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Copyright 2009, 2012
NORD is very grateful to Jakub Tolar, MD, PhD, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Blood and Marrow Transplantation, University of Minnesota, for the assistance in the preparation of this report.
Wolman disease is a rare genetic disorder characterized by complete absence of an enzyme known as lysosomal acid lipase (LIPA or LAL). This enzyme is required to breakdown (metabolize) certain fats (lipids) in the body. Without the LIPA enzyme, certain fats may abnormally accumulate in the tissues and organs of the body causing a variety of symptoms. Wolman disease may cause bloating or swelling of the stomach (abdominal distention), vomiting, and significant enlargement of the liver or spleen (hepatosplenomegaly). Life-threatening complications often develop during early childhood. Wolman disease is caused by mutations of the lysosomal acid lipase (LIPA) gene. The disorder is inherited as an autosomal recessive trait.
Wolman disease is the most severe expression of LIPA deficiency. Milder forms of the disorder are known as cholesteryl ester storage deficiency (see the Related Disorders section of this report). Wolman disease belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that break down certain fats and carbohydrates. Defective lysosomal enzymes associated with Wolman disease leads to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.
The symptoms of Wolman disease usually become apparent shortly after birth, usually during the first few weeks of life. Affected infants may develop bloating or swelling of the stomach (abdominal distention) and may have significant enlargement of the liver and spleen (hepatosplenomegaly). Scarring (fibrosis) of the liver may also occur. In some cases, fluid may accumulate in the abdominal cavity (ascites).
Infants with Wolman disease have serious digestive abnormalities including malabsorption, a condition in which the intestines fail to absorb nutrients and calories form food. Malabsorption associated with Wolman disease causes persistent and often forceful vomiting, frequent diarrhea, foul-smelling, fatty stools (steatorrhea) and malnutrition. Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age and sex (failure to thrive).
Enlargement of the liver and spleen and protrusion of the abdomen can cause umbilical hernia, a condition in which the contents of the stomach may push through an abnormal opening or tear in the abdominal wall near the bellybutton. Additional symptoms may also occur in Wolman disease including yellowing of the skin, mucous membranes and whites of the eyes (jaundice), a persistent low-grade fever, and poor muscle tone (hypotonia). Infants may exhibit delays in the development of motor skills.
A distinct finding associated with Wolman disease is the hardening of adrenal gland tissue due to the accumulation of calcium (calcification). The adrenal glands are located on top of the kidneys and produce two hormones called epinephrine and norepinephrine. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. Calcification of the adrenal glands is not detectable by physical examination, but can be seen with x-ray study. Calcification may prevent the adrenal glands from producing enough essential hormones and can affect metabolism, blood pressure, the immune system and other vital processes of the body.
Infants with Wolman disease may experience the loss of previously acquired skills required the coordination of muscle and motor skills (psychomotor regression). The symptoms of Wolman disease often get progressively worse eventually leading to life-threatening complications during infancy including extremely low levels of circulating red blood cells (severe anemia), liver (hepatic) dysfunction or failure, and physical wasting away and severe weakness often associated with chronic disease and marked by weight loss and loss of muscle mass (cachexia or inanition).
Wolman disease is caused by mutation of the lysosomal acid lipase (LIPA) gene. It is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the LIPA gene is located on the long arm (q) of chromosome 10 (10q24-q25). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p13" refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The LIPA gene contains instructions for producing the enzyme lysosomal lipase acid. This enzyme is essential for breaking down (metabolizing) certain fats in the body, especially cholesterol (specifically cholesteryl esters) and to a lesser degree triglycerides. Without proper levels of this enzyme, these fats abnormally accumulate in and damage various tissues and organs of the body. Mutations of the LIPA gene result in the lack of production of the LIPA enzyme or production of a defective, inactive form of the LIPA enzyme.
Wolman disease is an extremely rare disorder that affects males and females in equal numbers. More than 50 cases have been reported in the medical literature. However, cases may go undiagnosed or misdiagnosed making it difficult to determine the disorder's true frequency in the general population. Wolman disease is named after one of the physicians who first identified the disorder in the medical literature in 1956.
Symptoms of the following disorders can be similar to those of Wolman disease. Comparisons may be useful for a differential diagnosis.
Cholesteryl ester storage disease (CESD) is a rare genetic disorder characterized by deficiency or inactivity of an enzyme known as lysosomal acid lipase (LIPA). This enzyme is required to breakdown (metabolize) certain fats (lipids) in the body. Deficiency of the LIPA enzyme causes these fats to abnormally accumulate in the tissues and organs of the body potentially causing a variety of symptoms. The symptoms of CESD can vary greatly depending on how much residual enzyme activity remains. The key finding (and sometimes the only clinical sign) is an abnormally enlarged liver (hepatomegaly). Some individuals may not be diagnosed with CESD until adulthood. CESD is caused by different mutations of the same gene [lysosomal acid lipase (LIPA) gene] that causes Wolman disease. CESD is inherited as an autosomal recessive trait. (For more information on this disorder, choose "cholesteryl ester storage disease" as your search term in the Rare Disease Database.)
