Wolman's disease: what is it, symptoms, treatment, prognosis

What is Wolman's disease?

Wolman's disease (or Wolman's syndrome) Is a type of lysosomal acid lipase deficiency (LALL); a rare genetic disorder characterized by the complete absence of an enzyme known as lysosomal acid lipase (LAL). This enzyme is required for the breakdown (metabolism) of certain fats (lipids) in the body. Without the LAL enzyme, some fats can accumulate in the tissues and organs of the body, causing various symptoms. Wolman's disease can cause bloating or swelling of the stomach, vomiting, and significant enlargement of the liver or spleen (hepatosplenomegaly). Life-threatening complications often develop in early childhood. Wolman's disease is caused by mutations in the gene for lysosomal acid lipase (gene LIPA) and is inherited as an autosomal recessive trait.

Wolman's disease is the most serious manifestation of LAL deficiency; a milder form of LAL deficiency is known as cholesterol ester storage disease. (See section "Symptoms Related to Diseases" in this article). Gene mutations 

LIPAcausing cholesterol ester storage disease, lead to some enzymatic activity, while gene mutations LIPAthat cause Wolman's disease produce an enzyme with no residual activity or no enzyme at all. Genetic and biochemical data indicate that cholesterol ester storage disease and Wolman's disease are characterized by residual lysosomal acid lipase activity.

Signs and symptoms

Wolman's disease symptoms usually appear shortly after birth, usually within the first few weeks of life. Affected infants may develop bloating or swelling of the stomach, and there may also be a significant increase in the liver and spleen (hepatosplenomegaly). Liver scarring may also occur (liver fibrosis). In some cases, fluid may accumulate in the peritoneum (abdominal ascites).

Babies with Wolman disease have severe digestive problems, including intestinal malabsorption - a condition in which the intestines cannot absorb nutrients and calories from food. Malabsorption associated with Wolman's disease causes persistent and often violent vomiting, frequent diarrhea, foul odor, fatty stools (steatorrhea), and malnutrition. Because of these digestive complications, sick babies usually cannot grow and gain weight at the expected rate for their age and gender (inability to develop).

Enlargement of the liver and spleen, as well as protrusion of the abdomen, can cause an umbilical hernia - a condition when where stomach contents can push through a small opening or tear in the abdominal wall next to navel. Additional symptoms may also occur with Wolmann's disease, including yellowing of the skin, mucous membranes, and whites of the eyes (jaundice), persistent low-grade fever and poor muscle tone (hypotension). Babies may have a delay in motor development.

A hallmark associated with Wolman's disease is adrenal tissue hardening due to calcium build-up (calcification). Adrenal glands are located above the kidneys and secrete two hormones called adrenaline and norepinephrine. Other hormones produced by the adrenal glands help regulate fluid and electrolyte balance in the body. Adrenal calcification is not detectable on physical examination, but can be detected on x-ray. Calcification can prevent the adrenal glands from producing enough essential hormones and can affect metabolism, blood pressure, immune system and other vital processes in the body.

Babies with Wolman's disease may experience a loss of previously acquired skills needed to coordinate muscles and motor skills (psychomotor regression). The symptoms of Wolman's disease often progressively worsen, ultimately leading to dangerous life-threatening complications in infancy, including extremely low levels of circulating red blood cells (heavy anemia), liver dysfunction or failure (liver failure), as well as physical exhaustion and severe weakness, often associated with a chronic illness characterized by loss of weight and muscle mass (cachexia or wasting).

Causes

Wolman's disease is caused by mutations in the gene for lysosomal acid lipase (gene LIPA). Gene LIPA Contains instructions for the production of the enzyme lysosomal acid lipase (LAL). This enzyme is required for the breakdown (metabolism) of certain fats in the body, especially cholesterol (especially cholesterol esters) and, to a lesser extent, triglycerides. Without proper levels of this enzyme, these fats accumulate abnormally in various tissues and organs of the body and damage them. Gene mutations LIPAthat cause Wolman's disease, lead to a lack of production of the LAL enzyme or the production of a defective inactive form of the LAL enzyme.

