Gaucher Disease

Gaucher Disease is a genetically determined lysosomal storage disorder with an autosomal recessive inheritance pattern. It is caused by a mutation in the GBA gene, which encodes the enzyme glucocerebrosidase. 

Several clinical forms of the disease are distinguished: type 1, non-neuronopathic with a chronic course (approximately 1 in 50,000 births), type 2, acute neuronopathic infantile form (approximately 1 in 100,000 births), and type 3, subacute neuronopathic form (approximately 1 in 100,000 births). 

The disease is named after Dr. Philippe Gaucher, who first described its symptoms in 1882. It is caused by the accumulation of glucosylceramide in cells. It is a rare inherited enzyme deficiency (glucocerebrosidase deficiency), leading to the accumulation of glucosylceramide in various parts of the body, such as the spleen, liver, and bones.

Gaucher is very difficult rare disease to diagnose, and many patients are diagnosed very late (after the disease has already progressed) or never diagnosed at all. It is estimated that there are about 72,000 to 80,000 people with Gaucher disease worldwide, according to the article “Global Epidemiology of Gaucher Disease: an Updated Systematic Review and Meta-analysis”, published in the Journal of Pediatric Hematology/Oncology. 

What causes Gaucher Disease

Gaucher Disease (GD) belongs to the group of lysosomal storage disorders, of which there are approximately 60 known types. This genetically conditioned disorder is inherited in an autosomal recessive manner. 

The cause of Gaucher disease is a genetic mutation that leads to reduced activity of the enzyme β-glucocerebrosidase. Consequently, glucocerebroside accumulates in cells, tissues, and organs.

Depending on the presence or absence of neurological symptoms, three main types of Gaucher Disease are distinguished.

The disease is named after Philippe Gaucher, who first described it in the late 18th century.

Diagnosis 

Diagnosis of Gaucher Disease may be initiated due to the presence of general symptoms (fatigue), hematological symptoms (thrombocytopenia), visceral symptoms (enlarged liver and spleen), bone complications (including pathological fractures), or disorders affecting the nervous system and vision.

Initially, the diagnostic process includes medical history, physical examination, laboratory tests, and imaging studies. These steps help exclude other causes of the symptoms and confirm pathological changes characteristic of this condition.

Definitive diagnosis involves measuring the activity of beta-glucocerebrosidase in peripheral blood leukocytes or skin fibroblasts, along with genetic testing to confirm mutations in the GBA1 gene. Additional tests may reveal typical blood clotting and hematological abnormalities associated with the disease.

Symptoms of Gaucher Disease

The clinical presentation varies among patients and depends on the type of Gaucher Disease.

• Type 1 – The most common form, often referred to as the “adult type.” It can manifest at any age but usually appears during adolescence. The residual enzyme activity in type 1 patients makes the disease course less aggressive than in other types. Symptoms include thrombocytopenia, splenomegaly, anemia, hepatomegaly, and bone changes (e.g., bone necrosis), leading to fatigue, a tendency to bleed, frequent infections, abdominal distension, growth impairment, bone pain, and skin discoloration. There are no neurological symptoms.
• Type 2 – Acute infantile neuronopathic form. It involves both visceral and neurological symptoms such as strabismus, seizures, progressive psychomotor deterioration, brainstem dysfunction (leading to weakened sucking and swallowing reflexes), muscle tone disorders, facial dysmorphism, and thrombocytopenia. Generalized swelling, low motor activity, and growth failure are also observed. In its most severe forms, Gaucher Disease can be fatal even in the fetal stage.
• Type 3 – Subacute (juvenile) neuronopathic form, considered intermediate between types 1 and 2. It is further subdivided into subtypes IIIa, IIIb, and IIIc. IIIa is associated with progressive myotonia and intellectual disability, IIIb with isolated supranuclear gaze palsy, and IIIc, linked to the homozygous D409H genotype, is characterized by heart valve calcification, corneal clouding, and horizontal gaze impairment.

Prognosis 

In patients with type 2 Gaucher Disease, symptoms often lead to death within the first two years of life. Individuals with type 3, if untreated, typically die within a few years (untreated type 3b GD leads to the death of half of affected individuals before the age of 12). 

In contrast, the prognosis for type 1 patients is good—if properly treated, they can live a lifespan comparable to healthy individuals, though continuous treatment is necessary.

How to treat it

For types 1 and 3 of Gaucher Disease, enzyme replacement therapy (ERT) (imiglucerase/velaglucerase) and substrate reduction therapy (SRT) (miglustat) are available. SRT is an alternative for patients who cannot undergo ERT or have a mild/moderate form of type 1 GD. This therapy works by inhibiting the production of glucosylceramide.

ERT is administered through slow intravenous infusions every two weeks for life. Depending on the patient’s age and condition, doses range from 15-60 U/kg body weight. ERT should not be discontinued during pregnancy, as it reduces the risk of miscarriage and bleeding complications during childbirth.

These therapies are ineffective for type 2 Gaucher Disease. The primary goals of treatment are to halt disease progression, improve hematological parameters, reduce hepatomegaly and splenomegaly, alleviate bone complications, and enhance the overall quality of life.

Each patient should receive treatment at a reference center near their place of residence and attend regular follow-ups.

Prevalence 

Gaucher Disease is pan-ethnic, meaning it occurs in all ethnic groups. The estimated prevalence is 1 in 50,000 to 200,000 people, although more specific data vary by source. In Western countries, the prevalence is estimated at 1 in 40,000–60,000 live births in the general population. The incidence of neuropathic forms (the most severe cases) is estimated at 1 in 500,000 individuals.

Some numbers across the world:

• Poland: there are currently several dozen diagnosed cases of Gaucher disease
• In Germany, according to studies, the prevalence is around 30 cases per one million inhabitants. With a population of approximately 83 million, it can be estimated that about 2,490 people in the country are living with a diagnosis of Gaucher disease.
• USA: 6,000 diagnosed patients, according to the National Organization for Rare Disorders. 
• Brazil: 1234 patients, as reported by the study “Gaucher disease in Brazil: a comprehensive 16 year retrospective study on survival, cost, and treatment insights”, published by Frontiers in Pharmacology
• Colombia: As of December 31, 2023, a total of 204 people with a diagnosis of Gaucher disease were reported to the Colombian government’s high-cost CAC account. This represents a crude prevalence of 0.39 cases per 100,000 population, slightly higher than previous reports from Latin America. 
• LATAM: according to the NIH there isn’t a precise, single number for the exact number of patients in Latin America, studies suggest that Gaucher disease is relatively common in the region, with a prevalence ranging from 0.15 to 0.32 per 100,000 population. 

Still, due to the diagnostic challenges associated with rare diseases, the actual numbers may be underestimated.