The Wolman's disease It is a rare genetic condition related to an incorrect breakdown and use of fats and cholesterol, that is, an altered lipid metabolism. It is a type of lysosomal acid lipase deficiency.
This disease owes its name to Moshe Wolman, who described in 1956, together with two other doctors, the first case of lysosomal acid lipase (LAL) deficiency. They observed that it was characterized by chronic diarrhea that was related to calcification of the adrenal glands.
However, little by little more aspects of this disease have been discovered: how it manifests itself, what mechanism underlies it, what are its causes, what symptoms it presents, etc. As well as its possible prevention and treatment.
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Generally, patients with this disease have very high levels of lipids that accumulate in the liver, spleen, bone marrow, intestine, lymph nodes, and adrenal glands. It is very common for calcium deposits to form in the latter.
Due to these digestive complications, it is expected that affected children stop gaining weight and their growth seems delayed compared to their age. Life-threatening liver failure can develop as the disease progresses.
Wolman's disease would be a type of lysosomal acid lipase (LAL) deficiency, and it can appear under this name. However, two different clinical conditions have been distinguished within this type:
- Cholesteryl ester storage disease (CESD), which occurs in children and adults.
- Wolman's disease, which is exclusively in childhood patients.
This condition is inherited, with an autosomal recessive pattern that leads to mutations in the LIPA gene..
Specifically, for this disease to occur, each parent must be a carrier of a defective copy of the LIPA gene, the affected person presenting mutations in both copies of the LIPA gene..
In addition, with each pregnancy, parents who have already had a child with Wolman disease have a 25% chance of having another child with the same disease..
The LIPA gene is responsible for giving instructions to facilitate the production of the lysosomal acid lipase (LAL) enzyme, which is located in lysosomes (cellular components that are dedicated to digesting and recycling substances).
When the enzyme works properly, it breaks down cholesterol esters and triglycerides into low-density lipoprotein particles, transforming them into free cholesterol and free fatty acids that our body can reuse..
Therefore, when mutations occur in this gene, the level of lysosomal acid lipase is reduced and therefore different types of fats accumulate within cells and tissues. This leads to serious digestive problems such as poor absorption of nutrients, vomiting and diarrhea..
As the body cannot use lipids to obtain nutrients and energy, a state of malnutrition occurs.
At birth, those affected by Wolman disease are healthy and active; later manifesting the symptoms of the disease. They are usually observed around the first year of life. The most frequent are:
- They do not properly absorb nutrients from food. This leads to severe malnutrition.
- Hepatosplenomegaly: consisting of swelling of the liver and spleen.
- Liver failure.
- Hyperkeratosis: thicker-than-normal outer layer of skin.
- Vomiting, diarrhea, and abdominal pain.
- Ascites.
- Cognitive impairment.
- Delayed development.
- Low muscle tone.
- Low but persistent fever.
- Weight loss or difficulty gaining it.
- Arteriosclerosis.
- Congenital liver fibrosis.
- Multiple lipomas.
- Excessively greasy stools.
- Yellowing of the skin and whites of the eyes (jaundice).
- Anemia (low iron levels in the blood).
- Great physical weakness or cachexia.
It appears in approximately 1 in 350,000 newborns worldwide, although it tends to be underdiagnosed. The prevalence seems to be the same for both female and male sex..
The earliest onset of lysosomal acid lipase (LAL) deficiency is what must be diagnosed as Wolman's disease, appearing in newborns and even before birth.
The later form of LAL deficiency (which can extend into adulthood) is diagnosed as cholesterol ester storage disease (CESD)..
Diagnosis can be made before birth through chorionic villus test (CVS) or amniocentesis. In the first, samples of fetal tissue and enzymes are collected. While, in the second, a sample of the fluid that surrounds the fetus (amniotic fluid) is obtained for later study.
In babies suspected of having this condition, an ultrasound exam may be done to check for calcification of the adrenal glands. This can help the diagnosis since it has been observed that approximately 50% of newborns with this disease have this calcification.
Through blood tests, iron levels and lipid profile status can be checked. If there is Wolman disease, low iron levels (anemia) and hypercholesterolemia will occur.
If a liver biopsy is performed, a bright orange color of the liver, hepatocytes and Kupffer cells flooded with lipids, micro and macrovesicular steatosis, cirrhosis and fibrosis will be observed..
The best tests that can be carried out in this case are genetic tests since the disease can be detected as soon as possible and measures taken. If there are previous cases of this disease in the family, it is advisable to carry out a genetic study to detect the carriers of the possible mutations, since it is possible to be a carrier and not develop the disease.
Wolman's disease is a serious, life-threatening condition. In fact, very few babies reach more than one year of life. The oldest surviving children died at 4 and 11 years of age. Of course, in conditions in which an effective treatment was not established.
As we will see in the next point, in recent years there has been a great advance regarding the treatment.
It is important to note that before 2015 there was no treatment for Wolman disease, so that very few babies reached more than one year of life. Currently, it has been possible to develop an enzyme replacement therapy, through the intravenous administration of alpha sebelipase (also known as Kanuma)..
This therapy has been approved in Europe, the United States and Japan in 2016. It consists of an injection with this substance once a week, with positive results being found in the first six months of life. In cases where the symptoms are not so severe, it will be enough to administer it every two weeks.
However, other drugs that regulate the production of the adrenal glands can be given. In contrast, people who experience CESD are in a less serious situation, being able to improve thanks to a diet low in cholesterol.
Before this drug was approved, the main treatment that newborns received focused on reducing the impact of symptoms and possible complications.
The specific interventions that were carried out consisted of changing the milk for another formula that was very low in fat, or feeding them intravenously, administering antibiotics for possible infections and steroid replacement to compensate for the malfunction of the adrenal glands.
Another option is the so-called hematopoietic stem cell transplant (HSCT), also known as bone marrow transplantation, which is performed mainly to prevent the progression of the disease.
Kivit et al., In 2000 presented the first case of Wolman disease treated successfully with this method. In addition, a long-term follow-up of this patient was performed..
They indicate that thanks to this intervention there was a normalization of the activity of the lysosomal acid lipase enzyme that remained in time. Cholesterol and triglyceride levels remained normal, diarrhea disappeared, and liver function was adequate. The child was 4 years old and was stable and reaching normal development.
However, there are authors who indicate that it increases the risk of serious complications and can even lead to death.
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