Gaucher disease is a hereditary metabolic disorder that is typically caused by mutations in the GBA gene. Depending on the patient's age at symptom onset, the presence of central nervous system involvement and neurological symptoms, Gaucher disease types 1, 2, and 3 are distinguished. Gaucher disease type 1 (GD1) is characterized by onset in childhood or adolescence, lack of central nervous system involvement and neurological deficiencies. Therefore, it is also referred to as non-cerebral juvenile Gaucher disease.
The clinical presentation of GD1 is highly variable, even within the same family. Although symptom onset most commonly occurs during the first decade of life, it may be delayed until adolescence or adulthood  . Literature also contains reports of asymptomatic individuals known to carry two pathogenic GBA alleles.
GD1 patients often present with hepatosplenomegaly, signs and symptoms of pancytopenia. They result from liver, spleen, and bone marrow involvement. Neurological symptoms are absent. Hepatosplenomegaly may result in early satiety, upper abdominal pain, and distension. It may also aggravate cytopenias: While the accumulation of glucosylceramides in the bone marrow certainly interferes with hematopoiesis, splenic involvement may be associated with excess erythrocyte destruction and leukocyte removal . In general, anemic patients are pale and report fatigue and weakness. Severe anemia may also cause tachycardia, dyspnea, and dizziness. Deficiencies in leukopoiesis result in a propensity to infections, and thrombocytopenia is related to an increased tendency to bleed.
In the long term, disrupted glucocerebroside catabolism in the bone marrow may disrupt the supply of oxygen and nutrients to the bone, thereby giving rise to bone pain, osteonecrosis, and a reduction of bone density  . Growth retardation becomes evident in childhood, and eventually, patients may develop deformities like Erlenmeyer flask deformity and suffer pathological fractures. Delayed puberty is also common and is usually attributed to a general retardation in physical development .
The clinical presentation of GD1 is non-specific, and many patients undergo a myriad of treatments before being diagnosed. In this context, it is particularly important to obtain the patient's full medical and familial history. Affected individuals generally have a family history of the disease, and family members may have shown additional symptoms that prove decisive in diagnosing this rare metabolic disorder.
The gold standard for the diagnosis of Gaucher disease is the identification of the causal mutation in the GBA gene. What's more, precise knowledge regarding the underlying GBA mutation is the prerequisite for a thorough familial workup, genetic counseling, and prenatal diagnosis. Additionally, the enzymatic activity of glucosylceramidase β should be determined in patient-derived leukocytes or fibroblasts . In individuals suffering from GD1, the activity of this enzyme is <15% of that of healthy controls. Heterozygosity for pathogenic GBA mutations is associated with activity levels of approximately 50%, which doesn't usually result in clinical disease. Otherwise, residual glucosylceramidase β activity doesn't seem to correlate with the severity of the disease. Of note, neither molecular genetic analyses nor enzyme activity measurements allow for the differentiation between distinct types of Gaucher disease.
Lifelong enzyme replacement therapy is the mainstay of GD1 treatment and should be considered in all patients with symptomatic disease. Imiglucerase, taliglucerase alfa, and velaglucerase alfa are approved for GD1 treatment. Dose and administration frequency should be adjusted to the individual patient's needs, and clinical symptoms as well as hematological parameters may be used to measure their response to treatment . Most patients require biweekly intravenous applications of these drugs, which contain recombinant human glucosylceramidase β and are among the most expensive drugs sold.
GD1 patients may develop antibodies against the recombinant enzyme, and some patients don't tolerate enzyme replacement therapy. In these cases, substrate reduction is recommended. Affected individuals benefit from a reduction of the burden of substrates of glucosylceramidase β. Eliglustat and miglustat are approved to this end. Their precise mechanisms of action remain unknown, but it has been suggested that they inhibit glucosylceramide synthase, an enzyme that catalyzes the glycosylation ceramide to form glucosylceramide. They are administered per os. Similar to the drugs mentioned above, their high costs pose enormous challenges for health care.
