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Gaucher Disease and Genetics

What is Gaucher disease?

Gaucher disease is a rare autosomal recessive (two copies of a mutated gene must be present for the disease to develop) genetic disorder, which is due to a deficit of a lysosomal enzyme called glucocerebrosidase, which causes the storage of complex lipids in different parts of the body, such as the brain or other organs [1].

 

Typologies of Gaucher disease [2]:

  • Non-neuropathic Gaucher disease type 1: does not affect the central nervous system (CNS), but people with this type of disease tend to have low levels of platelets, leading to frequent bruising and fatigue due to anemia. In this case there are patients who have a mild form of the disease and do not show any symptoms. Adults with type 1 Gaucher disease usually have a normal life expectancy under treatment.
  • Acute infantile neuropathic Gaucher disease type 2 affects the CNS very rapidly. Symptoms begin at 3 months of age and are characterized by extensive brain damage, seizures, and poor sucking and swallowing. Life expectancy in children with type 2 Gaucher disease is usually two years.
  • Gaucher disease type 3 chronic neuropathy : also causes CNS damage but very slowly. Patients with this disorder suffer seizures, cognitive deficits, poor coordination and respiratory problems among other consequences.Both types 2 and 3 have a worse prognosis, as they are more aggressive forms of the disease.

 

Enfermedad de Gaucher

 

Symptoms of Gaucher disease

The symptoms of Gaucher disease are very diverse and can appear in early life as well as in adulthood. Among the most prominent are the following:

  • Hepatomegaly: consists of enlargement of the liver due to the accumulation of complex lipids (glucocerebrosides) in liver cells, which may result in a feeling of abdominal fullness and discomfort.
  • Splenomegaly: is the enlargement of the spleen caused by an excess of glucocerebrosides in the spleen cells, causing enlargement and increased tenderness in the abdominal area.
  • Cytopenias: the normal production of blood cells in the bone marrow is affected, which can manifest itself in the form of anemia, which is a decrease in red blood cells; leukopenia or reduction of white blood cells; and thrombocytopenia or a decrease in platelets. All this results in an increased feeling of fatigue, susceptibility to infections and coagulation problems.
  • Bone pain: The accumulation of lipids in the bones can cause bone and joint pain, bone fractures and skeletal deformities.
  • Pulmonary involvement: This disease can affect the lungs, causing respiratory distress and chronic cough.
  • Neurological complications: In types 2 and 3, which are the rarest and most severe types of Gaucher disease, damage to the central nervous system has been seen to occur, manifesting as seizures, cognitive impairment and learning difficulties.

 

World figures

Worldwide the incidence of Gaucher disease is between 1/40,000 and 1/60,000 newborns, being especially prevalent in Ashkenazi Jews, since in this population 1 out of every 800 births suffers from this disease [1]. The higher incidence in this population is explained by the genetic inheritance of this group. Ashkenazi Jews (Ashkenazi) are a Jewish ethnic subgroup originating from Eastern Europe, who throughout history have migrated to various countries (diaspora). As a result, this population has experienced a founder effect, a genetic phenomenon that occurs when a small, isolated population expands from a limited number of ancestors. In this process, certain genetic mutations may become more common due to the lack of genetic diversity of the founders and inbreeding within the community.

In the case of Gaucher disease, a specific mutation, known as N370S, is believed to have originated in the Ashkenazi Jewish population and has been passed down through the generations [4].

As mentioned above, there are 3 types of this disease, with type 1 being the most prevalent, accounting for more than 90% of cases in the Western world, and characterized by visceral damage. While type 2 and type 3 are present in less than 10% of patients with Gaucher disease and are related to neurological damage.

 

Enfermedad de gaucher niños

 

Causes and/or risk factors of Gaucher disease.

It is a monogenic disease caused by mutations in GBA1, which means that it is caused by mutations in a single gene. In addition, carriers of a mutated copy of the gene are more predisposed to develop Parkinson’s and dementia with Lewy bodies [1], the second most common cause of degenerative dementia in older people, only behind  Alzheimer.

 

Treatment of Gaucher disease

Treatment is currently based on intravenous enzyme replacement therapy, which consists of the administration of specific enzymes every two weeks to supplement the deficient or absent enzymes in the patient’s body. This treatment is very effective for types 1 and 3, as it reduces the size of the liver and spleen and reduces skeletal abnormalities [2].

Blood transfusions are also performed with some frequency to treat the anemia caused by this disorder, while some patients require joint replacement surgery to improve mobility and quality of life. On the other hand, on rare occasions, partial or total removal of the spleen is performed to prevent fat accumulation in this organ [3].

However, there is still no treatment that is effective when severe brain damage occurs in types 2 and 3 of this disease and life expectancy in these cases is lower than in type 1.

 

24Genetics and Gaucher disease

As it is a monogenic disease, it is important to detect mutations in the GBA1 gene, since, if two mutated copies of this gene are present, it can be stated that this person has the disease. It is also important to know if a single copy of the mutated gene is present, since it can be transmitted to offspring and, if both parents are carriers of a mutation in the GBA1 gene, there is a 25% chance that they will have a child with this pathology.

It is essential to have a genetic test that analyzes this gene to know if the offspring can inherit this disease. At 24Genetics we have a health test that analyzes the different mutations that the GBA1 gene can present, thus helping the population to know if they suffer from type 1 Gaucher disease.

In addition, our report also analyzes the GBA gene to determine whether there is a greater predisposition to suffer from Parkinson’s disease, since as mentioned above, carriers of a mutated copy of this gene have been linked to the development of this disease.

 

Bibliography

[1] Stirnemann J;Belmatoug N;Camou F;Serratrice C;Froissart R;Caillaud C;Levade T;Astudillo L;Serratrice J;Brassier A;Rose C;Billette de Villemeur T;Berger MG; (no date) A review of Gaucher disease pathophysiology, clinical presentation and treatments, International journal of molecular sciences. Available at: https://pubmed.ncbi.nlm.nih.gov/28218669/. 

[2] Enfermedad de Gaucher (no date) National Institute of Neurological Disorders and Stroke. Available at: https://espanol.ninds.nih.gov/es/trastornos/enfermedad-de-gaucher. 

[3] Enfermedad de Gaucher (no date a) Genetic and Rare Diseases Information Center. Available at: https://rarediseases.info.nih.gov/espanol/13400/enfermedad-de-gaucher. 

[4] Diaz GA, Gelb BD, Risch N, Nygaard TG, Frisch A, Cohen IJ, Miranda CS, Amaral O, Maire I, Poenaru L, Caillaud C, Weizberg M, Mistry P, Desnick RJ. Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations. Am J Hum Genet. 2000 Jun;66(6):1821-32. doi: 10.1086/302946. Epub 2000 Apr 21. PMID: 10777718; PMCID: PMC1378046.

 

Written by Manuel de la Mata

Geneticist

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