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Gaucher disease (GD) is the most common lysosomal disorder resulting from deficient activity of the β-glucosidase enzyme, that causes accumulation of glucosylceramide in the macrophage-monocyte system. Notably, because of non-specific symptoms and a lack of awareness, GD patients experience long diagnostic delays. The aim of this study is to apply...
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Context 1
... clinical features and laboratory parameters of GD patients were compared to DBS-negative patients in our cohort (Tables 3 and 4). Table 3 confirms that bone pain (42% vs. 22%), history of haemorrhage (14% vs. 4.8%) and growth retardation (14% vs. 1%) can be to some extent suggestive signs of GD, whereas neither bipolar spleen diameter nor history of fracture or gallstones is significant. ...Context 2
... clinical features and laboratory parameters of GD patients were compared to DBS-negative patients in our cohort (Tables 3 and 4). Table 3 confirms that bone pain (42% vs. 22%), history of haemorrhage (14% vs. 4.8%) and growth retardation (14% vs. 1%) can be to some extent suggestive signs of GD, whereas neither bipolar spleen diameter nor history of fracture or gallstones is significant. Concerning the laboratory tests including CBC, liver function, iron and ferritin status, and serum protein electrophoresis, serum ferritin is the only parameter significantly increased in these patients with GD (median 531 ng/mL, range 294-1457 ng/ mL) compared to patients without GD (median 119 ng/mL, range 5-1500 ng/mL, P = 0.005) ( Table 4). ...Similar publications
Background:
Gaucher disease (GD) is an autosomal recessive disorder characterized by excessive accumulation of glucosylceramide in multiple organs. This study was performed to determine the detection rate of GD in a selected patient population with unexplained splenomegaly in Korea.
Methods:
This was a multicenter, observational study conducted...
Citations
... The inclusion of GD in differential diagnosis has been extensively implemented through education programs, diagnostic algorithms, and many studies that have evaluated the prevalence of GD in high-risk populations in different regions [16,[35][36][37][38][39]. These programs, in addition to the development of specific and sensitive easy-to-use tools of great support to clinicians for the analysis of glucocerebrosidase activity on DBS, have contributed to the consideration of Gaucher disease as among the possible diagnostic hypotheses and to an increase in testing of suspected cases. ...
Background: Gaucher disease is a lysosomal storage disorder caused by functional glucocerebrosidase enzyme deficiency. Hepatosplenomegaly and hematological complications are found in both Gaucher disease and Acid Sphingomyelinase Deficiency, which is caused by acid sphingomyelinase dysfunction. The possible overlap in clinical presentation can cause diagnostic errors in differential diagnosis. For this reason, in patients with an initial clinical suspicion of Gaucher disease, we aimed to carry out a parallel screening of acid sphingomyelinase and glucocerebrosidase. Methods: Peripheral blood samples of 627 patients were collected, and enzymatic activity analysis was performed on both glucocerebrosidase and acid sphingomyelinase. The specific gene was studied in samples with null or reduced enzymatic activity. Specific molecular biomarkers helped to achieve the correct diagnosis. Results: In 98.7% of patients, normal values of glucocerebrosidase activity excluded Gaucher disease. In 8 of 627 patients (1.3%), the glucocerebrosidase enzymatic activity assay was below the normal range, so genetic GBA1 analysis confirmed the enzymatic defect. Three patients (0.5%) had normal glucocerebrosidase activity, so they were not affected by Gaucher disease, and showed decreased acid sphingomyelinase activity. SMPD1 gene mutations responsible for Acid Sphingomyelinase Deficiency were found. The levels of specific biomarkers found in these patients further strengthened the genetic data. Conclusions: Our results suggest that in the presence of typical signs and symptoms of Gaucher disease, Acid Sphingomyelinase Deficiency should be considered. For this reason, the presence of hepatosplenomegaly, thrombocytopenia, leukocytopenia, and anemia should alert clinicians to analyze both enzymes by a combined screening. Today, enzyme replacement therapy is available for the treatment of both pathologies; therefore, prompt diagnosis is essential for patients to start accurate treatment and to avoid diagnostic delay.
... When we compared laboratory data of GD patients with the rest of the cohort, we found that serum ferritin was significantly elevated in GD patients. This finding is consistent with previous reports from adults [25,26]. Since this finding is probably related to macrophage activation and the subsequent release of IFs and IL-4 pathway-mediated cytokines [27], it is reasonable to assume that enzyme replacement therapy (ERT) can reduce ferritin levels by modulating inflammatory response [28]. ...
