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Gaucher Disease: Causes, Symptoms and Diagnosis

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Gaucher disease is a rare, autosomal recessive genetic disorder. It is caused by a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in macrophages. In the general population, its incidence is approximately 1/40,000 to 1/60,000 births, rising to 1/800 in Ashkenazi Jews. The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells.

Lysosomal storage diseases (LSDs) are a group of heterogeneous inherited diseases caused by mutations affecting genes that encode either the function of the lysosomal enzymes required for the degradation of a wide range of complex macromolecules, but sometimes the function of specific transporters needed to export degraded molecules from the lysosomes. The resulting lysosomal dysfunction leads to cellular dysfunction and clinical abnormalities. In one group of LSDs, the sphingolipidoses, there is a dysfunction in the enzyme-degrading abilities of the metabolites which are essential components of cell membranes and regulators of various signaling pathways

Type-1 Gaucher disease, which affects the majority of patients (90% in Europe and USA, but less in other regions), is characterized by effects on the viscera, whereas types 2 and 3 are also associated with neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 gene should be identified as they may be of prognostic value in some cases.

Mutations in the GBA1 gene lead to a marked decrease in GCase activity. The consequences of this deficiency are generally attributed to the accumulation of the GCase substrate, GlcCer, in macrophages, inducing their transformation into Gaucher cells. Under light microscopy, Gaucher cells are typically enlarged, with eccentric nuclei and condensed chromatin and cytoplasm with a heterogeneous “crumpled tissue paper” appearance. This feature is related to the presence of GlcCer aggregates in characteristic twisted, fibrillar arrangements that can be visualized using electron microscopy. Gaucher cells mainly infiltrate bone marrow, the spleen, and liver, but they also infiltrate other organs and are considered the main protagonists factors in the disease’s symptoms. The monocyte/macrophage lineage is preferentially altered because of their role in eliminating erythroid and leukocytes, which contain large amounts of glycosphingolipids, a source of GlcCer. GlcCer accumulation in Gaucher cells is considered the first step towards bone involvement, leading to the vascular compression which is the source of necrotic complications. The pathophysiological mechanisms of neurological involvement remain poorly explained; GlcCer turnover in neurons is low and its accumulation is only significant when residual GCase activity is drastically decreased, i.e., only with some types of GBA1 mutations.

Fatigue is common (50% of patients) and often has an impact on school life or socio-professional activities. In children, growth retardation and delayed puberty are common (growth <5th percentile in 34% of children).

Splenomegaly is observed in more than 90% of patients and is sometimes massive, with a spleen weighing up to several kilograms and causing abdominal pain or distension. Indeed, it may be the only clinical sign, leading to unnecessary tests if GD is not considered. Splenic infarction may complicate matters; spleen rupture only occurs very rarely

Dried blood spots can also be used for the enzymatic assay, but any potential deficiency should be confirmed using the previous method. Flow cytometry analysis of blood monocytes is a more accurate method, but it has not been validated by different centers. The very rare saposin C deficiency should be tested for when GCase activity is normal but the clinical picture and biomarkers point to GD and especially when chitotriosidase activity is very high. The diagnosis is made by PSAP gene sequencing.

Prenatal diagnosis of GD can be performed by genetic analysis, using either chorionic villus sampling (sampled at 10–12 weeks of amenorrhea) or amniotic fluid cells (as early as 16 weeks of amenorrhea), but only if the index case genotype has been previously identified. It can also be done by measuring glucocerebrosidase activity on fresh chorionic villi or cultured amniotic cells.

Abdominal magnetic resonance imaging (MRI) is the most appropriate examination for assessing liver and spleen dimensions (organ volume) and morphology. The spleen sometimes presents nodules suggestive of lymphoma. When MRI is unavailable or in cases of uncontrollable claustrophobia, an abdominal ultrasound may be used instead. Computed tomography (CT) has previously been used for estimating Gaucher organ volumes; nonetheless, MRI, because of justifiable concerns about CT radiation, is preferable because repeat assessments are routinely required.

All GD patients require regular monitoring, however specific medication is not justified in all cases. Once it has been initiated, treatment must generally be administered for life. There are currently two specific types of treatment for GD: enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The goal is to treat patients before the onset of complications, the sequelae of which are disabling or not improved by further treatment, including massive fibrous splenomegaly, AVN, secondary osteoarthritis, vertebral compression and other fractures, hepatic fibrosis and lung fibrosis.

Patients with type-1 GD—but also carriers of GBA1 mutation—have been found to be predisposed to developing Parkinson’s disease, and the risk of neoplasia associated with the disease is still subject to discussion. Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules (imiglucerase, velaglucerase, or taliglucerase). Orally administered inhibitors of glucosylceramide biosynthesis can also be used (miglustat or eliglustat). Dose and administration frequency vary depending on the country, often with individual adjustments of dosages. For children and “at risk adults”, a starting dose of 60 U/kg every other week (EOW) has been recommended. Pregnancy is not a contraindication to imiglucerase replacement therapy since no fetal malformations have been described in pregnant women for whom treatment continued. Velaglucerase also appears to be well tolerated.

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The aim of substrate reduction therapy (SRT) is to reduce excess cell GlcCer by decreasing its production. Miglustat (Zavesca®, Actelion) is a GlcCer synthase inhibitor which reduces the biosynthesis of GlcCer in Gaucher cells. Miglustat is administered orally at the recommended dose of 100 mg, three times daily, but doses may need to be progressively increased at treatment initiation to improve tolerance. Miglustat can produce side effects (diarrhea, weight loss, hand tremors or possible peripheral neuropathy) although these generally regress with dose reduction or treatment discontinuation.

Currently, available treatments make it possible to reduce cytopenias and organomegalies and to significantly decrease bone manifestations, considerably improving a patient’s quality of life.

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