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 [1] [2]. 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 [2]. 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 [1] [2]. 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 [1].

• Splenomegaly

  INTRODUCTION: In the absence of a known affected family member, frequent symptoms of Gaucher disease (GD), a rare lysosomal storage disorder, such as thrombocytopenia or splenomegaly, often lead to hematological diagnostic workup. [ncbi.nlm.nih.gov]

  Indeed, studies show that only 20% of haematologists consider GD type 1 in their differential diagnosis for patients presenting with splenomegaly and/or thrombocytopenia. [moh-it.pure.elsevier.com]

  Assessment of splenomegaly should be combined with an examination of spleen parenchyma using abdominal ultrasound or magnetic resonance imaging. [touchoncology.com]

• Easy Bruising

  The main signs and symptoms of Gaucher disease are: Anemia (low red blood cell count) Fatigue(tiredness) Low platelet count, that can lead to easy bruising Enlarged spleen and liver (hepatosplenomegaly) Easy bleeding that is difficult to stop Bone pain [medicinenet.com]

  If too many lipids accumulate in your body, this can lead to: more frequent and easy bruising bone pain/fractures fewer healthy blood cells to carry oxygen throughout the body and fight off germs and bacteria Even though this disease is a rare condition [practicalpainmanagement.com]

  They also typically have low platelet counts that can cause easy bruising and bleeding problems. Bleeding problems: Low platelet counts prevent normal blood clotting processes. [gaucherdisease.org]

  Gaucher Type 1, 2, & 3 -- peripheral effects The peripheral systems affected in Gaucher disease tend to be similar in all three types of the diseae with enlargement of the liver and spleen, anemia, nose bleeds, reduced platelets (resulting in easy bruising [youtube.com]

  It's a rare condition that can cause a variety of symptoms, from weakening of your bones to easy bruising. [webmd.com]

• Anemia

  IMPORTANCE: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. [ncbi.nlm.nih.gov]

• Fatigue

  However, general effects (such as fatigue, bone pain) reported in some patients, emphasize the importance of maintaining appropriate individualized dosing. [ncbi.nlm.nih.gov]

  CONTINUE SCROLLING OR CLICK HERE FOR RELATED SLIDESHOW SLIDESHOW The 14 Most Common Causes of Fatigue See Slideshow Last Editorial Review: 1/11/2017 [medicinenet.com]

  This can make you bruise easily and feel very tired (fatigued). Your symptoms can start at any age. You might have an enlarged liver or spleen. You may also have kidney, lung, or skeletal problems. Type 2. [urmc.rochester.edu]

  The disorder can result in pain, fatigue, jaundice, bone damage, anaemia and even death. Gaucher disease is an autosomal recessive disorder. [brainfoundation.org.au]

• Splenectomy

  Transition probabilities depended on disease severity (DS3 score) at treatment initiation and whether patients had undergone a total splenectomy or had an intact spleen/partial splenectomy prior to starting treatment. [ncbi.nlm.nih.gov]

• Sepsis

  The causes of death included hemorrhage secondary to esophageal varices (two cases), respiratory distress (one case), hepatic failure (one case) and postoperative sepsis (one case). [ncbi.nlm.nih.gov]

  […] bone crises.24 Conversely, a study in 17 patients with GD with delayed diagnosis (up to 10 years) found that approximately 25% developed irreversible complications including avascular bone necrosis, severe bleeding, chronic bone pain, life-threatening sepsis [touchoncology.com]

  The individual died due to sepsis but had shown regression of disease manifestations ( Rappeport 1984 ). [cochranelibrary.com]

  […] multiple Positive rheumatoid factor polyarthritis Posner-Schlossman syndrome Post Finasteride syndrome - See Adverse events of 5-alpha-reductase inhibitors Post orgasmic sick syndrome - See Postorgasmic illness syndrome Post Polio syndrome Postanginal sepsis [rarediseases.info.nih.gov]

• Amyloidosis

  全身性アミロイドーシス Amyloid neuropathy, Familial type 家族性アミロイドポリニューロパチー 1 HPS0224* HPS0225* HPS0226* 2 HPS0227* HPS0228* Systemic amyloidosis, hereditary amyloidosis 全身性アミロイドーシス家族性 1 不要 有 HPS2018 HPS2019 HPS2020 HPS2021 HPS2022 HPS2023 Systemic amyloidosis, [cell.brc.riken.jp]

  See AL amyloidosis Primary systemic amyloidosis - See AL amyloidosis Primary T-Cell Immunodeficiency Disorders - See T cell immunodeficiency primary Primary thrombocythemia - See Essential thrombocythemia Primary tubular proximal acidosis Primary tumor [rarediseases.info.nih.gov]

