Wolman Disease

Wolman Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Wolman Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Acid Cholesteryl Ester Hydrolase Deficiency, Wolman Type
  • Lysosomal Acid Lipase Deficiency, Wolman Type

Disorder Subdivisions

  • None

General Discussion

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.

Symptoms

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).

Causes

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.

Affected Populations

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.

Standard Therapies

Diagnosis

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.



Treatment

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.

Investigational Therapies

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.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

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.



JOURNAL ARTICLES

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

Scheinfeld NS. Lysosomal Storage Disease. Emedicine Journal, Dec 5, 2011. Available at: http://www.emedicine.com/neuro/topic668.htm Accessed on: Dec 29, 2011.



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.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



Vaincre Les Maladies Lysosomales

2 Ter Avenue

Massy, 91300

France

Tel: 0169754030

Fax: 0160111583

Email: accueil@vml-asso.org

Internet: http://www.vml-asso.org



National Tay-Sachs and Allied Diseases Association, Inc.

2001 Beacon Street

204

Brookline, MA 02146-4227

USA

Tel: (617)277-4463

Fax: (617)277-0134

Tel: (800)906-8723

Email: info@ntsad.org

Internet: http://www.NTSAD.org



March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



Children's Liver Disease Foundation

36 Great Charles Street

Birmingham, B3 3JY

United Kingdom

Tel: 01212123839

Fax: 01212124300

Email: info@childliverdisease.org

Internet: http://www.childliverdisease.org



Lysosomal Diseases New Zealand

16 Woodleigh Place

Ohauiti

Tauranga, 6008

New Zealand

Tel: 075448868

Email: jenny.noble@xtra.co.nz

Internet: http://www.ldnz.org.nz



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



LAL Solace, Inc.

191 Barnstable Court

Harvest, AL 35749

Tel: (256)425-2638

Email: lalsolace@gmail.com

Internet: http://www.lalsolace.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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