 2 Aland Islander sibs who died at the age of about 3 months during the 1950s. Genealogic analyses showed that the 2 families had ancestors from the same restricted area as well as common ancestors during the 17th century. The parents of the 2 affected sibs were born on a small island and were related to each other 'in many different ways.'
Jones et al. (2016) reviewed the records of 35 patients with lysosomal lipase deficiency, 26 of whom had early growth failure. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% CI, 0.009-0.220). Among patients with early growth failure, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI, 0.000-0.112). Treated patients (9 with hematopoietic stem cell transplant (HSCT), 1 with HSCT and liver transplant) in the overall population and the early growth failure subset survived longer than untreated patients, but survival was still poor, with a median age of death of 8.6 months.
Patrick and Lake (1969) demonstrated deficiency of an acid lipase (cholesteryl ester hydrolase) which apparently leads to the progressive accumulation of triglycerides and cholesterol esters in lysosomes in the tissues of patients with Wolman disease.
Burton and Reed (1981) demonstrated material crossreacting with antibodies to acid lipase in fibroblasts of 3 patients with Wolman disease and 3 with cholesterol ester storage disease. Quantitation of the CRM showed normal levels in both cell types. Enzyme activity was reduced about 200-fold in Wolman disease fibroblasts and 50- to 100-fold in cholesterol ester storage disease cells. Cholesterol ester storage disease was proposed to be a disorder allelic to Wolman disease (Assmann and Fredrickson, 1983). Supporting the allelic nature of Wolman and cholesteryl ester storage disease is the occurrence of possible genetic compounds, i.e., cases of intermediate severity (Schmitz and Assmann, 1989). In both Wolman disease and cholesteryl ester storage disease, Chatterjee et al. (1986) demonstrated that renal tubular cells shed in the urine are laden with cholesteryl esters and triacylglycerol and that LIPA is lacking in these cells.
The transmission pattern of WOLD in the family reported by Wolman et al. (1961) was consistent with autosomal recessive inheritance.
Aguisanda et al. (2017) stated that the estimated incidence rate for Wolman disease is less than 1/100,000 births; for CESD, it is 2.5/100,000 births. Wolman disease occurs more frequently in Iranian-Jewish populations (1/4,200 births).
In a proband with Wolman disease, the child of unrelated parents, Anderson et al. (1994) found compound heterozygosity for mutations in the LIPA gene, a 1-bp insertion (613497.0004) and a missense mutation (L179P; 613497.0001). The proband had 2 older affected sibs.
Aslanidis et al. (1996) reported mutations in 1 patient with cholesteryl ester storage disease and 2 patients with Wolman disease and demonstrated that the functionally relevant genetic difference between the phenotypes is that the splice site mutation detected in the Wolman disease patient (613497.0005) permitted no correct splicing, whereas the defect observed in a CESD patient (613497.0002) allowed some correct splicing (3% of total mRNA), and therefore the synthesis of functional enzyme.
In an infant, born of unrelated parents, with Wolman disease, Lee et al. (2011) identified compound heterozygosity for a truncating mutation in the LIPA gene (613497.0007) and an intragenic deletion of the LIPA gene. The patient presented at age 6 weeks with abdominal distention and failure to thrive. He had hepatosplenomegaly and calcified adrenals; LIPA activity was undetectable. He died of multiorgan failure within the following month.
Yoshida and Kuriyama (1990) described lysosomal acid lipase deficiency in rats.
Du et al. (1998) produced a mouse model of lysosomal acid lipase deficiency by a null mutation produced by targeting disruption of the mouse gene. Homozygous knockout mice produced no Lip1 mRNA, protein, or enzyme activity. The homozygous deficient mice were born in mendelian ratios, were normal appearing at birth, and followed normal development into adulthood. However, massive accumulation of triglycerides and cholesteryl esters occurred in several organs. By 21 days, the liver developed a yellow-orange color and was up to 2 times larger than normal. The accumulated cholesteryl esters and triglycerides were approximately 30-fold greater than normal. The heterozygous mice had approximately 50% of normal enzyme activity and did not show lipid accumulation. Male and female homozygous deficient mice were fertile and could be bred to produce progeny. This mouse model is the phenotypic model of human CESD and a biochemical and histopathologic mimic of human Wolman disease.
Aguisanda, F., Thorne, N., Zheng, W. Targeting Wolman disease and cholesteryl ester storage disease: disease pathogenesis and therapeutic development. Curr. Chem. Genomics Transl. Med. 11: 1-18, 2017. [PubMed: 28401034] [Full Text: https://doi.org/10.2174/2213988501711010001]
Anderson, R. A., Byrum, R. S., Coates, P. M., Sando, G. N. Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc. Nat. Acad. Sci. 91: 2718-2722, 1994. [PubMed: 8146180] [Full Text: https://doi.org/10.1073/pnas.91.7.2718]
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