... 24 Department of Pediatric and Gynecology, Pediatric Onco-hematology, Perugia Regional Hospital, Perugia, Italy. 25 Department of Obstetrics and Gynaecology, AOR San Carlo, Potenza, Italy. 26 Ospedale Civile, Pescara, Italy. ...
Background
Gaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD.
Materials and methods
DBS samples were collected and tested for β-glucocerebrosidase enzyme activity for 154 patients selected through the algorithm proposed by Di Rocco et al. Patients showing β-glucocerebrosidase activity below normal values were recalled to confirm the enzyme deficiency with the gold standard essay on cellular homogenate. Patients tested positive at the gold standard analysis were evaluated through GBA1 gene sequencing.
Results
14 out of 154 patients were diagnosed with GD, with a prevalence of 9.09% (5.06–14.78%, CI 95%). Hepatomegaly, thrombocytopenia, anemia, growth delay/deceleration, elevated serum ferritin, elevated Lyso-Gb1 and chitotriosidase were significantly associated with GD.
Conclusions
GD prevalence in a pediatric population at high-risk appeared to be higher compared to high-risk adults. Lyso-Gb1 was associated with GD diagnosis. The algorithm proposed by Di Rocco et al. can potentially improve the diagnostic accuracy of pediatric GD, allowing the prompt start of therapy, aiming to reduce irreversible complications.
... In 2011 Mistry e al. published the first algorithm for early diagnosis of GD1 in adult patients [18], then implemented in a multicenter study in Italy [19]. Five hundred subjects have been enrolled, and the prevalence of GD1 in a high-risk predominantly Caucasian population with splenomegaly and/or thrombocytopenia resulted above 3% [20]. ...
... However, early diagnosis of GD1 and ASMD is crucial for appropriate management, including specific treatment with ERT or SRT. We previously showed that applying an algorithm for Gaucher disease to a high-risk population with splenomegaly and/or thrombocytopenia [19,20] positively impacts age at diagnosis. Based on this experience, we herein present an algorithm that could support the physician in suspecting GD1 and ASMD in subjects presenting with splenomegaly or hepatomegaly and further differentiating signs or symptoms. ...
Lysosomal storage disorders are a group of inborn errors of metabolism due to defects in proteins crucial for lysosomal function. Gaucher disease is the most common autosomal recessive lysosomal storage disorder due to mutations in the GBA1 gene, resulting in the lysosomal deficiency of glucocerebrosidase activity. Gaucher disease is characterized by the toxic accumulation of glucosylceramide in the reticuloendothelial system. Acid sphingomyelinase deficiency (ASMD), previously known as Niemann Pick A/B disease, is also an autosomal recessive lysosomal storage disorder due to mutations in the SMPD1 gene, which result in acid sphingomyelinase deficiency and the accumulation of sphingomyelin in mononuclear phagocytic system and hepatocytes. The phenotypic expression of Gaucher disease type 1 (GD1), the most common type, and chronic visceral ASMD may overlap for several signs or symptoms. Splenomegaly is detectable in approximately 90% of the patients in both conditions; however, since GD1 is more frequent than ASMD, clinicians are more prone to suspect it, often neglecting the diagnosis of ASMD.
Based on previous experience, a group of experts in the clinical and laboratory diagnosis, management, and treatment of lysosomal storage disorders developed an algorithm for both GD1 and ASMD to support physicians, including primary care providers, internists, and specialists (e.g., hepatologists, hematologists, and pulmonologists) to suspect and differentiate GD1 and ASMD and to provide the appropriate referral.
... A study conducted in Italy reported that 3.3% of patients with splenomegaly and/or thrombocytopenia were diagnosed with GD [11]. Our study enrolled patients with unexplained splenomegaly without the requirement for additional symptoms such as thrombocytopenia to make the screening available for a wider population; additionally, it relied on interim data from the Cappellini study in which all (100%) identified patients had splenomegaly and none had thrombocytopenia alone [13]. ...
... The GBA mutations in Korean patients were different from those of patients from other countries, including Italy, but were similar to those in patients from Japan and China [5,13]. N370S, the most common mutation in the Ashkenazi Jewish population that is known to be associated with GD1 has never been reported in Korean patients, including those enrolled in previous studies [5,15]. ...
... According to a recent report from the International Collaborative Gaucher Group (ICGG) registry, the diverse global population has two GBA mutations in patients with GD3; L444P (77%) and D409H (7%) [16]. In Korea, L444P (20.8%) is the most prevalent mutation and is often associated with a neuronopathic form of the disease, followed by G46E (13.9%), which is suspected to be associated with the non-neuronopathic form, and F213I (12.5%) [13]. The most frequent allele found in Japan is F213I, which is associated with neurological manifestations of GD and is identified in all three types of GD in the Korean population [13,17]. ...