  Differential Diagnosis Necrobiotic xanthogranuloma Orbital lipogranulomas Juvenile xanthogranulomata Erdheim-Chester disease Wegener granulomatosis Lipoid proteinosis Primary systemic amyloidosis Necrobiosis lipoidica Sarcoid Atypical lymphoid infiltrate [statpearls.com]

• Dyspnea

  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. [symptoma.com]

  […] number of red blood cells or hemoglobin 0001903 Bruising susceptibility Bruise easily Easy bruisability Easy bruising [ more ] 0000978 Diplopia Double vision 0000651 Dysphagia Poor swallowing Swallowing difficulties Swallowing difficulty [ more ] 0002015 Dyspnea [rarediseases.info.nih.gov]

• Abdominal Pain

  pain, upper abdominal pain, back pain, and extremity pain. [ncbi.nlm.nih.gov]

  Hepatosplenomegaly may result in early satiety, upper abdominal pain, and distension. [symptoma.com]

  Some of the symptoms are listed below: Liver Hepatomegaly – large liver Enlarged abdomen Cirrhosis – scarred liver Abnormal liver tests, jaundice & other signs of liver disease Predisposition to gall stones Often no symptoms – sometimes abdominal pain [cuh.nhs.uk]

  pain Pain in stomach Stomach pain [ more ] 0002027 Anemia Low number of red blood cells or hemoglobin 0001903 Bruising susceptibility Bruise easily Easy bruisability Easy bruising [ more ] 0000978 Diplopia Double vision 0000651 Dysphagia Poor swallowing [rarediseases.info.nih.gov]

• Abdominal Distension

  Hepatosplenomegaly may result in early satiety, upper abdominal pain, and distension. [symptoma.com]

  Patients had mild and transient adverse events to oral eliglustat, arthralgia metacarpo-phalangeal and proximal interphalangeal joints (Case 4); abdominal distension (Case 5). Only patient 1 persists with mild dry skin (Case 1). [clinmedjournals.org]

• Bleeding Gums

  Bleeding gums 0000225 Kyphosis Hunched back Round back [ more ] 0002808 Pancytopenia Low blood cell count 0001876 Ptosis Drooping upper eyelid 0000508 Respiratory insufficiency due to muscle weakness Decreased lung function due to weak breathing muscles [rarediseases.info.nih.gov]

• Hepatosplenomegaly

  Discussion Gaucher disease patients are generally diagnosed by symptoms of hepatosplenomegaly or bone disease in childhood, whereas lesser degrees of hepatosplenomegaly occur in adults [2,3]. [karger.com]

  Hepatosplenomegaly, anemia, thrombocytopenia, bone pain, and skeletal changes are found. Cutaneous signs are infrequent and nonspecific. Brown spots at the edge of the cornea are sometimes found. [youtube.com]

  The multisystem disease is predominantly characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. [ncbi.nlm.nih.gov]

  Additionally, up to 1-year post-treatment, hepatosplenomegaly and growth parameters improved with no side effects. [mdmag.com]

• Hepatomegaly

  Radiographically, hepatomegaly and splenomegaly respond more rapidly than skeletal changes. Glucosylceramide synthase inhibitors are available for patients with type 1 GD who cannot receive enzyme replacement therapy 8. [radiopaedia.org]

  LS, hepatomegaly, splenomegaly, hemoglobin, platelets, and growth rate were measured every 6 months after beginning ERT for 30 months. [ncbi.nlm.nih.gov]

  Splenomegaly and hepatomegaly No cases of splenomegaly or hepatomegaly were reported prior to, or post, eliglustat treatment (Table 1). [clinmedjournals.org]

• Bone Pain

  pain and bone crises. [ojrd.biomedcentral.com]

  GD-related events were spontaneously reported by the study investigators for 39% of the whole study population, including asthenia/fatigue (8%), bone infarction and bone pain (4% each), and hepatomegaly (3%). [ncbi.nlm.nih.gov]

  Skeletal involvement by Gaucher disease is common and can take the form of bone pain, fractures of bone, and a defect of the thigh bone (femur). [medicinenet.com]

• Osteopenia

  They manifest as deformations, osteopenia that sometimes causes pathological fractures or vertebral compression, bone infarctions or even aseptic osteonecrosis. [orpha.net]

  Dual-energy X-ray absorptiometry (DEXA) scanning: evaluation of osteopenia. [patient.info]

  Osteopenia and cortical thinning is likely related to increased osteoclast activation by delivery of proinflammatory cytokine from storage cells which infiltrate bone. [hindawi.com]

