Gaucher disease (pronounced as GO-SHEY) is an autosomal recessive inborn error of metabolism caused by mutations in the glucocerebrosidase (GBA1) gene. GBA1 is an enzyme that cleaves beta-glucosidic linkage of glucocerebroside lipids. Inborn errors of metabolism are particularly relevant in pediatrics since their presentation is very often (but not always) in the neonatal period of infancy. There are five known types of Gaucher disease: type 1, type 2, type 3, perinatal lethal and cardiovascular. The perinatal lethal form is the most severe and its complications can begin before birth or in early infancy.
Knowing the major manifestations of any inborn error of metabolism is the key to making a diagnosis. Inborn errors of metabolism primarily result from the lack (or insufficient levels) of specific enzymes needed: (1) convert fat or carbohydrates to energy or to; (2) breakdown amino acids or other metabolites, allowing them to accumulate and become toxic if not treated. Gaucher disease is a “toxic accumulation” inborn error of metabolism due to the accumulation of glucocerebroside lipids. It is the most common cause of lysosomal storage diseases. Lysosomes are subcellular organelles responsible for the physiological turnover of cell constituents. Toxic accumulation inborn errors of metabolism fall into three major categories, localized toxicity, circulating toxicity or a combination of both. Gaucher disease is an example of localized toxicity.
The underlying cause of all forms of Gaucher disease is mutations in the GBA1 gene resulting in a lysosomal deficiency of glucocerebrosidase activity. All forms of Gaucher disease lead to the toxic accumulation of glucocerebroside lipids, primarily in the liver, spleen, and bone marrow. A glucocerebroside is composed of a glucose molecule linked to the oxygen atom on carbon atom 1 of the sphingosine moiety of ceramide. All forms of Gaucher disease are also classified as lysosomal storage disorders. There are at least 40 other lysosomal storage disorders including mucopolysaccharidosis, Tay-Sachs disease, and Fabry disease. All lysosomal storage disorders tend to get worse over time, in other words, they are progressive. Lysosomes are spherical intracellular organelles where many lipids and macromolecules are delivered for degradation by hydrolytic enzymes. Lysosomes are abundant in macrophages. The lysosomes in the macrophages of patients with Gaucher disease become progressively enlarged and filled with undigested glucocerebroside. The lysosomes can eventually be filled with undigested lipids that resemble “crumpled tissue paper” when visualized by electron microscopy. In the absence of appropriate treatment, the liver can expand two-fold to three-fold its normal size and the spleen by 15-fold.
Despite knowing the precise genetic causes of most forms of Gaucher disease, the exact cause remains unknown. It is possible for patients with the same mutation to have very different signs and symptoms. It is also possible for patients with similar signs and symptoms to have very different genetic mutations. Environmental factors, as well as an individual's particular genetic makeup, most likely influence the phenotypic expression of Gaucher disease.
Gaucher disease is the most common autosomal recessive disease in the Ashkenazi (Eastern European) Jewish population with a carrier frequency of 6% compared to 0.7% to 0.8% of the non-Jewish population. Cystic fibrosis (4% carrier frequency) and Tay-Sachs Disease (3.7% carrier frequency) are also common in the Ashkenazi population.
The most common form of Gaucher disease is type 1 which has a very variable phenotype ranging from early childhood symptoms to no symptoms throughout life but typically does not have a neurological component. In contrast to type 1, both type 2 and 3 are rare and do affect the central nervous system. Both type 2 and the perinatal lethal typically result in neonatal death whereas type 3 results in mid to early adulthood death.
The signs and symptoms of Gaucher disease can be classified into visceral, hematologic, skeletal, and metabolic components. The visceral components include enlarged liver and spleen (hepatosplenomegaly).
Hematological components can include thrombocytopenia, anemia, and leukopenia. Cerebroside accumulation in the bone marrow is thought to decrease platelet production resulting in low platelet count. Similarly, cerebroside accumulation in the spleen is thought to result in an excessive break down of red blood cells resulting in anemia as well as more active removal of white blood cells (WBC) resulting in a low WBC count.
The skeletal components can include bone crisis, the death of bone cells (called avascular necrosis or osteonecrosis), a low bone density compared to normal peak density, pathological bone fracture, and Erlenmeyer flask deformity. Much of these skeletal abnormalities are attributed to the buildup of glucocerebroside-laden macrophages in the bone-marrow where they restrict blood flow and the delivery nutrients and oxygen which can result in intense pain, bone cell necrosis, low bone density, and growth abnormalities.
The diagnosis of Gaucher disease depends upon finding a low GBA1 enzyme level in peripheral blood leukocytes as well as establishing the presence of mutant alleles in the GBA1 gene. Despite the fact that only a blood sample is needed to diagnosis Gaucher disease, some patients undergo unnecessary invasive bone marrow or liver biopsy before making a correct diagnosis. Physician awareness of the signs and symptoms of Gaucher disease can help avoid such mishaps. Moreover, before an accurate diagnosis is made, many patients with an enlarged liver or spleen are told they could have cancer.
Treatment for Gaucher disease falls into two categories, enzyme replacement therapy and substrate reduction therapy. In general, enzyme replacement therapy provides an intravenous infusion containing the enzyme that is deficient or absent in the body. In the case of Gaucher disease, this would be the GBA1 enzyme (also called beta-glucosylceramidase or beta-glucocerebrosidase). The FDA has approved both Cerezyme (imiglucerase) and VPRIV (velaglucerase alfa) for Gaucher disease type 1 and 3 enzyme replacement therapy. Enzyme replacement therapy typically cannot replace an enzyme deficient in the brain due to the blood-brain barrier and therefore is not effective for the treating the central nervous systems problems associated with type 2 and 3 Gaucher disease. Enzyme replacement therapy will help with the “non-brain” signs and symptoms associated with type 3 Gaucher disease, e.g., enlarged organs and skeletal issues.
Enzyme replacement therapy does not correct the underlying genetic defect and acts only to relieve signs, symptoms and ongoing damage caused by the accumulation of toxins. Moreover, it is possible to develop antibodies to the replacement enzyme.
Substrate reduction therapy is an orally administered small-molecule drug (not protein) that relies on a strategy distinct from that of enzyme replacement therapy. In substrate reduction therapy the goal is to reduce the levels of a substrate such that toxic accumulation of the substrate’s subsequent degradative product is diminished to a level that is clinically less toxic. In the case of Gaucher disease, the goal is to use substrate reduction therapies that can inhibit the first committed step in glycosphingolipid biosynthesis. There are two FDA-approved substrate reduction therapy drugs to treat patients with Gaucher disease, i.e., Cerdelga (eliglustat) and Zavesca (miglustat). Cerdelga, a glucosylceramide synthase inhibitor, does not effectively cross the blood-brain barrier is indicated only for type 1 Gaucher disease. It is not yet known if Cerdelga is safe or effective in children. Miglustat can cross the blood-brain barrier and could, therefore, be potentially beneficial for type 2 and 3 Gaucher disease. Nevertheless, miglustat is currently indicated only for the treatment mild to moderate type 1 Gaucher disease only in adults.