Edit concept Question Editor Create issue ticket

Wolman Disease

Lysosomal Acid Lipase Deficiency

Wolman disease is an abnormal accumulation of cholesteryl esters in the body tissues caused by a deficiency of lysosomal acid lipase enzyme. It is a rare inherited disease and is usually fatal.

Wolman Disease - Symptom Checker

Ad Check possible symptoms of Wolman Disease now!

Presentation

The clinical presentation of children with Wolman disease can vary from an early presentation on the first day of birth with abdominal swelling, vomiting, fatty stools to presenting weeks or months later with a failure to thrive [25] [26]. Life expectancy is usually less than one year with mortality mainly caused by complications of the disease in the liver, small intestine and the adrenal glands.

Due to the pathophysiology of the illness, there is a buildup of cholesteryl esters and triglycerides in several body tissues and organs. Accumulations in the liver and spleen may cause hepatomegaly and splenomegaly, possibly leading to liver failure. Similarly, a buildup of these substances in the intestines affects intestinal absorption, thus leading to severe weight loss [27]. In the adrenals, the disease can lead to adrenocortical insufficiency.

Splenomegaly
  • Other signs often include splenomegaly, high total cholesterol and LDL-cholesterol, elevated triglycerides, and low HDL-cholesterol. The diagnosis of LAL deficiency requires clinical experience and specialized laboratory tests.[ncbi.nlm.nih.gov]
  • Abdominal distention may be present because of hepatomegaly, splenomegaly and generalized lymphadenopathy 2. The underlying biochemical abnormality is a deficiency of acid lipase/acid esterase.[radiopaedia.org]
  • Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased.[ncbi.nlm.nih.gov]
  • Hepatomegaly, splenomegaly, and lymphadenopathy are also visible on computed tomography (CT) and magnetic resonance imaging (MRI). They may also show calcifications in the enlarged adrenal glands.[symptoma.com]
  • Nearly all affected individuals develop an enlarged liver (hepatomegaly); an enlarged spleen (splenomegaly) may also occur. About two-thirds of individuals have liver fibrosis, eventually leading to cirrhosis.[ghr.nlm.nih.gov]
Generalized Lymphadenopathy
  • Abdominal distention may be present because of hepatomegaly, splenomegaly and generalized lymphadenopathy 2. The underlying biochemical abnormality is a deficiency of acid lipase/acid esterase.[radiopaedia.org]
Anemia
  • The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Later, severe anemia and cachexia become apparent. Etiology The enzymatic deficiency results from severe mutations of the acid lipase gene (LIPAor LAL ), localised to 10q24-q25.[orpha.net]
  • Treatment for the disease involves a focus on management of the persons symptoms, such as malnutrition and anemia.[disabled-world.com]
  • Common symptoms in infants include enlarged liver and spleen, poor weight gain, low muscle tone, jaundice, vomiting, diarrhea, developmental delay, anemia, and poor absorption of nutrients from food.[diseaseinfosearch.org]
  • Peripheral blood showed macrocytic anemia with mild neutropenia, thrombocytopenia, and acanthocytes. Approximately 20% of lymphocytes demonstrated between 1 and 7 cytoplasmic vacuoles (panels A-C; May–Grünwald–Giemsa stain).[imagebank.hematology.org]
Developmental Delay
  • Common symptoms in infants include enlarged liver and spleen, poor weight gain, low muscle tone, jaundice, vomiting, diarrhea, developmental delay, anemia, and poor absorption of nutrients from food.[diseaseinfosearch.org]
  • Potential symptoms include enlarged liver or spleen, vomiting, jaundice, anemia, diarrhea, little or no weight gain, poor muscle tone, developmental delays, and poor absorption of nutrients from food.[disabled-world.com]
  • These may include an enlarged liver and spleen, poor weight gain, low muscle tone, a yellow tint to the skin and the whites of the eyes (jaundice), vomiting, diarrhea, developmental delay, low amounts of iron in the blood (anemia), and poor absorption[ldnz.org.nz]
