The Wolman's disease Owes its name to Moshe Wolman , Who described in 1956, together with two other doctors, The first case of lysosomal acid lipase deficiency (LAL). They observed that it was characterized by chronic diarrhea that was related to the calcification of the adrenal glands (Krivit et al., 2000).
However, more and more aspects of this disease have gradually been discovered: how it manifests itself, what mechanism underlies it, what its causes are, what symptoms it presents, and so on. As well as its possible prevention and treatment.
Characteristics of Wolman's disease
This disease, which has been classified as a type of lysosomal acid lipase deficiency, is a rare genetic condition related to an incorrect decomposition and use of fats and cholesterol, ie an altered lipid metabolism.
Generally, subjects suffering from this disease have very high levels of Lipids Which accumulate in the liver, spleen, bone marrow, intestine, lymph nodes and adrenal glands. It is very common that calcium deposits arise in the latter.
Because of these digestive complications, it is to be expected that the affected children stop gaining weight and their growth seems delayed with respect to the age they have. As the disease progresses, it can occur liver failure Which endangers the life of the person.
Classification
Wolman's disease would be a type of lysosomal acid lipase deficiency (LAL), and may appear under this name. However, two different clinical conditions have been distinguished:
- Cholesteryl ester storage disease (CESD), which occurs in children and adults.
- Wolman's disease, which is exclusively for children.
Causes
This condition is inherited, with an autosomal recessive pattern that results in 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, presenting the affected mutations in both copies of the LIPA gene.
In addition, with each pregnancy, parents who have already had a child with Wolman's 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 enzyme lysosomal acid lipase (LAL), which is located in the Lysosomes (Cellular components that are dedicated to digesting and recycling substances).
When the enzyme functions properly, it breaks down the cholesterol and triglyceride esters into Lipoproteins Of low density, transforming into free cholesterol and free fatty acids that our body can reuse (Hoffman et al., 2015) (Reiner et al., 2014).
Therefore, when mutations occur in this gene, the level of lysosomal acid lipase is reduced and therefore different types of fats are accumulated within the cells and tissues. This leads to severe digestive problems such as malabsorption of nutrients, vomiting and diarrhea.
Since the body can not use lipids to obtain nutrients and energy, there is a Malnutrition .
symptom
At birth, those affected by Wolman's disease are healthy and active; The symptoms of the disease being manifested later. They are usually observed over the first year of life. The most frequent are:
- Do not properly absorb nutrients from food. This causes severe malnutrition.
- Hepatosplenomegaly : Which consists of swelling of the liver and spleen.
- Liver failure.
- Hyperkeratosis : Outer layer of skin thicker than normal.
- Vomiting, diarrhea and abdominal pain.
- Ascites .
- Cognitive impairment .
- Development delayed.
- Low muscle tone.
- Low but persistent fever.
- Weight loss or difficulty gaining it.
- Arteriosclerosis .
- Congenital hepatic fibrosis.
- Multiple lipomas.
- Excessively greasy stool.
- Skin and whites of yellowish-colored eyes ( jaundice ).
- Anemia (Low levels of iron in blood).
- Great physical or Cachexia .
Prevalence
Approximately it appears in 1 of 350,000 newborns worldwide, although it tends to underdiagnose. Prevalence appears to be the same for both the female and the male sex.
Diagnosis
The earliest occurrence of lysosomal acid lipase (LAL) deficiency is to be diagnosed as Wolman's disease, appearing in newborns and even before birth.
The later form of LAL deficiency (which may extend into adulthood) is diagnosed as cholesterol ester storage disease (CESD).
Diagnosis can be made before birth through the chorionic villus test (CVS) or a amniocentesis . In the first, samples of fetal tissue and enzymes are collected. While in the second, a sample of the fluid surrounding the fetus (amniotic fluid) is obtained for further study.
In infants in whom this condition is suspected, an ultrasound examination may be done to check the calcification of the adrenal glands. This may help the diagnosis since it has been observed that approximately 50% of the newborns who have this disease present such calcification.
Through blood tests, iron levels and the status of the lipid profile can be checked. If Wolman's disease is present, low iron levels (anemia) and Hypercholesterolemia .
If a liver biopsy is performed, a bright and orange color of the liver will be observed, Hepatocytes Y Kupffer cells Lipid-flooded, micro and macrovesicular steatosis, cirrhosis and fibrosis (Reiner et al., 2014).
The best tests that can be done in this case, are the genetic tests that can detect the disease as soon as possible and take action. 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 they can be carriers and do not develop the disease.
Forecast
Wolman's disease is a serious condition, which endangers the life of the affected person. In fact, very few babies reach more than one year of life. The children who survived the most years died at 4 and 11 years of age. Of course, under conditions in which no effective treatment was established.
As we will see in the next point, in recent years there has been a breakthrough with respect to treatment.
Treatment
It is important to note that before 2015 there was no treatment for Wolman's disease, so that very few babies were older than one year. Enzyme replacement therapy has now been developed 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, finding positive results in the first six months of life. In cases where the symptoms are not so severe, it will be sufficient to administer it every two weeks.
However, other drugs that regulate the production of Kidney glands . In contrast, people experiencing CESD are in a less severe situation, Diet low in cholesterol.
Before the drug was approved, the main treatment for newborns was focused on reducing the impact of symptoms and possible complications.
The specific interventions that were performed were to change the milk by another formula that was very low in fat, or to feed them by intravenous route, to administer antibiotics for the possible infections and replacement of Steroids To compensate for malfunctioning of the adrenal glands.
Another option is the so-called hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation, which is performed primarily to prevent disease progression.
Kivit et al., In 2000 presented the first case of Wolman disease successfully treated with this method. In addition, 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 the time. Cholesterol and triglyceride levels remained normal, diarrhea disappeared and hepatic 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 may even lead to death (Reiner et al., 2014).
References
- Hoffman, E.P., Barr, M.L., Giovanni, M.A., et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30. In: Pagon R.A., Adam M.P., Ardinger H.H., et al., Editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
- Krivit, W., Peters, C., Dusenbery, K., Ben-Yoseph, Y., Ramsay, N.K., Wagner, J.E., & Anderson, R. (2000). Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplantation, 26 (5), 567-570.
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- NINDS Acid Lipase Disease Information Page. (February 23, 2016). Retrieved from the National Institute of Neurological Disorders and Stroke.
- Reiner, Ž., Guardamagna, O., Nair, D., Soran, H., Hovingh, K., Bertolini, S., &... Ros, E. (2014). Review: Lysosomal acid lipase deficiency - An under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis, 23521-30.
- Wolman disease. (June 2, 2016). Retrieved from Genetic and Rare Diseases (GARD) Information Center.
- Wolman Disease. (June 7, 2016). Retrieved from the Genetics Home Reference.
- Wolman Disease. (2015). Retrieved from the National Organization for Rare Disorders.