1. BioWolman - Biomarker for Wolman disease

BioWolman - Biomarker for Wolman disease

Clinical trial started on March 09, 2015


Wolman disease is a rare genetic disorder characterized by the complete absence of an enzyme known as lysosomal acid lipase (LIPA or LAL). This enzyme is required to breakdown (metabolize) lipids in the body. Without the LIPA enzyme, lipids 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 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.

New methods, like such as mass-spectrometry, provide give a good chance to characterize specific metabolic alterations in the blood (plasma) of affected patients that in the future will allow us to diagnose diagnosing in the future the disease earlier, with a higher sensitivity and specificity.

Therefore it is the goal of thise study to identify and validate a new biochemical marker from the plasma of the affected patients, helping to benefit other patients by with an early diagnossise and thereby with an earlier treatment. Examining saliva samples will allow us to determineing whether measurement is feasible in saliva samples and will further promote early detection of Wolman disease.

Background information

Wolman disease is the most severe expression of LIPA deficiency. Milder forms of the disorder are known as cholesteryl ester storage deficiency. The symptoms of Wolman disease usually become apparent shortly after birth, most often during the first few weeks of life. Affected infants may develop bloating or abdominal distention and may have significant hepatosplenomegaly. 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 from 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).

Hepatosplenomegaly 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 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 in x-rays. 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 become progressively worse, eventually leading to life-threatening complications during infancy including extremely low levels of circulating red blood cells (severe anemia), 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.

The LIPA gene contains instructions for producing the enzyme lysosomal lipase acid. This enzyme is essential for 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 the 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 the 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.

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 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 hepatosplenomegaly. The different types of Niemann-Pick disease are inherited as autosomal recessive traits.

Chanarin Dorfman syndrome is a rare genetic disorder of fat (lipid) metabolism. It is characterized by ichthyosis, myopathy, and abnormal white blood cells with small spaces (vacuoles) filled with lipids. Additional symptoms may occur, including hearing loss, vision abnormalities, 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.

There are several types of metabolic disorders in which there is secondary accumulation of certain triglycerides in the body. These disorders include galactosemia, fructose intolerance, and specific disorders of amino acid metabolism.