  • In addition, affected infants often have calcium deposits in small hormone-producing glands on top of each kidney ( adrenal glands ), low amounts of iron in the blood ( anemia ), and developmental delay.[ghr.nlm.nih.gov]
  • It is the most severe type of lysosomal acid lipase deficiency. 0003270 Adrenal calcification 0010512 Global developmental delay 0001263 Hepatic failure Liver failure 0001399 Hepatomegaly Enlarged liver 0002240 Nausea and vomiting 0002017 Steatorrhea[rarediseases.info.nih.gov]
Weight Loss
  • Similarly, a buildup of these substances in the intestines affects intestinal absorption, thus leading to severe weight loss. In the adrenals, the disease can lead to adrenocortical insufficiency.[symptoma.com]
  • loss, ascites, and hepatosplenomegaly.[imagebank.hematology.org]
  • Symptoms [ edit ] Infants may present with feeding difficulties with frequent vomiting, diarrhea, swelling of the abdomen, and failure to gain weight or sometimes weight loss. [3] As the disease progresses in infants, increasing fat accumulation in the[en.wikipedia.org]
  • Eating disorders: “Anorexia has been found to interrupt normal sleep patterns, possibly due to malnutrition and excessive weight loss,” says Wellman.[everydayhealth.com]
Death in Infancy
  • Wolman disease is characterized by severe diarrhea and malnutrition leading to death during infancy. Lysosomal acid lipase deficiency is the cause of the symptoms and signs. It is inherited in an autosomal recessive manner.[ncbi.nlm.nih.gov]
  • […] in infancy ensuing (usually within 6 months).[radiopaedia.org]
  • […] in infancy Leads to abnormal collections of cholesterol esters and triglycerides in “foam cells” Diffuse punctate calcifications in adrenals which may be enlarged but maintain adreniform shape Hepatosplenomegaly Imaging Findings CT is the study of choice[learningradiology.com]
Weakness
  • […] attacks Birthday attack Digital Signatures and Certificates LZW (Lempel–Ziv–Welch) Compression technique RC4 Encryption Algorithm RC5 Encryption Algorithm SHA-512 Hash RSA Algorithm in Cryptography RSA Algorithm using Multiple Precision Arithmetic Library Weak[geeksforgeeks.org]
Vomiting
  • In addition to hepatomegaly, vomiting and diarrhoea, characteristic radiological findings confirmed the diagnosis of the rare heritable lipidosis, Wolman's disease.[ncbi.nlm.nih.gov]
  • Affected infants show signs of lipid storage in most tissues, including hepatosplenomegaly, abdominal distension, vomiting, steatorrhea, failure to thrive, and adrenal calcifications.[ncbi.nlm.nih.gov]
  • The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease. The clinical picture is more variable in CESD.[ncbi.nlm.nih.gov]
  • Patients with Wolman disease typically present during the first two months of life with failure to thrive, diarrhea and vomiting. Abdominal distention may be present because of hepatomegaly, splenomegaly and generalized lymphadenopathy 2.[radiopaedia.org]
Diarrhea
  • Diarrhea is no longer present. Now, at 4 years of age, this patient is gaining developmental milestones. Cholesterol and triglyceride levels are normal. Liver function is normal.[ncbi.nlm.nih.gov]
  • Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function.[ncbi.nlm.nih.gov]
  • The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease. The clinical picture is more variable in CESD.[ncbi.nlm.nih.gov]
  • Patients with Wolman disease typically present during the first two months of life with failure to thrive, diarrhea and vomiting. Abdominal distention may be present because of hepatomegaly, splenomegaly and generalized lymphadenopathy 2.[radiopaedia.org]
Failure to Thrive
  • In infants, poor weight gain, massive hepatosplenomegaly, calcified adrenal glands (present about 2/3 of the time), vomiting, diarrhea and failure to thrive are indicative of Wolman disease. The clinical picture is more variable in CESD.[ncbi.nlm.nih.gov]
  • Affected infants show signs of lipid storage in most tissues, including hepatosplenomegaly, abdominal distension, vomiting, steatorrhea, failure to thrive, and adrenal calcifications.[ncbi.nlm.nih.gov]
  • Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands.[ncbi.nlm.nih.gov]
  • The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Patients with Wolman disease typically present during the first two months of life with failure to thrive, diarrhea and vomiting. Abdominal distention may be present because of hepatomegaly, splenomegaly and generalized lymphadenopathy 2.[radiopaedia.org]
Abdominal Distension
  • Affected infants show signs of lipid storage in most tissues, including hepatosplenomegaly, abdominal distension, vomiting, steatorrhea, failure to thrive, and adrenal calcifications.[ncbi.nlm.nih.gov]
  • Wolman disease is characterized by neonatal abdominal distension, major or even massive hepatosplenomegaly and calcified adrenal glands, cholesteryl ester storage disease presents with microvesicular steatosis leading to hepatomegaly and hypercholesterolaemia[orpha.net]
  • distension/failure to thrive/elevated transaminases are currently underway.[ncbi.nlm.nih.gov]
  • Clinical description The disease can sometimes present in the fetus (hepatomegaly, ascitis, calcified adrenal glands), but onset more typically occurs in the first weeks of life with abdominal distension and major or even massive hepatosplenomegaly (which[orpha.net]
Hepatosplenomegaly
  • Infant leukemia most commonly present with pallor and hepatosplenomegaly.[ncbi.nlm.nih.gov]
  • Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function.[ncbi.nlm.nih.gov]
  • Plain radiograph bilateral calcification of the adrenal glands, which are enlarged 2,4 CT may show hepatosplenomegaly (with fatty liver ) bilaterally enlarged calcified (punctate calcification) adrenal glands that retain their normal triangular shapes[radiopaedia.org]
  • Hepatosplenomegaly is a constant feature and occurs as early as fourth day of life. Progressive mental deterioration may occur after few weeks of onset of symptoms.[ncbi.nlm.nih.gov]
  • Affected infants show signs of lipid storage in most tissues, including hepatosplenomegaly, abdominal distension, vomiting, steatorrhea, failure to thrive, and adrenal calcifications.[ncbi.nlm.nih.gov]
Hepatomegaly
  • hepatomegaly and abdominal distension/failure to thrive/elevated transaminases are currently underway.[ncbi.nlm.nih.gov]
  • In addition to hepatomegaly, vomiting and diarrhoea, characteristic radiological findings confirmed the diagnosis of the rare heritable lipidosis, Wolman's disease.[ncbi.nlm.nih.gov]
  • Hepatomegaly is noted on CT scan in both WD and CESD. MRI may demonstrate accumulation of cholesterol esters and may be useful to study effects of potential medical therapies.[ncbi.nlm.nih.gov]
  • Wolman disease is characterized by neonatal abdominal distension, major or even massive hepatosplenomegaly and calcified adrenal glands, cholesteryl ester storage disease presents with microvesicular steatosis leading to hepatomegaly and hypercholesterolaemia[orpha.net]
  • Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy.[ncbi.nlm.nih.gov]
Jaundice
  • The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Other symptoms that can develop in children include: Jaundice Calcium deposits in the adrenal glands, which causes them to harden The onset of CESD varies, and in some cases the disorder may not be diagnosed until the child reaches adulthood.[medic8.com]
  • Common symptoms in infants include enlarged liver and spleen, poor weight gain, low muscle tone, jaundice, vomiting, diarrhea, developmental delay, anemia, and poor absorption of nutrients from food.[diseaseinfosearch.org]
  • They may have signs of bile duct problems, like itchiness, jaundice, pale stool, or dark urine. Their feces may be excessively greasy.[en.wikipedia.org]
  • These may include an enlarged liver and spleen, poor weight gain, low muscle tone, a yellow tint to the skin and the whites of the eyes (jaundice), vomiting, diarrhea, developmental delay, low amounts of iron in the blood (anemia), and poor absorption[ldnz.org.nz]

