Wolman disease

Wolman disease is an inherited genetic disorder caused by a mutation in the LIPA gene. The disease affects the breakdown and use of fats and cholesterol in the body and belongs to a family of disorders called lipid storage disorders. In affected individuals, harmful amounts of lipids accumulate in the spleen, liver, bone marrow, small intestine, adrenal glands, and lymph nodes. In addition to fat deposits, calcium deposits in the adrenal glands are also seen.

Location of LIPA gene. Source: NIH

Other Names

• Acid Lipase Deficiency
• Familial Xanthomatosis
• LAL Deficiency
• LIPA Deficiency
• Liposomal Acid Lipase Deficiency, Wolman Type
• Lysosomal Acid Lipase Deficiency

Signs and Symptoms

Infants with Wolman disease are healthy and active at birth but soon develop signs and symptoms of the disorder. These may include:

• Enlarged liver and spleen (hepatosplenomegaly)
• Poor weight gain
• Low muscle tone
• Jaundice (a yellow tint to the skin and the whites of the eyes
• Vomiting
• Diarrhea
• Developmental delays
• Anemia (low amounts of iron in the blood)
• Poor absorption of nutrients from food.

Children affected by this condition develop severe malnutrition and generally do not survive past early childhood.

Causes

Wolman disease is caused by mutations in the LIPA gene. The LIPA gene encodes for an enzyme called lysosomal acid lipase, which is found in the lysosomes (intracellular structures that digest and recycle substances) and breaks down fats such as cholesteryl esters and triglycerides so they can be used by the body. A wide range of mutations leading to defective enzyme activity have been identified.^[1]

A shortage of lysosomal acid lipase leads to the accumulation of triglycerides, cholesteryl esters, and other fats within the cells of affected individuals. This accumulation as well as malnutrition caused by the body's inability to use lipids properly result in the signs and symptoms of Wolman disease.

LIPA mutations can also cause cholesteryl ester storage disease, which is diagnosed later in life and is usually much more benign (less harmful) than Wolman disease.

Diagnosis

X-ray findings characteristic of Wolman disease include a characteristic pattern of calcification (outlining the outline of the cortex of both glands) in enlarged but normally shaped adrenal glands.

Computed tomography (CT) scan and Magnetic Resonance Imaging (MRI) show enlargement of the liver and spleen, calcification of both adrenal glands and lymphadenopathy (enlarged lymph nodes).

The definitive diagnosis of Wolman's disease is made by demonstration of deficient lysosomal acid lipase activity in leukocytes (white blood cells) or fibroblasts (cells that manufacture the supporting matrix of the cell.)

Amniocentesis can be performed for the prenatal diagnosis of Wolman disease.

Treatment

There is currently no cure for Wolman disease, so treatment focuses on management of the symptoms. If the adrenal gland is not making enough hormones and steroids, replacement steroids and hormones can be given. Nutrition can be given intravenously to decrease the risk of failure to thrive.

Bone marrow and cord blood transplantion are currently being tested in humans as treatments for Wolman disease. Researchers are also studying ways for replacing the deficient enzyme through gene therapy in animal models.

Chances of Developing Wolman disease

Wolman disease is estimated to occur in 1 in 350,000 newborns. ^[2] The disease is inherited in an autosomal recessive pattern, meaning that defective copies of the LIPA gene must be inherited from both parents for the disease to be present. The appearance of an affected infant identifies both parents as carriers of the defective gene and increases the chance that subsequent children will have the disease to 25%.

Clinical Trials

A clinical trial involving stem cell transplantation for inborn errors of metabolism, such as Wolman disease, is currently recruiting participants. Information is available at ClinicalTrials.gov: Wolman disease trial

Research

Recent discoveries

• The use of plant-produced human lysosomal lipase was shown to be a promising therapy for Wolman disease in mice. ^[3]
• The first successful umbilical cord stem cell transplant was recently reported. The procedure can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.^[4]

Current research

• The pulmonary complications of pediatric patients with storage disorders such as Wolman disease are being studied. ^[5]

Expected Outcome

Infants with Wolman disease usually die during the first year of life. Death is often due to complications of malnourishment and deficiency of adrenal function.

History

Etymology

Wolman disease was named for an Israeli neuropathologist, Moshe Wolman, born in 1914.

References

1. ↑ Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999 Nov;68(3):333-45. Abstract
2. ↑ Genetics Home Reference. Wolman disease
3. ↑ Du H, Cameron TL, Garger SJ. Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice. J Lipid Res. 2008 Aug;49(8):1646-57. Epub 2008 Apr 15. Abstract
4. ↑ Stein J, Garty BZ, Dror Y, Fenig E, Ziegler M, Yaniv I. Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation. Eur J Pediatr. 2007 Jul;166(7):663-6. Epub 2006 Oct 11. Abstract
5. ↑ ClinicalTrials.gov. Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

External Links

Cincinnati Children's Hospital Medical Center: Cincinnati STAR Center for Lysosomal Diseases

Madisons Foundation: Information and support for parents of children with rare and life-threatening diseases.