WOLMAN DISEASE: SYMPTOMS, CAUSES, TREATMENT - NEUROPSYCHOLOGY - 2024

The Wolman disease is a rare genetic condition associated with improper decomposition 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 associated with calcification of the adrenal glands.

Moshe wolman

However, little by little more aspects of this disease have been discovered: how it manifests itself, what mechanism underlies it, what its causes are, what symptoms it presents, etc. As well as its possible prevention and treatment.

Characteristics of Wolman disease

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 the latter to form calcium deposits.

Due to these digestive complications, it is expected that affected children stop gaining weight and their growth seems delayed compared to their age. As the disease progresses, life-threatening liver failure can develop.

Classification

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 child patients.

Causes

This condition is hereditary, 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.

Additionally, 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 enzyme lysosomal acid lipase (LAL), which is located in lysosomes (cellular components that are dedicated to digesting and recycling substances).

When the enzyme works properly, it breaks down cholesterol and triglyceride esters into low-density lipoprotein particles, transforming them into free cholesterol and free fatty acids that our bodies 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 for nutrients and energy, a state of malnutrition occurs.

Symptoms

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 causes severe malnutrition.

- Hepatosplenomegaly: consisting of swelling of the liver and spleen.

- Liver failure.

- Hyperkeratosis: outer layer of the skin thicker than normal.

- 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.

- Yellowish skin and whites of the eyes (jaundice).

- Anemia (low levels of iron in the blood).

- Great physical weakness or cachexia.

Prevalence

It appears in approximately 1 in 350,000 newborns worldwide, although it tends to be underdiagnosed. The prevalence appears to be the same for both male and female sex.

Diagnosis

The earliest onset of lysosomal acid lipase (LAL) deficiency is what must be diagnosed as Wolman 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 aid in the diagnosis since it has been observed that approximately 50% of newborns who have 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 you do a liver biopsy, you will see a bright orange color of the liver, hepatocytes and Kupffer cells flooded with lipids, micro and macrovesicular steatosis, cirrhosis and fibrosis.

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 one can be a carrier and not develop the disease.

Forecast

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 where an effective treatment was not established.

As we will see in the next point, in recent years there has been a great advance regarding treatment.

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 replacement of steroids to compensate for the malfunction of the adrenal glands.

Hematopoietic stem cell transplantation

Another option is a so-called hematopoietic stem cell transplant (HSCT), also known as bone marrow transplantation, which is performed mainly to prevent the disease from progressing.

Kivit et al., In 2000 presented the first case of Wolman disease treated successfully with this method. Furthermore, 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.

References

1. Hoffman, EP, Barr, ML, Giovanni, MA, et al. Lysosomal Acid Lipase Deficiency. 2015 Jul 30. In: Pagon RA, Adam MP, Ardinger HH, et al., Editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2016.
2. Krivit, W., Peters, C., Dusenbery, K., Ben-Yoseph, Y., Ramsay, NK, Wagner, JE, & Anderson, R. (2000). Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplantation, 26 (5), 567-570.
3. Lysosomal acid lipase deficiency. (2016, June 3). Obtained from Wikipedia.
4. NINDS Acid Lipase Disease Information Page. (February 23, 2016). Obtained from National Institute of Neurological Disorders and Stroke.
5. 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.
6. Wolman disease. (2016, June 2). Obtained from Genetic and Rare Diseases (GARD) Information Center.
7. Wolman Disease. (2016, June 7). Obtained from Genetics Home Reference.
8. Wolman Disease. (2015). Obtained from National Organization for Rare Disorders.