Workup

The laboratory diagnosis of Wolman disease is based on the confirmation of a deficient LAL in the white blood cells or dermal fibroblasts.

The characteristic finding on imaging is normally shaped but bilaterally enlarged adrenal glands with pathognomonic calcifications outlining the cortex. Differential diagnoses of adrenal calcification in children include neuroblastoma and adrenal hemorrhage, though they differ in their pattern of calcification.

Hepatomegaly, splenomegaly, and lymphadenopathy are also visible on computed tomography (CT) and magnetic resonance imaging (MRI). They may also show calcifications in the enlarged adrenal glands. Likewise, abdominal ultrasound can be used to examine abdominal viscera [28].

Treatment

Management of WD is mainly symptomatic with no definitive treatment options available. Bone marrow and umbilical cord blood transplants are promising treatment interventions. However, the lack of matched donors and the severe, fast wasting seen in affected individuals limit the therapeutic efficacy of bone marrow transplantation [5] [6].

There are few therapeutic measures in CESD with the target to attenuate consequences of LAL-D. Research involving LAL enzyme replacement therapy for definitive management is currently underway.

Lipid-lowering therapies

The use of HMG-CoA reductase inhibitors (statins) in lowering lipid levels in patients with CESD has had mixed results with some reports of success and some reported persistence of dyslipidemia [14] [20] [29]. Although a decrease in liver size has been seen in some patients treated with HMG-CoA inhibitors [15] [30], liver fibrosis has continued in these patients [19] [31]. Similarly, some evidence is available on the protective benefits of HMG-CoA inhibitors on the heart, but liver damage still progressed in these patients with some ending up with liver failure [15] [19].

In a 15-year-old test subject with CESD, six months of therapy on a cholesterol absorption inhibitor (Ezetimibe) was able to bring liver transaminases to normal and decrease total cholesterol and LDL-levels, as well as reduce cytokines and oxidative stress parameters measured in the serum [32]. Ezetimibe may thus, be of benefit in certain cases.

Hematopoietic stem cell and liver transplantation

Although there is inadequate data on long-term outcomes, liver transplant in WD patients with liver failure has improved survival in a few patients for up to 5 years [19] [33] [34]. Similarly, hematopoietic stem cell transplantation has been studied in some patients with WD, but problems related to their toxicity and the multi-organ nature of the disease have limited the efficacy of this therapy [35] [36] [37] [38].

Enzyme replacement therapy

Enzyme replacement therapy aims to replace the deficient lysosomal acid lipase enzyme in LAL-D patients.

Sebelipase alfa, a human recombinant LAL enzyme, is currently undergoing clinical testing with promising results regarding an improvement of liver function test values, reducing the accumulation of cholesteryl esters in the lysosomes of cells and an absence of severe side effects to therapy [39] [40].

Prognosis

The prognosis of WD patients is generally very poor and characterized with a life expectancy of less than one year. The quality of life of CESD patients tends to be diverse based on the broad spectrum of clinical presentations. No evidence-based quality of life scales are available at present. The clinical manifestations of the disease can vary from unnoticed signs and symptoms to very severe features with some infants having an early liver failure and requiring transplantation, while others may have a stroke, aneurysm or coronary artery disease [19] [20] [21] [22] [23] [24].

Etiology

Wolman disease is an inherited disorder passed down by autosomal recessive inheritance. The inherited defective gene in WD is lysosomal acid lipase gene (LIPA). The LIPA gene is responsible for the synthesis of lysosomal acid lipase enzyme which is a highly important part of the metabolism of cholesterol and triglycerides. The abnormality in the LIPA gene, therefore, leads to a deficiency and/or defective lysosomal acid lipase enzyme production leading to a massive buildup of unmetabolized cholesterol and triglycerides in the body. These fats end up in tissues and organs of the body causing various degrees of damage. There is a less severe manifestation of lysosomal acid lipase deficiency named

There is a less severe manifestation of lysosomal acid lipase deficiency named cholesteryl ester storage disease (CESD).

Epidemiology

Wolman disease is estimated to occur in less than 1 per 300,000 live births although the actual incidence remains uncertain [1] [8]. Studies in some populations, like the Iranian Jews in Los Angeles have shown incidence rates of 1 in 4200 births; however, this study population is too insulated to be representative [9].

