Gaucher disease: symptoms, causes and types

Lysosomal storage diseases are associated with impaired function of certain enzymes, which causes lipid and protein to accumulate in cells.

In this article we will analyze symptoms, causes and the three types of Gaucher disease, the most frequent of the disorders of this class, which affects multiple functions of the organism.

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What is Gaucher disease?

Gaucher disease is a disorder caused by genetic mutations that are transmitted by autosomal recessive inheritance. It affects the blood, brain, spinal cord, bones, liver, spleen, kidneys and lungs, and severe forms of the disorder cause death or significantly reduce life expectancy.

It was described by Philippe Gaucher, a French doctor specializing in dermatology, in 1882. Gaucher initially believed that the symptoms and signs were manifestations of a specific class of spleen cancer; it was not until 1965 that the true underlying causes, related to biochemical and nonimmunological aspects, were identified.

Gaucher disease belongs to a group of disorders that are known as “lysosomal storage diseases” or “lysosomal storage diseases”, related to a deficit in the function of enzymes. It is one of the most common of this group, since it occurs in approximately 1 in 40,000 births.

The prognosis of this disease depends on which of the three existing variants we refer to. Type 1, the most common in the West, can be managed by enzyme replacement therapies and reduction of the concentration of the accumulated substances that cause the pathology, while the neurological signs of types 2 and 3 are not treatable.

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Main symptoms and signs

Gaucher disease causes changes in many different organs and tissues, as well as in the blood; this explains the appearance of signs of a varied character. A fundamental criterion when determining the severity of the disease is the presence or absence of neurological damage, which is life-threatening and significantly interferes with development.

Among the most common symptoms and signs and remarkable of Gaucher disease we find the following:

• Enlarged liver and spleen (hepatosplenomegaly) causing swelling of the abdomen
• Bone and joint pain, arthritis, osteoporosis, and increased frequency of bone fractures
• Anemia (decreased number of red blood cells) causing fatigue, dizziness, or headache
• Increased ease with which you bruise and bleed
• Increased risk of developing diseases in the lungs and other organs
• Yellowish or brownish pigmentation of the skin
• Brain injuries, impaired brain development, apraxia, seizures, muscle hypertonia, abnormal eye movements, apnea, olfactory deficits (if there are neurological abnormalities)

Causes and pathophysiology

Gaucher disease appears as a consequence of a deficiency in the enzyme glucocerebrosidase, which is located in the membranes of lysosomes (cellular organelles that contain a large number of enzymes) and has the function of breaking down fatty acids of the glucocerebroside class, as well as other types different.

Alterations in the function of glucocerebrosidase make it impossible to adequately eliminate certain substances in the lysosomes. Consequently they accumulate in the body, giving rise to the symptoms of Gaucher disease. There are other disorders with similar causes, such as Tay-Sachs disease, Hunter disease, or Pompe disease.

In the case of Gaucher disease, these alterations are due to a genetic mutation that is transmitted by autosomal recessive inheritance. Therefore, for it to affect a person, they must have inherited the genetic defect from both their father and their mother; if both parents present it, the risk of suffering from the disease is 25%.

The mutation causing the symptoms varies depending on the variant of Gaucher disease, but is always associated with the beta-glucosidase gene, which is located on chromosome 1. Approximately 80 different mutations have been found and have been grouped into three categories; We will dedicate the following section to these.

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Types of Gaucher disease

In general, Gaucher disease is divided into three types depending on the severity of the neurological alterations: type 1 or non-neuropathic, type 2 or childhood acute neuropathic and type 3 chronic neuropathic.

It is important to highlight that the validity of this categorization has been questioned and accused of reductionism by various experts.

1. Type 1 (non-neuropathic)

Type 1 is the most common variant of Gaucher disease in Europe and the United States; in fact, approximately 95% of the cases detected in these regions fall into this category. The term "non-neuropathic" refers to the absence or mild central nervous system involvement.

In people with type 1 Gaucher disease, no alterations in brain development are observed, unlike what happens in types 2 and 3. The most notable symptoms include a feeling of fatigue, an enlarged spleen and liver, and bone-related problems.

2. Type 2 (infantile acute neuropathic)

Childhood acute neuropathic Gaucher disease is the most severe form of the disorder. Causes irreversible brain damage and neurological abnormalities, including brainstem malformation, for which there is currently no treatment, and usually causes the death of the affected infant before the age of 2.

3. Type 3 (chronic neuropathic)

Although the chronic neuropathic type is rare in Western countries, it is the most common variant in the rest of the world. The severity of type 3 falls somewhere between those of types 1 and 2: causes class 1 symptoms but also some neurological disorders, and reduces life expectancy to less than 50 years.