Wolman disease

Wolman disease

Wolman Disease (also known as Wolman’s Disease, early onset LAL Deficiency, and LAL Deficiency) is a rare genetic disorder caused by a deficiency of an enzyme known as lysosomal acid lipase (LAL or LIPA). This enzyme is necessary to break down certain lipids inside the cells. Deficiency of the LAL/LIPA enzyme causes a build-up of fat in the liver, gut and other parts of the body.

• Wolman disease belongs to a group of diseases known as Lysosomal Storage Disorders (LSDs).
  
  • Lysosomes function as recycling centers within cells breaking down a number of unwanted materials into substances that the cell can reuse.
    
  • Enzymes are highly specialized proteins within lysosomes that break down or digest particular nutrients, such as certain fats and carbohydrates.
    
  • When these enzymes are defective or missing altogether because of genetic mutations, LSDs develop as a result of abnormal build-up of material in the body's cells.
    
• Wolman disease is the early onset form of LAL Deficiency.
  
  • This form of the disease typically develops during the first few weeks or month of life.
    
  • Late onset form which is known as Cholesteryl ester storage disease (CESD) typically presents later in childhood or even adulthood.
    

Inheritance and Diagnosis

Wolman disease has an autosomal recessive pattern of inheritance.

What causes Wolman Disease? Every person has two copies of the LAL gene (sometimes known as the LIPA gene). One copy is inherited from the father and one from the mother. LAL Deficiency occurs when a person has defects (mutations) in both copies of the LAL gene. Each parent of a patient with LAL deficiency carries one copy of the defective LAL gene. With every pregnancy, parents with a son or daughter affected by LAL Deficiency have a 1 in 4 (25%) chance of having another affected child. A person born with defects in both LAL genes is not able to produce adequate amounts of the LAL enzyme.
Lysosomes function as recycling centers within cells breaking down unwanted materials into substances that the cells can reuse. The LAL enzyme is responsible for the breakdown of specific fats within the lysosomes. When the lysosome does not have enough LAL enzyme, it is unable to breakdown these fats.
How common is Wolman Disease? Like many rare diseases, Wolman disease may go undiagnosed or misdiagnosed which means that there is not much information in the medical literature about how common this condition is. Wolman disease affects males and females in equal numbers. In one report, 8 cases of Wolman disease were identified out more than 4.2 million births over the 16-year period. This translates to an incidence around 1 case per 500,000 live births. For a country the size of the United States, this means there may be 8 babies with Wolman disease born each year.
Are there any specific populations that get Wolman disease more frequently than others? Because Wolman disease is autosomal recessive, it is expected to occur at higher frequencies in certain populations where marriages between genetically related individuals occur (consanguinity). A higher frequency of an abnormal LAL gene has been recently described in the Iranian-Jewish population.

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 detailed 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 may also be made by confirming that there are mutations (defects) in both copies of the LIPA gene.
• 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.

Symptoms

The signs and symptoms of Wolman disease usually appear shortly after birth, typically in the first few weeks of life. Affected infants may have the following:

• Feeding difficulties with frequent vomiting
  
• Diarrhea (loose frequent stools)
  
• Swelling of the abdomen (abdominal distention)
  
• Enlargement of the liver (hepatosplenomegaly) and spleen (splenomegaly)
  
• Failure to gain weight or sometimes weight loss
  

The accumulation of fat in the walls of the gut in Wolman disease leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food. The malabsorption associated with Wolman disease is often accompanied by persistent and often forceful vomiting, frequent diarrhea, foul-smelling and fatty stools (steatorrhea). Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age (failure to thrive).
As the disease progresses, increasing fat accumulation in the liver leads to other complications including yellowing of the skin and whites of the eyes (jaundice), and a persistent low-grade fever.

A distinct finding associated with Wolman disease is the accumulation of chalky material (calcification) in the adrenal gland.

• The adrenal glands are located on top of the kidneys and produce hormones (chemicals that help regulate various functions in the body).
  
• Calcification of the adrenal glands is not detectable by physical examination, but can be seen with an X-ray, CT scan or other imaging investigations.
  
• This finding is very useful in helping make a diagnosis as there are very few other conditions that cause vomiting, failure to gain weight and adrenal calcification.
  
• Not all cases of Wolman disease show this finding and diagnosis in these cases is more difficult and often delayed.
  
• 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.
  
• It has not been definitely established in Wolman disease that the adrenal calcification causes abnormalities in adrenal function.
  

The complications of Wolman disease progress over time, eventually leading to life-threatening problems such as extremely low levels of circulating red blood cells (severe anemia), liver dysfunction or failure, and physical wasting (cachexia). Very few infants with Wolman disease survive beyond the first year of life.

Prognosis

There are currently no approved treatments for Wolman disease and no treatments have been shown in clinical trials to stop or reverse the abnormalities in patients with Wolman disease.
Treatment is mainly focused on reducing specific complications and these complications may differ between patients. Treatment is often provided in specialized centers and may require input from a team of different specialists. Genetic counseling may be of benefit for affected individuals and their families. Specific interventions may include:

• A change from breast or normal bottle formula to a specialized low fat formula
  
• Introduction of intravenous feeding (parenteral nutrition)
• Antibiotics for infections
• Steroid replacement therapy because of concerns about adrenal function

Investigational Therapies
Some children with Wolman Disease have had an experimental therapy called hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, to try to prevent the disease from getting worse.

• 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.
• Stem cell replacement, which requires the child to be hospitalized and treated with very strong medicines before and after the procedure, has its own significant risks and potential benefits
  • 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 improvement of existing symptoms and avoidance of additional complications such as liver failure.
  • HCST for Wolmans disease at present is associated with a high risk of serious complications including death, graft-versus-host disease and other long-term and late effects.
  • More research is necessary to determine the long-term safety and effectiveness of this potential therapy for infants with Wolman disease
    

Researchers are currently studying enzyme replacement therapy for LSDs 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 successfully treat individuals with other LSDs including Fabry disease and Gaucher disease.

Gene therapy is also being studied as another possible approach to therapy for some LSDs. 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.

Synageva BioPharma Corp. of Lexington, Massachusetts, is developing a treatment for Wolman Disease, the early onset form of LAL Deficiency.

Eponym

Wolman disease is named after Moshe Wolman.

External links

• LSD clinical trials
• Synageva BioPharma Corp.
• National Organization for Rare Disorders (NORD)
• Hide & Seek Foundation For Lysosomal Disease Research