Hematopoietic stem cell transplantation has repeatedly been discussed as a therapeutic alternative. However, evidence regarding the efficacy of this procedure and the acceptability of associated risks is scarce . In general, hematopoietic stem cell transplantation is considered a low-benefit, high-risk measure inferior to effective, well-tolerated enzyme replacement and substrate reduction therapies . Gene therapy may constitute an alternative for curing GD1 but is not yet sufficiently developed for practical use .
GD1 is the least severe type of Gaucher disease but still follows a progressive course. In the absence of functional glucosylceramidase β, increasingly large amounts of glucosylceramides accumulate within cells of the monocyte-macrophage system. Enzyme replacement and substrate reduction therapies may slow down disease progression, but are unable to reverse existing complications like fibrous changes in liver and spleen, and skeletal anomalies. Thus, GD1 patients may have to face reduced life quality. Nevertheless, GD1 is rarely life-threatening, and most patients experience significant improvements of organomegalies and abnormalities of the bone .
GD1 patients may be predisposed to Parkinson's disease and certain types of cancer . With regard to Parkinson's disease, it has been observed that glucosylceramidase β activity levels inversely correlate with α-synuclein concentrations and that low levels of enzyme activity increase the risk of this neurodegenerative disease . This also applies to patients who are heterozygous for pathogenic GBA mutations and who have relatively high but nevertheless reduced glucosylceramidase β activity. Thus, clinical Gaucher disease is not a prerequisite for an elevated risk of Parkinson's disease . Little is known about the risk of asymptomatic carriers to develop any form of cancer, but GD1 patients are known to have increased risks of multiple myeloma and hematological malignancies .
Similar to Gaucher disease types 2 and 3, GD1 is caused by mutations in the GBA gene. This gene is located on the long arm of chromosome 22 and encodes for glucosylceramidase β, an enzyme required for the cleavage of β-glycosidic bonds of glucosylceramides. The latter are cerebrosides and sphingolipids, and they are essential components of myelin and cell membranes. Glucosylceramides consist of a glucose residue linked to a ceramide. They are degraded in the lysosome and split into sphingosine, fatty acids, and monosaccharides. Glucosylceramidase β locates to the lysosomal membrane and catalyzes the hydrolysis of glucosylceramides to acylsphingosine and glucose. Pathogenic GBA mutations are associated with reduced enzyme activity, and consequently with the intralysosomal accumulation of glycosylceramides.
All types of Gaucher disease comprise the accumulation of glucosylceramides in the liver, spleen, and bone marrow, but the clinical presentation of affected individuals varies largely  . What's more, mutations in the GBA gene may induce other types of Gaucher disease, which are characterized by the involvement of additional organ systems. It is, in fact, not usually possible to distinguish GD1 from other types of the disease based on the results of sequencing of the GBA gene: Several hundred mutations have been described to date, and very few have solely been associated with type 1 disease. One of these few is GBA mutation c.1226A>G, whereby compound heterozygosity with all other mutations results in GD1 . In sum, little is known about the determinators of disease type, course, and severity. It is assumed that as-of-yet unknown genetic features and environmental factors play crucial roles in the etiology and pathogenesis of Gaucher disease .
The global frequency of carriers of pathogenic GBA mutations has been estimated to 0.7-0.8%. By contrast, about 6% of the Ashkenazi Jewish population are assumed to carry such alleles . According to similar studies, the incidence of Gaucher disease is about 1 in 50,000 live births in the general population, and 1 in 800 among Ashkenazi Jews . The vast majority of individuals who are homozygous or compound heterozygous for pathogenic GBA variants develops GD1: In Europe and the USA, GD1 accounts for up to 90% of all cases  . About 70% of Ashkenazi Jews diagnosed with Gaucher disease are carriers of GBA mutation c.1226A>G, one of the few mutations that have exclusively been identified in GD1 patients .
