Lysosomal Acid Lipase Deficiency
A number sign (#) is used with this entry because lysosomal acid lipase deficiency is caused by homozygous or compound heterozygous mutation in the LIPA gene (613497) on chromosome 10q23.
DescriptionDeficiency of lysosomal acid lipase causes 2 distinct phenotypes in humans: Wolman disease and cholesteryl ester storage disease (CESD). Wolman disease 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. Wolman disease is very rare, with an incidence of less than one in 100,000 live births. CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters. This slowly progressive visceral disease has a very 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).
Clinical FeaturesWolman Disease
Wolman et al. (1961) described 3 sibs 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. 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 5th day of life.
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.
Cholesteryl Ester Storage Disease
Schiff et al. (1968) described cholesterol ester storage disease of the liver in teenage brother and sister whose livers were orange in color. Four younger sibs showed milder changes. The parents were not known to be related. Tissue accumulation of cholesterol esters and triglycerides occurs in both this disease and Wolman disease. The chemical and enzymatic abnormalities are similar. The marked difference in phenotypic expression is unexplained but is comparable to the difference between Hurler (607014) and Scheie (607016) syndromes, the late infantile and adult forms of metachromatic leukodystrophy (see also 607015), and the classic and visceral forms, A and B (607616), respectively, of Niemann-Pick disease. In contrast to Wolman disease, cholesterol ester storage disease is relatively benign; however, in 1 sibship 3 sisters died of acute hepatic failure at the ages of 7, 9, and 17 years (Beaudet et al., 1977). Accumulation of neutral fats and cholesterol esters in the arteries predispose affected persons to atherosclerosis. Hypercholesterolemia is common. Massive hepatomegaly and hepatic fibrosis may lead to esophageal varices. Lysosomal acid lipase A, the enzyme deficient in both Wolman disease and cholesterol ester storage disease, is one of 3 acid lipase isozymes. See lipase B (LIPB; 247980) and C (LIPC; 151670).
Young and Patrick (1970) commented on the existence of cases with the same biochemical and histologic changes as in the acute infantile form (Wolman disease) but with later onset and a much less fulminant course. One of their cases was alive and well at age 8 years, showing no clinical abnormality other than moderate hepatomegaly. The same enzyme is deficient in all these cases. Hence, they suggested the term 'acid lipase deficiency' for the whole group, with Wolman disease as the designation for the acute infantile form.
Besley et al. (1984) reported the first patient observed in Ireland. Then aged 39, with hepatomegaly and sea-blue histiocytes in the bone marrow, the patient had suffered from recurring periods of general malaise and diarrhea since age 21.
Cagle et al. (1986) concluded that patients with CESD are at risk for the development of pulmonary hypertension. Such was recognized in a 15-year-old patient who died at age 18.
Biochemical FeaturesPatrick and Lake (1969) demonstrated deficiency of an acid lipase (cholesteryl ester hydrolase; EC 3.1.1.13) which apparently leads to the progressive accumulation of triglycerides and cholesterol esters in lysosomes in the tissues of affected persons.
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 diseases 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.
DiagnosisDesai et al. (1987) made the prenatal diagnosis of CESD by demonstration of deficient lysosomal acid lipase activity in cultured amniocytes from an at-risk fetus. The findings in the affected fetus at 17 weeks were described. Massive lysosomal cholesterol and lipid accumulation was demonstrated in fetal hepatocytes, adrenal cells, and syncytiotrophoblasts. Of particular note was the finding of extensive necrosis in the fetal adrenal glands. Necrosis of the adrenal may precede the calcification observed later in these patients.
Clinical ManagementDi Bisceglie et al. (1990) could demonstrate no significant changes in serum lipoprotein concentrations or liver histopathology after 12 months or more of treatment with lovastatin, a cholesterol-lowering agent. Yokoyama and McCoy (1992) observed some improvement with combined cholestyramine and lovastatin therapy.
Burton et al. (2015) reported the results of a 20-week phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency in a multicenter randomized double-blind placebo-controlled study involving 66 patients. Thirty-six patients received 1 mg/kg of sebelipase alfa intravenously every other week, while 30 patients received a placebo; at the end of 20 weeks all patients entered the open-label period. There was substantial disease burden at baseline, including a very high level of LDL cholesterol (greater than 190 mg/dl) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase was normal in 11 of 36 patients (31%) in the treatment group and 2 of 30 (7%) in the placebo group (p = 0.03), with mean changes from baseline of -58 U/L versus -7 U/L (p less than 0.001). With respect to prespecified key secondary efficacy end points, Burton et al. (2015) observed improvements in lipid levels and reduction in hepatic fat content (p less than 0.001 for all comparisons, except p = 0.04 for triglycerides). The number of patients with adverse events was similar in the 2 groups. Most events were mild and were considered by the investigator to be unrelated to treatment. The authors concluded that sebelipase alfa therapy results in the reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency.
Molecular GeneticsIn a 12-year-old patient with cholesteryl ester storage disease from a nonconsanguineous Polish-German family, Klima et al. (1993) detected compound heterozygosity for mutations in the LIPA gene, a splice site mutation resulting in exon skipping (613497.0002) and a null allele. Aslanidis et al. (1996) determined that the null LIPA allele of this patient carried a premature termination mutation (613497.0003).
In a proband with Wolman disease, the child of unrelated parents, who had 2 older affected sibs, 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).
Aslanidis et al. (1996) reported mutations in 1 CESD and 2 Wolman disease patients 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 CESD (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.
Animal ModelYoshida 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.
Du et al. (2001) expressed mannose-terminated human LAL in Pichia pastoris (phLAL) and administered it by tail vein injections to lal -/- mice. Mannose receptor (153618)-dependent uptake and lysosomal targeting of phLAL were evidenced ex vivo using competitive assays with mannose receptor-positive J774E cells, a murine monocyte/macrophage line, immunofluorescence, and western blots. Following (bolus) IV injection, phLAL was detected in Kupffer cells, lung macrophages, and intestinal macrophages in lal -/- mice. Two-month-old lal -/- mice that received phLAL injections once every 3 days for 30 days (10 doses) showed nearly complete resolution of hepatic yellow coloration and a 36% decrease in hepatic weight. Histologic analyses of numerous tissues from phLAL-treated mice showed a reduction in macrophage lipid storage. Triglyceride and cholesterol levels decreased by 50% in liver, 69% in spleen, and 50% in small intestine. The authors proposed that therapy for human Wolman disease and cholesteryl ester storage disease using recombinant LAL enzyme replacement is feasible.