Background:
Gaucher disease (GD) is an autosomal recessive disorder characterized by excessive accumulation of glucosylceramide in multiple organs. This study was performed to determine the detection rate of GD in a selected patient population with unexplained splenomegaly in Korea.
Methods:
This was a multicenter, observational study conducted at 18 sites in Korea between December 2016 and February 2020. Adult patients with unexplained splenomegaly were enrolled and tested for β-glucosidase enzyme activity on dried blood spots (DBS) and in peripheral blood leukocytes. Mutation analysis was performed if the test was positive or indeterminate for the enzyme assay. The primary endpoint was the percentage of patients with GD in patients with unexplained splenomegaly.
Results:
A total of 352 patients were enrolled in this study (male patients, 199; mean age, 48.42 yr). Amongst them, 14.77% of patients had concomitant hepatomegaly. The most common sign related to GD was splenomegaly (100%), followed by thrombocytopenia (44.32%) and, anemia (40.91%). The β-glucosidase activity assay on DBS and peripheral leukocytes showed abnormal results in sixteen and six patients, respectively. Eight patients were tested for the mutation, seven of whom were negative and one patient showed a positive mutation analysis result. One female patient who presented with splenomegaly and thrombocytopenia was diagnosed with type 1 GD. The detection rate of GD was 0.2841% (Exact 95% CI, 0.0072-1.5726).
Conclusion:
The detection rate of GD in probable high-risk patients in Korea was lower than expected. However, the role of hemato-oncologists is still important in the diagnosis of GD.
... Visceral organs, bone marrow and bones are affected in almost all. The most common finding is splenomegaly (10). Isolated thrombocytopenia alone is the most common cytopenia. ...
Gaucher disease (GD) is a rare hereditary lysosomal storage disease that arises due to deficiency of glucocerebrosidase. Early diagnosis is very important for starting proper treatment and preventing complications. Splenomegaly, anemia, and thrombocytopenia are the most common findings in GD and so most patients are initially referred to hematologists. The Turkish Society of Hematology established its Rare Hematological Diseases Subcommittee in 2015. One of the main topics of this subcommittee was to increase and improve awareness and education of rare diseases among hematologists in Turkey. This review presents GD with an overview of its clinical features, pathophysiology, and treatment options for hematologists.
... Motta et al. [22] revealed that the prevalence of GD in patients with splenomegaly and/or thrombocytopenia was 3.6% (95% CI = 1.4-7.2; 1/28 patients) diagnosed by acid β-glucosidase enzyme activity on DBS testing. ...
... A long duration is often required before a correct diagnosis or treatment, which implies considerable discomfort for the patients with rare diseases, such as GD, and their families. To the best of our knowledge, few studies have focused on health service utilization and costs of GD, including the diagnosis [20]. ...
... The main reason for the prolonged diagnostic delay most likely is insufficient knowledge on GD [31][32][33] by the medical community due to its low prevalence, extreme variations in clinical manifestations [28,34], and severity of symptoms (e.g., bone pain/bone crisis, thrombocytopenia, and splenomegaly ) [20,26,28]. Nevertheless, a survey revealed that only one of five hematologist-oncologist considers GD in the differential diagnosis of patients with a history of anemia, thrombocytopenia, hepatomegaly, splenomegaly, and bone pain. ...
Background
The diagnosis and health care of patients with rare diseases present a tremendous challenge worldwide. This study described the health care service utilization through participants’ perspective and estimated the cost of illness (COI), and patients with Gaucher disease (GD)’s/caregivers’ health-related quality of life in China.
Method
An online retrospective survey of patients with GD and their caregivers was conducted during May–June 2018. Socio-demographic, health service utilization, disease-related expenses, social support, sleep quality (Pittsburgh Sleep Quality Index [PSQI]), and the Short Form Health Survey (SF-36) were investigated. Using self-reported information, we estimated the annual COI, including direct healthcare, direct non-healthcare, and indirect costs.