Sex distribution
Age distribution

Pathophysiology

Neutral lipids like cholesteryl esters and triglycerides derived from LDL are metabolized by LAL in the lysosomes of cells. The byproducts of this metabolism (fatty acids and free cholesterol) or the neutral lipids themselves directly modulate the expression of genes responsible for the production/uptake of cholesterol and lipogenesis through their interaction with transcription factors named sterol regulatory element-binding proteins (SREBPs) [2] [10]. Physiologically, an unusually high amount of cholesterol acts via SREBP-2 to decrease cellular uptake of cholesterol (by downregulation of LDL receptors), reduce cholesterol synthesis (by inhibiting hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase) and increase cholesterol esterification through acyl-cholesterol acyltransferase. Similarly, high fatty acids in cells act via SREBP-1c to reduce fatty acid production through reduction in triglyceride and phospholipid synthesis [11].

In response to a lack of intracellular free cholesterol caused by the inability of LAL to break down cholesteryl esters and triglycerides, SREBP-2 senses this deficiency of free cholesterol and ramps up the production of HMG-CoA reductase, leading to increased levels of free cholesterol inside the cell [12]. SREBP in this free cholesterol deficiency scenario also causes increased endocytosis by the LDL receptors and enhanced production of apolipoprotein B (ApoB) and very-low-density lipoprotein cholesterol (VLDL-C) [12].

It is speculated that the HMG-CoA reductase induced a rise in free cholesterol level in lysosomal acid lipase deficiency (LAL-D) causes a reduction in LDL-C clearance and inhibition of LDL receptor action. Cholesterol movement in LAL-D, however, appears to be different. In what could be a significant cause of hypercholesterolemia in LAL-D, a high VLDL-C synthesis (the natural export mechanism for cholesterol from hepatocytes) has been observed in response to high cholesterol production and this further leads to increased LDL-C synthesis [13].

The lipid profile of LAL-D patients shows derangements in all the components of the panel with raised total cholesterol and TGs caused by the buildup of ApoB lipoproteins like VLDL-C and LDL-C. Low HDL-C may be possibly caused by reduced adenosine triphosphate-binding cassette transporter A1 (ABCA1) which leads to decreased synthesis of mature α-HDL particles [14] [15]. Normally, high cellular cholesterol acts via oxysterol to stimulate this ABCA1 gene. In LAL-D with its attendant low intracellular free cholesterol (due to accumulation of cholesteryl esters within lysosomes), the reverse is the case with reduced oxysterol-dependent activation of ABCA1. This reduced action of ABCA1 leads to reduced synthesis of α-HDL particles by affecting the cholesterol-dependent, ABCA1-mediated transfer of cholesterol to the extracellular lipid-poor apolipoprotein A1 (ApoA-I), an important step in the α-HDL particles synthesis [16] [17]. Evidence for these processes has been demonstrated in experiments where the introduction of recombinant LAL to LAL deficient cells reverses these steps, thus boosting α-HDL formation [18].

Prevention

There are currently no preventive strategies.

Summary

Wolman disease (WD) is often seen in childhood with an estimated incidence of less than 1/300,000 live births and the average survival being about six months [1]. It is caused by mutations in the lysosomal acid lipase gene, thereby producing a defective lysosomal acid lipase (LAL) enzyme. This enzyme is responsible for hydrolyzing cholesteryl esters (CE) and triglycerides (TG) which enter the lysosomes through receptor-mediated endocytosis [2]. The consequence of this deficiency is a massive buildup of CEs and TGs in the macrophages of several organs in the body. Such accumulations in the liver can cause liver cirrhosis, while a buildup in the lungs can lead to pulmonary fibrosis. WD may also result in calcifications in the zona reticularis of the adrenal gland, thus causing adrenal insufficiency [3] [4] [5] [6]. In the intestines, the buildup of TGs and CEs leads to abnormal intestinal absorption leading to massive weight loss. In addition to the above, some patients can develop atherosclerosis due to dyslipidemia [3] [4] [7]. A less severe manifestation of lysosomal acid lipase deficiency is called cholesteryl ester storage disease (CESD).

Bone marrow and umbilical cord blood transplants are promising treatment interventions. However, the lack of matched donors and the severe, fast wasting seen in affected individuals limit the therapeutic efficacy of bone marrow transplantation [5] [6].