Glucosylceramides mainly accumulate within cells of the monocyte-macrophage system. Due to glucosylceramidase β deficiency, these cerebrosides cannot be degraded and exported from these cells' lysosomes, which progressively enlarge as they fill up with undigested lipids . Disease progression is thus associated with morphological changes of macrophages in liver, spleen, bone marrow, and other organs. They turn into so-called Gaucher cells, which have eccentric nuclei containing condensed chromatin and dense cytoplasm. When visualized by light microscopy, lysosomes of Gaucher cells appear like crumpled tissue paper. Glucosylceramides gradually aggregate to twisted, fibrillar structures that give the lysosomes this heterogenous appearance, and they can be observed under an electron microscope  .
Affected families may benefit from genetic counseling. Furthermore, a prenatal diagnosis of Gaucher disease is feasible. Both chorionic villi and amniotic fluid cells can be used to determine whether a child inherited pathogenic GBA variants, and to assess glucosylceramidase β activity levels . However, it isn't usually possible to predict the severity and course of the disease based on the results of the aforementioned studies. It may not even be possible to predict the type of Gaucher disease the child will develop.
Gaucher disease is a lysosomal storage disease. It is also the most common sphingolipidosis, whereby sphingolipidoses are the largest subgroup of lysosomal storage diseases. This subgroup comprises a variety of disorders caused by the inadequate degradation of sphingolipids due to enzyme deficiencies . Other sphingolipidoses are Fabry disease, Krabbe disease, and Niemann-Pick disease.
The vast majority of patients diagnosed with Gaucher disease are homozygous or compound heterozygous for pathogenic mutations in the GBA gene, but mutations in the PSAP gene have been detected in isolated cases. It has been shown that PSAP mutations result in saponin C deficiency and atypical Gaucher disease  . The much more common GBA mutations give rise to the dysfunction of an enzyme involved in the breakdown of glucosylceramides, which are important structural components of myelin and cell membranes. Individuals who carry a functional GBA allele have residual enzyme activities that suffice to prevent clinical disease. Accordingly, Gaucher disease is inherited in a recessive manner.
Gaucher disease may be diagnosed based on genetic findings and measurements of enzyme activity, but the differentiation of distinct types of Gaucher disease relies on phenotypical features. GD1 accounts for up to 90% of all cases and is characterized by onset in childhood or adolescence and the absence of neurological deficits. By contrast, central nervous system involvement is a clinical hallmark of Gaucher disease types 2 and 3. In any case, the strict division into three types seems less and less viable, and it has repeatedly been suggested to rather consider Gaucher disease a phenotypic continuum  .
Gaucher disease is a hereditary disorder. It is caused by mutations in the GBA gene, which encodes for an enzyme involved in the breakdown of components of myelin and cell membranes. In individuals suffering from Gaucher disease, the activity of this enzyme is largely reduced. Consequently, the aforementioned components of myelin and cell membranes cannot be degraded and accumulate within cells in the liver, spleen, and bone marrow.
According to the patient's age at symptom onset and the severity of the disease, three types of Gaucher disease may be distinguished. Gaucher disease type 1 (GD1) is the least severe type of Gaucher disease. Symptom onset usually occurs in childhood but may be delayed until adolescence or adulthood. Due to the progressive enlargement of liver and spleen, GD1 patients often present with early satiety, upper abdominal pain, and abdominal distension. Bone marrow involvement results in anemia, leukopenia, and thrombocytopenia. GD1 patients may thus suffer from fatigue and weakness, be prone to infections and show a tendency to bleed. Bone pain, fractures, and growth retardation are also common.
GD1 is diagnosed based on the results of genetic studies, enzyme activity measurements, and clinical findings. Therapy mainly consists in replacing the deficient enzyme and reducing the burden of substrates. Although major complications of GD1 are irreversible, most patients respond to treatment and experience significant improvements that increase their quality of life.