Results
Forty patients and their 49 caregivers were surveyed. The patients’ onset age of GD was 9.3 ± 10.9; their disease course was 3.5 ± 3.1 years. 21 (42.9%) patients had ≥ 2 caregivers, but 35 (71.4%) caregivers reported have no experience as a caregiver. 79.6% caregivers have stopped working, and 87.8% changed weekly working schedule. Before final diagnosis, patients visited 3.9 ± 3.1 (max = 20) hospitals and took 1.2 ± 1.7 (max = 6.6) years for confirmed diagnosis. On average, 5.0 ± 9.6 misdiagnoses occurred, and the per-patient diagnoses cost was USD ($) 7576. After GD confirmation, 8 (16.3%) patients received no treatment, 40 (81.6%) received pharmacotherapy, 10 (20.4%) received surgery, 38 (77.6%) received outpatient service (8.8 ± 9.1 times/annually), and 37 (77.5%) received inpatient service (4.0 ± 3.5 times/annually). Annual per-patient COI was USD ($) 49,925 (95% confidence interval: 29,178, 70,672). Average direct healthcare cost was $41,816, including pharmaceutical ($29,908), inpatient ($7,451), and outpatient ($1,838). Productivity loss per-caregiver was $1,980, and their Zarit Burden Inventory score was moderate-severe (48.6 ± 19.6). Both patients/caregivers reported lower social support (32.4 ± 7.4, 34.9 ± 7.6), two times higher PSQI (7.9 ± 2.9, 8.7 ± 3.6), and half lower SF-36 (41.3 ± 18.6, 46.5 ± 19.3) than those reported for healthy Chinese individuals.
Conclusions
The high misdiagnosis rate, together with delayed diagnosis, substantial costs, and deteriorated health-related quality of life of GD patients as well as their heavy care burden, calls for extreme attention from policymakers in China. Further efforts of government and society are urgently demanded, including pharmaceutical reimbursement, screening newborns, developing precise diagnostic tools, and training doctors.
... It is an autosomal recessive disorder with an elevated prevalence in the Ashkenazi Jewish population (1/600, carrier rate 1/15) compared to the non-Ashkenazi population (1/75000 births). The application of the above cited diagnostic algorithm led to the diagnosis of GD in 7 out of 196 previously undiagnosed patients, allowing substitutive enzymatic therapy [64,65]. ...
Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5′-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
... Although an enzymatic assay for GBA has been available since 1970 [8], tissue sampling, including bone biopsies, is also widely performed as the first step in the hematological diagnostic process [9]. In an Italian population presenting with splenomegaly and/or thrombocytopenia, the prevalence of GD was high at 3.6% (95% CI: 1.4-7.2) [10]. Actually, in Japan, a Gaucher disease patient was diagnosed by the identification of thrombocytopenia at a routine medical checkup. ...
Gaucher disease is a rare genetic disorder caused by the deficiency of acid β-glucosidase to effectively catalyze the degradation of glucosylceramide to glucose and ceramide. We report here the case of a 31-year-old male Japanese patient with Gaucher disease who switched from enzyme replacement therapy (ERT) to substrate reducing therapy (SRT). Liver dysfunction was identified at a routine medical checkup, and the patient was referred to our hospital with “idiopathic liver disease.” Clinical laboratory tests indicated thrombocytopenia and splenomegaly, which are characteristic symptoms of Gaucher disease. To definitively diagnose Gaucher disease, a bone marrow biopsy and acid β-glucosidase activity measurement were conducted; the results supported a diagnosis of Gaucher disease. This case emphasizes that it is possible for periodic medical checkups in adults to lead to the diagnosis of rare genetic disorders. The patient underwent ERT treatment with imiglucerase for 5 years; the platelet count rapidly increased and the spleen size rapidly decreased, indicating a good response to the drug. However, the patient increasingly felt the burden of visiting the hospital for 2 h of infusion ERT every 2 weeks. Consequently, it was jointly decided that he should switch from ERT to SRT with an oral drug. This switch was successful with no deterioration of laboratory data. This case report is the first to describe a Japanese Gaucher disease patient treated with eliglustat for >2 years. We showed that SRT is a well-tolerated and effective option for the treatment of Gaucher disease.
... www.nature.com/scientificreports/ of GD1 in a high-risk population presenting to the hematologist with splenomegaly and/or thrombocytopenia associated with other hematological signs or symptoms suggestive of GD1. Preliminary results of this study on the first 196 patients have been previously published, showing a GD1 prevalence of 3.6% in a high-risk population 7 . ...
Hematologists are frequently involved in the diagnostic pathway of Gaucher disease type 1 (GD1) patients since they present several hematological signs. However, GD1 is mainly underdiagnosed because of a lack of awareness. In this multicenter study, we combine the use of a diagnostic algorithm with a simple test (β-glucosidase activity on Dried Blood Spot) in order to facilitate the diagnosis in a population presenting to the hematologist with splenomegaly and/or thrombocytopenia associated with other hematological signs. In this high-risk population, the prevalence of GD1 is 3.3%. We propose an equation that predicts the probability of having GD1 according to three parameters that are routinely evaluated: platelet count, ferritin, and transferrin saturation.