Recessive genetic disorders occur when a person inherits two copies of an altered gene for the same trait, one from each parent. If a person inherits one normal gene and one gene for the disease, they will carry the disease but are usually asymptomatic. The risk for two carrier parents of passing on the altered gene and having a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents is 25%. The risk is the same for men and women.

Parents who are close relatives (blood relatives) have a higher chance than unrelated parents parents who have the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.

Affected populations

Wolman's disease is an extremely rare disease that affects men and women equally. More than 50 cases have been described in the medical literature. However, cases of the disease can go undiagnosed or misdiagnosed, making it difficult to determine the true incidence of the disorder in the general population. Wolman's disease is named after one of the doctors who first identified the disease in the medical literature in 1956.

Diseases similar in symptoms

Symptoms of the following conditions may be similar to those of Wolman's disease. Comparisons can be useful for differential diagnosis.

• Cholesterol ester storage disease (BNEC) is a type of lysosomal acid lipase deficiency (LAL); a rare genetic disease characterized by a deficiency of the LAL enzyme. This enzyme is required for the hydrolysis of triglycerides and cholesterol esters in lysosomes. LAL enzyme deficiency causes the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) in the cells of many body tissues, potentially causing many symptoms. This results in an abnormal enlargement of the liver (hepatomegaly) due to hepatic steatosis and fibrosis, which can lead to micronodular cirrhosis of the liver. Some patients may only be diagnosed with BNEC in adulthood. Cholesterol ester storage disease is caused by mutations in the lysosomal acid lipase (LIPA) gene and is inherited in an autosomal recessive manner.
• Niemann-Pick disease (BNP) is a group of rare hereditary disorders of fat metabolism. At least five types of Niemann-Pick disease (types A, B, C, D, and E) have been identified. Symptoms of types A and B result from a deficiency of the enzyme acid sphingomyelinase, which is required to break down sphingomyelin, a fatty substance found mainly in the brain and nerves system. This deficiency results in an abnormal accumulation of excessive amounts of sphingomyelin in many organs of the body, such as liver, spleen and the brain. Symptoms of type C BNP arise from impaired movement of large molecules within cells, resulting in accumulation of excessive amounts of cholesterol and other lipids (glycosphingolipids) in tissues throughout body. A metabolic disorder of type C can lead to a secondary decrease in the activity of acid sphingomyelinase in some cells. Symptoms common to all types of BNP include yellow discoloration of the skin, eyes and / or mucous membranes (jaundice), progressive loss of motor skills, difficulty feeding, learning disabilities, and abnormally enlarged liver and / or spleen (hepatosplenomegaly). Various types of BNP are inherited in an autosomal recessive manner.
• Chanarin-Dorfman syndrome - a rare genetic disorder of fat (lipid) metabolism. It is characterized by scaling of the skin (ichthyosis), muscle degeneration (myopathy), and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids). Additional symptoms may occur, including hearing loss, visual impairment, enlarged liver (hepatomegaly) and a condition in which fat accumulates in the liver (liver steatosis or "fatty" liver infiltration). In some cases, cognitive decline may occur. Chanarin-Dorfman syndrome is inherited in an autosomal recessive manner.

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

Diagnostics

The diagnosis of Wolman's disease can be suspected in newborns based on the detection of characteristic symptoms such as an abnormally enlarged liver and gastrointestinal problems. The diagnosis can be confirmed by careful clinical evaluation, the patient's detailed history (including family history), and special tests that detect the absence or insufficient activity of the enzyme lysosomal acid lipase (LAL) in certain cells and tissues organism. Molecular genetic testing for gene mutations is also available LIPA.

Standard treatments

In December 2015, the US Food and Drug Administration (FDA) approved Kanumu (sebelipase alfa) as the first treatment for patients with lysosomal acid lipase deficiency (DLKL).

Other treatments are aimed at addressing specific symptoms that each person experiences. 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 can be used to replace the hormones normally produced by these glands.

The treatment of patients with Wolman's disease may require a team approach, which may include special social support and other medical services. Genetic counseling is recommended for patients and their families.

Forecast

In the absence of radical therapy, few children survive to one year of age. Enzyme replacement therapy, if started early, can prolong survival, but its long-term consequences remain unknown.