Niemann-Pick disease (NPD) is a group of rare inherited disorders of fat metabolism. At least five types of Niemann-Pick disease have been identified (NPD types A, B, C, D, and E). Symptoms of types A and B occur as a result of a deficiency of the enzyme acid sphingomyelinase (ASM), which is needed to break down sphingomyelin, a fatty substance found mostly in the brain and nervous system. This deficiency results in abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body such as the liver, spleen, and brain. Symptoms of type C occur because of impaired trafficking of large molecules within cells, which results in the accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) tissues throughout the body. The metabolic defect in type C can lead to a secondary reduction in ASM activity in some cells. Symptoms common to all types of Niemann-Pick disease include yellow discoloration of the skin, eyes, and/or mucous membranes (jaundice), progressive loss of motor skills, feeding difficulties, learning disabilities, and an abnormally enlarged liver and/or spleen (hepatosplenomegaly). The different types of Niemann-Pick disease are inherited as autosomal recessive traits. (For more information on this disorder, choose "Niemann Pick" as your search term in the Rare Disease Database.)
Chanarin Dorfman syndrome is a rare genetic disorder of fat (lipid) metabolism. It is characterized by scaly skin (ichthyosis), degeneration of the muscles (myopathy), and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids). Additional symptoms may occur including hearing loss, vision abnormalities, an enlarged liver (hepatomegaly) and a condition in which fat accumulates in the liver (liver steatosis or "fatty" liver). Cognitive decline may occur in some cases. Chanarin Dorfman syndrome is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Chanarin Dorfman" as your search term in the Rare Disease Database.)
There are several types of metabolic disorders in which secondary accumulation of certain fats (triglycerides) in the body. These disorders include galactosemia, fructose intolerance, and specific disorders of amino acid metabolism. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of Wolman disease may be suspected in newborn infants based upon identification of characteristic symptoms such as abnormally enlarged liver and gastrointestinal problems. A diagnosis may be confirmed by a thorough clinical evaluation, a detail patient history (including family history) and specialized tests that reveal absence or deficient activity of the enzyme lysosomal lipase acid (LIPA) in certain cells and tissues of the body.
Diagnosis before birth (prenatally) is possible through chorionic villus sampling (CVS) or amniocentesis. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied.
No specific treatment is available for Wolman disease. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Proper nutrition can be maintained intravenously. If the adrenal glands are not functioning properly, medications may be used to supplement the hormones normally produced by these glands.
A team approach for individuals with Wolman disease may be necessary and may include special social support and other medical services. Genetic counseling may be of benefit for affected individuals and their families.
In the medical literature, a few children with Wolman disease were treated with hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells are specialized cells found in the bone marrow (the soft spongy material found in long bones). These blood stem cells grow and eventually develop into one of the three main types of blood cells-- red blood cells, white blood cells or platelets. A transplant is done to replace the bone marrow (and consequently the whole blood system) of an affected individual with marrow from a person who does not have a particular disorder. The healthy cells produced by the new marrow contain sufficient levels of lysosomal acid lipase required to breakdown cholesterol and triglycerides. Individuals with Wolman disease treated with hematopoietic stem cell transplantation have shown dramatic improvement of existing symptoms and avoidance of additional complications such as liver failure. Researchers speculate that early diagnosis and prompt treatment with a hematopoietic stem cell transplant increases the chances of preserving liver function and preventing cognitive decline. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for infants with Wolman disease. Hematopoietic stem cell transplants are not without drawbacks. The procedure is expensive and carries the risk of serious complications including graft-versus-host disease and other long-term and late effects.
Researchers have been studying enzyme replacement therapy for lysosomal storage diseases such as Wolman disease. Enzyme replacement therapy involves replacing a missing enzyme in individuals who are deficient or lack the particular enzyme in question. Synthetic versions of missing enzymes have been developed and used to treat individuals with certain lysosomal diseases including Hurler syndrome, Fabry syndrome and Gaucher disease.
In 2010, Synageva BioPharma Corporation received orphan drug designation from the FDA for its program, SBC-102, which is an enzyme replacement therapy to treat Wolman disease. For more information, go to www.synageva.com.
Gene therapy is also being studied as another possible approach to therapy for some lysosomal storage disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a "cure." However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.
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Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3551-3572.
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. 2008;[Epub ahead of print].
Boldrini R, Devito R, Biselli R, Filocamo M, Bosman C. 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.
Krivit W, Peters C, Dusenbery K, et al. Wolman disease successfully treated by bone marrow transplantation Bone Marrow Transplantation. 2000;26:567-570.
Pagani F, Pariyarath R, Garcia R, et al. New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease. J Lipid Res. 1998;39:1382-1388.
FROM THE INTERNET
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Vanier MT. Wolman Disease. Orphanet encyclopedia, January 2007. Available at: www.orpha.net Accessed on: December 29, 2011.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 278000; Last Update: 7/28/10. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=278000 Accessed on: December 29, 2011.
Genetics Home Reference. Wolman Disease. October 2007. Available at: http://ghr.nlm.nih.gov/condition=wolmandisease Accessed On: December 29, 2011.
Report last updated: 2012/01/05 00:00:00 GMT+0