  Features of skeletal involvement include: osteopenia osteonecrosis pathological/crush fractures endosteal scalloping Erlenmeyer flask deformities H-shaped vertebrae paranasal sinus obliteration due to medullary expansion 9 MRI spleen massive splenomegaly [radiopaedia.org]

• Osteoporosis

  Brief Summary: Bone-related problems represent the principal unmet medical need in Gaucher disease (GD). 75% of GD type 1 patients develop skeletal complications, including bone remodeling defects, osteopenia, osteoporosis, marrow infiltration, avascular [clinicaltrials.gov]

  Gaucher disease tend to be similar in all three types of the diseae with enlargement of the liver and spleen, anemia, nose bleeds, reduced platelets (resulting in easy bruising and long clotting times), bone pain ("bone crises"), bone deterioration, osteoporosis [youtube.com]

  Osteoporosis can lead to an increased risk of fractures, pain, and other problems, and the higher risk of bleeding can also have an impact on different aspects of health. Some additional complications may occur. [medicalnewstoday.com]

  Skeletal disease may occur later for the infiltration of bone marrow by macrophages infiltration and bone resorption: bone involvement may be heterogeneously manifested by symptoms ranging from bone crisis to avascular necrosis, osteoporosis and defect [hindawi.com]

• Arthralgia

  […] following 10 adverse events noted in the eliglustat US Prescribing Information (USPI) and EU Summary of Product Characteristics (SmPC) were evaluated with regard to frequency, drug-relatedness, severity, seriousness, duration, and timing of onset: headache, arthralgia [ncbi.nlm.nih.gov]

  Patients had mild and transient adverse events to oral eliglustat, arthralgia metacarpo-phalangeal and proximal interphalangeal joints (Case 4); abdominal distension (Case 5). Only patient 1 persists with mild dry skin (Case 1). [clinmedjournals.org]

• Epistaxis

  A 71‐year‐old man with a 6‐year history of thrombocytopenia presented with epistaxis. Examinations showed a low platelet count and lesions in lung, pleura, and left ethmoid sinus. The liver and the spleen were unremarkable. [onlinelibrary.wiley.com]

  […] infiltrates Lung infiltrates 0002113 Vertebral compression fractures Compression fracture 0002953 Percent of people who have these symptoms is not available through HPO Abnormality of the eye Abnormal eye 0000478 Autosomal recessive inheritance 0000007 Epistaxis [rarediseases.info.nih.gov]

• Pelvic Pain

  […] lipomatosis Pelvic pain syndrome - See Interstitial cystitis - not a rare disease Pelvic retroperitoneal liposarcoma - See Retroperitoneal liposarcoma Pelviscapular dysplasia - See Cousin syndrome Pelvi-ureteric junction obstruction - See Multicystic [rarediseases.info.nih.gov]

• Headache

  The following 10 adverse events noted in the eliglustat US Prescribing Information (USPI) and EU Summary of Product Characteristics (SmPC) were evaluated with regard to frequency, drug-relatedness, severity, seriousness, duration, and timing of onset: headache [ncbi.nlm.nih.gov]

  See Erythromelalgia Primary Exertional Headache - See Exertional headache Primary familial and congenital polycythemia Primary familial brain calcification - See Primary Familial Brain Calcification Primary Familial Brain Calcification Primary familial [rarediseases.info.nih.gov]

• Asthenia

  GD-related events were spontaneously reported by the study investigators for 39% of the whole study population, including asthenia/fatigue (8%), bone infarction and bone pain (4% each), and hepatomegaly (3%). [ncbi.nlm.nih.gov]

  It is characterized by the association of frequent asthenia, growth retardation or delayed puberty, splenomegaly (90% of cases) that may be complicated by splenic infarctions (sometimes superinfected), hepatomegaly (80% of cases) and in rare cases can [orpha.net]

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 [1]. 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.

The aspiration or biopsy of liver, spleen, or bone marrow is not required for the diagnosis of GD1. However, if such samples are histologically examined, Gaucher cells may be observed.

• Leukopenia

  Decreased platelet counts (thrombocytopenia) as well as low hemoglobin (anemia) and decreased white blood cell counts (leukopenia) result in easy bruisability and hence black-and-blue marks (ecchymoses); easy bleeding--for example, after dental interventions [scientificamerican.com]

  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. [symptoma.com]

  Haematological abnormalities are common - eg, anaemia, thrombocytopenia and leukopenia. Immunological abnormalities are also common - eg, hypergammaglobulinaemia, T-lymphocyte deficiency in the spleen and impaired neutrophil chemotaxis. [patient.info]

  Skeletal weakness and bone disease may be extensive.[3] Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia, and leukopenia. [en.wikipedia.org]