Patient Information

Wolman disease is an uncommon disease caused by an abnormal change in the gene that produces an enzyme called lysosomal acid lipase. This leads to a deficiency of this enzyme causing a buildup of fats in body tissues and organs. These dangerous accumulations can occur in the liver, spleen, intestines, lymph nodes and adrenal glands, causing multiple complications in these organs. Wolman disease is an inherited disease wherein affected individuals get a defective gene from each of their parents.

Causes

Wolman disease is caused by an abnormal change in the lysosomal acid lipase gene (LIPA) and two of these abnormal genes are inherited by a patient from each parent. This gene is responsible for the production of lysosomal acid lipase enzyme, which acts inside cells to break down fats. An abnormal LIPA gene leads to the manufacture of a defective enzyme which cannot break down these fats in the cells; hence, these fats accumulate in harmful concentrations inside the cells, thereby causing complications.

Symptoms and clinical features

The symptoms of Wolman disease can vary and most children do not survive beyond 12 months of birth. There might be no symptoms immediately after birth. Between 4 to 8 weeks of age, clinical manifestations begin to appear and progress in a rapid fashion.

The clinical features of this disease include poor feeding with persistent vomiting, distension of the stomach, liver and spleen enlargement, passage of frequent watery or fatty stools, severe wasting or weight loss, enlargement and calcium deposition in the adrenal glands.

Diagnosis

Diagnosis of this disease can be difficult because it is an uncommon condition. The doctor will consider the patient's past medical records, family history, presenting signs and symptoms as well as laboratory and radiological investigations to make a diagnosis of Wolman disease.

Treatment

Research is still ongoing on a definitive treatment for Wolman disease. For now, all that is available is supportive and symptomatic care. Promising treatment options include bone marrow and cord blood transplantation. Similarly, enzyme replacement therapy with synthetic copies of the deficient lysosomal acid lipase enzyme is also under clinical trials and is showing promising results.

