Gaucher disease is an autosomal recessive disorder wherein both copies of the gene that encodes for a lysosomal enzyme called beta-glucocerebrosidase are mutated.

The mutation makes beta-glucocerebrosidase unable to efficiently break down a molecule called glucocerebroside into glucose (a simple sugar) and ceramide (a fat molecule). Hence, glucocerebroside accumulates throughout the body, especially in the spleen, liver, and bone marrow.

There are three main types of Gaucher disease. Type 1 Gaucher disease accounts for nearly 90% of all cases, and does not normally involve neurologic symptoms, whereas both types 2 and 3 do.

Type 1 Gaucher disease develops in individuals who carry a mutation in both copies of the GBA gene. The mutation causes an amino acid change in the beta-glucocerebrosidase sequence at position 370. (Amino acids are building blocks of proteins).

Symptoms

The symptoms of type 1 Gaucher disease can range from mild to severe and may appear anytime from childhood to adulthood. They include:

1. Enlarged spleen or splenomegaly, which is observed in nearly 90% of patients.
2. Enlarged liver or hepatomegaly, which is observed in around 60% to 80% of patients.
3. Focal lesions in the liver or spleen, seen in up to 40% of patients. In most cases, this is caused by a Gaucheroma or a benign lesion consisting of so-called Gaucher cells.
4. A low number of red blood cells (anemia), which is observed in 20% to 50% of patients.
5. Fatigue and shortness of breath, seen in around 50% of patients.
6. Low platelet counts or thrombocytopenia, which can cause spontaneous bleeding or bruising observed in 60% to 90% of patients.
7. Infiltration of Gaucher cells into the lungs that can cause emphysema (thinning and destruction of the alveoli or air sacs), pulmonary fibrosis (damaged and scarred lung tissue), and vascular abnormalities with pulmonary hypertension (high blood pressure in the arteries of the lungs).
8. Bone abnormalities such as acute pain crises, predominantly in the pelvis and lower limbs, which are observed in nearly 30% of patients.

Although type 1 Gaucher disease was originally described as a non-neurological condition, it has been associated with certain neurological symptoms in recent years. For example, patients with type 1 Gaucher disease have a four to 20-fold greater risk of developing Parkinson’s disease at a younger age. Moreover, the prevalence of peripheral neuropathies and small fiber sensory neuropathies is higher in type 1 Gaucher disease patients compared with the general population.

Treatments

Type 1 Gaucher disease can be treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT).

Enzyme replacement therapy (ERT)

ERT involves the intravenous infusion of a recombinant beta-glucocerebrosidase enzyme to balance the typically low levels of the enzyme in patients.

Three ERTs are approved by the U.S. Food and Drug Administration (FDA) for the long-term treatment of patients with type 1 Gaucher disease: Cerezyme (imiglucerase), Elelyso (taliglucerase alfa), and VPRIV (velaglucerase alfa).

Substrate reduction therapy (SRT)

SRT is given in the form of an oral medication that decreases the amount of glucocerebroside made by the body, thereby reducing excess buildup even in the absence of the beta-glucocerebrosidase enzyme.

The two FDA-approved SRTs for the long-term treatment of type 1 Gaucher disease are Cerdelga (eliglustat) and Zavesca (miglustat).

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