  […] obstruction 0005230 Cirrhosis Scar tissue replaces healthy tissue in the liver 0001394 Hematuria Blood in urine 0000790 Increased antibody level in blood 0010702 Interstitial pulmonary abnormality Abnormality in area between air sacs in lung 0006530 Leukopenia [rarediseases.info.nih.gov]

• Cytopenia

  PATIENTS AND METHODS: Six non-Jewish patients with sporadic GD1 were initially examined with ASP and TB to establish the cause of cytopenia and splenomegaly. In the current study, samples from each patient consisted of 2 bone marrow slides. [ncbi.nlm.nih.gov]

  Hepatosplenomegaly, anemia, leukocytopenia, thrombo-cytopenia are the pivotal clinical manifestations. Skeletal involvement, another important clinical feature of GD, is the most painful and debilitating symptom of the disease [2]. [hindawi.com]

  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. [symptoma.com]

• Liver Biopsy

  The liver biopsy specimen showed that numerous large cells with striated cytoplasm assembled in Glisson's capsule (fig. 2). [karger.com]

  Case 1 evaluated the misdiagnosis (from childhood) of spherocytosis in a 37-year-old Caucasian woman, which resulted in an inappropriate liver biopsy and delayed appropriate management and treatment. [mdmag.com]

  Liver disease (but not Gaucher disease [GD]) was suspected and therefore a liver biopsy was performed. [touchoncology.com]

  A bone marrow or liver biopsy is not necessary to establish the diagnosis. When the specific gene mutation causing Gaucher disease is known in a family, DNA testing can be used to accurately identify carriers. [genome.gov]

• Hepatocellular Carcinoma

  The National Gaucher Foundation suggests there is an increased risk of myeloma and hepatocellular carcinoma, or liver cancer. Parkinson’s disease: there may be a link with Parkinson’s, according to a study published in Autophagy. [medicalnewstoday.com]

  […] of Liver Cell - See Childhood hepatocellular carcinoma Pediatric Crohn's disease Pediatric Hepatocellular Carcinoma - See Childhood hepatocellular carcinoma Pediatric Hepatoma - See Childhood hepatocellular carcinoma Pediatric hypertension Pediatric [rarediseases.info.nih.gov]

  carcinoma, melanoma and pancreatic cancer).16–19 Skeletal disorders due to bone marrow infiltration (e.g. pathological fractures, osteolytic lesions and osteonecrosis) are also common and may be associated with a significantly reduced quality of life [touchoncology.com]

• Bone Marrow Gaucher Cells

  The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, of the spleen and the bone marrow (Gaucher cells). [orpha.net]

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 [1]. 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 [3]. 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 [1]. Gene therapy may constitute an alternative for curing GD1 but is not yet sufficiently developed for practical use [4].

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 [1].

GD1 patients may be predisposed to Parkinson's disease and certain types of cancer [1]. 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 [5]. 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 [6]. 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 [7].

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 [2] [8]. 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 [8]. 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 [4].

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 [2]. 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 [1]. 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 [1] [2]. 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 [6].

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 [2]. 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 [1] [2].

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 [9]. 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 [1]. 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 [10] [11]. 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 [1] [4].

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.

1. Stirnemann J, Belmatoug N, Camou F, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017; 18(2).
2. Stone WL, Master SR. Gaucher Disease. StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2018.
3. Somaraju UR, Tadepalli K. Hematopoietic stem cell transplantation for Gaucher disease. Cochrane Database Syst Rev. 2017; 10:Cd006974.
4. Mistry PK, Lopez G, Schiffmann R, Barton NW, Weinreb NJ, Sidransky E. Gaucher disease: Progress and ongoing challenges. Mol Genet Metab. 2017; 120(1-2):8-21.
5. Vilageliu L, Grinberg D. Involvement of Gaucher Disease Mutations in Parkinson Disease. Curr Protein Pept Sci. 2017; 18(7):758-764.
6. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009; 361(17):1651-1661.
7. Taddei TH, Kacena KA, Yang M, et al. The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients. Am J Hematol. 2009; 84(4):208-214.
8. Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008; 29(5):567-583.
9. Yoshida S, Kido J, Matsumoto S, et al. Prenatal diagnosis of Gaucher disease using next-generation sequencing. Pediatr Int. 2016; 58(9):946-949.
10. Diaz-Font A, Cormand B, Santamaria R, Vilageliu L, Grinberg D, Chabas A. A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity. Hum Genet. 2005; 117(2-3):275-277.
11. Motta M, Camerini S, Tatti M, et al. Gaucher disease due to saposin C deficiency is an inherited lysosomal disease caused by rapidly degraded mutant proteins. Hum Mol Genet. 2014; 23(21):5814-5826.