References

Article

  1. Meikle PJ, JJ Hopwood, AE Clague, et al. Prevalence of lysosomal storage disorders. J Am Med Assoc. 1999; 281: 249–254.
  2. Goldstein JL, SE Dana, JR Faust, et al. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem. 1975; 250:8487–8495.
  3. Assmann G, U Seedorf. Acid lipase deficiency: Wolman disease and cholesteryl ester storage disease. In Metabolic and Molecular Bases of Inherited Diseases. C. R. Scriver, A. L. Beaudet, D. Valle, and W. S. Sly, editors. McGraw-Hill, New York. 2001; 3551–3572.
  4. Boldrini R, R Devito, R Biselli, et al.Wolman disease and cholesteryl ester storage disease diagnosed by histological and ultrastructural examination of intestinal and liver biopsy. Pathol Res Pract. 2004; 200:231–240.
  5. Krivit W, C Peters, K Dusenbery, et al. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplant. 2000; 26:567–570.
  6. Stein J, BZ Garty, Y Dror, et al. Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation. Eur J Pediatr. 2006; 166:663–666.
  7. Beaudet AL, GD Ferry, BL Nichols, et al. Cholesterol ester storage disease: clinical, biochemical, and pathological studies. J. Pediatr. 1977; 90:910–914.
  8. Ługowska A. and Tylki-Szymańska A. Lysosomal acid lipase deficiency: Wolman disease and cholesterol ester storage disease. Current Medical Literature. 2012; 10(1): p. 1–8. 7.
  9. Valles-Ayoub Y, et al. Wolman disease (LIPA p.G87V) genotype frequency in people of IranianJewish ancestry. Genet Test Mol Biomarkers. 2011; 15(6): p. 395–8.
  10. Jeon TI, Osborne TF. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab. 2012; 23: 65–72.
  11. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002; 109:1125–1131.
  12. Cummings MH, Watts GF. Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in cholesteryl ester storage disease. Clin Chem. 1995; 41:111–114.
  13. Ginsberg HN, Le NA, Short MP, et al. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis. J Clin Invest. 1987; 80:1692–1697.
  14. Fouchier SW, Defesche JC. Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Curr Opin Lipidol. 2013; 24:332–338.
  15. Levy R, Ostlund RE, Schonfeld G, et al. Cholesteryl ester storage disease: complex molecular effects of chronic lovastatin therapy. J Lipid Res. 1992; 33:1005–1015.
  16. Oram JF, Heinecke JW. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev. 2005; 85:1343–1372.
  17. Boadu E, Bilbey NJ, Francis GA. Cellular cholesterol substrate pools for adenosine-triphosphate cassette transporter A1-dependent high-density lipoprotein formation. Curr Opin Lipidol. 2008; 19:270–276.
  18. Bowden KL, Bilbey NJ, Bilawchuk LM, et al. Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease. J Biol Chem. 2011; 286:30624–30635.
  19. Bernstein DL, Hulkova H, Bialer MG, et al. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013; 58:1230–1243
  20. Gasche C, Aslanidis C, Kain R, et al. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997; 27:744–750.
  21. Om Dahl S, Harzer K, Rolfs A, et al. Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation. J Hepatol. 1999; 31:741–746.
  22. Pisciotta L, Fresa R, Bellocchio A, et al. Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene. Mol Genet Metab. 2009; 97:143–148.
  23. Sloan HR, Fredrickson DS. Rare familial diseases with neutral lipid storage. in: J.B. Stanbury, J.B. Wyngaarden, D.S. Fredrickson (Eds.) The metabolic basis of inherited disease. McGraw Hill Inc, New York; 1972: 808.
  24. Yatsu FM, Hagemenas FC, Manaugh LC, et al. Cholesteryl ester hydrolase activity in human symptomatic atherosclerosis. Lipids. 1980; 15:1019–1022.
  25. Shome DK, Al-Jishi E, Greally JF, et al. The Middle-East connection of Wolman Disease. Saudi Med J. 2002; 23:597–601.
  26. Browne M, Somers G, Savoia H, Kukuruzovic R. Wolman’s disease in an infant. British Journal of Haematology. 2003; 122:522.
  27. Nchimi A, Rausin L, Khamis J. Ultrasound appearance of bowel wall in Wolman’s disease. Pediatr Radiol. 2003; 33:284–285.
  28. Ozman MN, Aygun N, Kilic I, et al. Wolman's disease: ultrasonographic and computed tomographic findings. Pediatr Radiol. 1992; 22(7):541–542.
  29. Quinn AG, Burton B, Deegan P, Di Rocco, et al. Sustained elevations in LDL cholesterol and serum transaminases from early childhood are common in lysosomal acid lipase deficiency. Mol Genet Metab. 2014; 111: S89.
  30. Tarantino MD, McNamara DJ, Granstrom P, et al. Lovastatin therapy for cholesterol ester storage disease in two sisters. J Pediatr. 1991; 118:131–135.
  31. Leone, L., Ippoliti, P.F., and Antonicelli, R. Use of simvastatin plus cholestyramine in the treatment of lysosomal acid lipase deficiency. J Pediatr. 1991; 119: 1008–1009.
  32. Abello F, Guardamagna O, Baracco V, et al. The treatment of colesteryl storage disease (CESD) by ezetimibe monotherapy. Atheroscler Suppl. 2010; 11: 28.
  33. Ambler GK, Hoare M, Brais R, et al. Orthotopic liver transplantation in an adult with cholesterol ester storage disease. JIMD Rep. 2013; 8:41–46.
  34. Ferry GD, Whisennand HH, Finegold, MJ, et al. Liver transplantation for cholesteryl ester storage disease. J Pediatr Gastroenterol Nutr. 1991; 12:376–378.
  35. Stein J, Garty BZ, Dror Y, et al. Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation. Eur J Pediatr. 2007; 166: 663–666.
  36. Tolar J, Petryk A, Khan K, et al. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease. Bone Marrow Transplant. 2009; 43:21–27.
  37. Gramatges MM, Dvorak CC, Regula DP, et al. Pathological evidence of Wolman's disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity. Bone Marrow Transplant. 2009; 44:449–450.
  38. Yanir A, Allatif MA, Weintraub M, et al. Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications. Mol Genet Metab. 2013; 109:224–226.
  39. Balwani M, Breen C, Enns GM, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013; 58: 950–957.
  40. Whitley CB. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Annual Meeting 2013 [Oral Presentation, 11 October 2013].

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 22:06