|Year : 2021 | Volume
| Issue : 3 | Page : 123-133
Diagnosis and management of hematological manifestations of gaucher disease: Insights from Saudi Arabia
Tarek Owaidah1, Fahad Alabbas2, Iman Alhazmi3, Hussain Al Saeed4, Saud Balelah5, Ghaleb ElYamany6, Ohoud Kashari7, Mohamad Qari8, Mahasen Saleh9, Sherif Roushdy10, Marwan ElBagoury10
1 King Faisal Specialist Hospital and Research Center; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
2 Department of Pediatric, Division of Pediatric Hematology and Oncology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
3 Department of Medicine, Division of Hematology and Oncology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
4 College of Medicine, Qatif Central Hospital, Qatif, Saudi Arabia
5 Department of Hematology, King Fahad Hospital, Madinah, Saudi Arabia
6 Department of Central Military Laboratory and Blood Bank, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
7 Department of Pediatrics, and Academic and Training Affairs, East Jeddah General Hospital, Jeddah, Saudi Arabia
8 Department of Hematology, King Fahd Medical Research Center, Hematology Research Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
9 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
10 Department of Medical Affairs, Sanofi-Genzyme, Gulf Region, Riyadh, Saudi Arabia
|Date of Submission||16-Jun-2021|
|Date of Decision||11-Jul-2021|
|Date of Acceptance||16-Jul-2021|
|Date of Web Publication||21-Oct-2021|
Prof. Tarek Owaidah
P.O Box: 3354, Riyadh, 11211
Source of Support: None, Conflict of Interest: None
Gaucher disease (GD) is a lysosomal storage disorder that occurs due to an inherited inborn error of metabolism. GD manifested due to the deficient activity of the glucocerebrosidase enzyme that results in the accumulation of the harmful glucocerebrosides glycolipids in different body cells. There are three main types of GD that differ from each other in their clinical presentations. Type I characterized by the absence of any neurological involvement, unlike Type II and Type III. Patients with Gaucher can be presented with visceral manifestations (including splenomegaly, hepatomegaly, or abdominal pain), hematological manifestation (anemia or thrombocytopenia or bleeding diathesis), bone manifestations (painful limbs or pathological fractures), or neurological manifestations (including neck rigidity, swallowing disorder, or oculomotor paralysis). In the Middle East, especially Saudi Arabia, a higher prevalence of genetic diseases was observed compared to reported rates in Europe and the United States. However, published data on the characteristics and treatment patterns of Gaucher patients in Saudi Arabia are still lacking in the literature. Therefore, the present manuscript aimed to present an overview of the GD situation in Saudi Arabia by bringing together a panel of Saudi hematology experts to share their views on current trends and practices in Saudi Arabia regarding GD. The experts agreed that there is no available data regarding the prevalence and incidence of GD in Saudi Arabia, therefore the experts recommend establishing a national registry for Gaucher cases. The diagnosis of GD is challenging as the disease is rare and obscure, even to hematologists. The experts also recommend shifting from the dried blood spots test to genetic testing in the future to confirm the diagnosis of GD. The experts agreed on the need to organize awareness campaigns to familiarize the primary care physicians and junior hematologists about the common presentations and management of GD.
Keywords: Gaucher disease, glucocerebrosidase, lysosomal storage disease, metabolic disorders, Saudi
|How to cite this article:|
Owaidah T, Alabbas F, Alhazmi I, Al Saeed H, Balelah S, ElYamany G, Kashari O, Qari M, Saleh M, Roushdy S, ElBagoury M. Diagnosis and management of hematological manifestations of gaucher disease: Insights from Saudi Arabia. J Appl Hematol 2021;12:123-33
|How to cite this URL:|
Owaidah T, Alabbas F, Alhazmi I, Al Saeed H, Balelah S, ElYamany G, Kashari O, Qari M, Saleh M, Roushdy S, ElBagoury M. Diagnosis and management of hematological manifestations of gaucher disease: Insights from Saudi Arabia. J Appl Hematol [serial online] 2021 [cited 2022 Jan 26];12:123-33. Available from: https://www.jahjournal.org/text.asp?2021/12/3/123/328723
| Introduction|| |
Gaucher disease (GD) is a rare, heterogeneous, inherited inborn error of metabolism which is classified as one of the lysosomal storage disorders (LSDs). It arises as a consequence of autosomal recessive inheritance of glucocerebrosidase (GBA) gene mutations, which is primarily encoding the lysosomal enzyme acid β-glucosidase. As a result of the inappropriate enzymatic activity, incremental piling up of glucosylceramide in lysosomes of macrophages takes place typically in the spleen, liver, bone, and bone marrow. Moreover, pathogenic secondary substrates (e.g, glucosylsphingosine) may also accumulate in different cells. GD discloses a wide range of manifestations, age at the first symptom, and disease severity. This range may extend from a fatal disease at the time of infancy to octogenarians as first age at symptoms onset.,
Of the all known LSDs (such as GD, Fabry disease, Niemann-Pick disease, Hunter syndrome, and Pompe disease), GD is the most common disorder worldwide. The epidemiology of GD has a pan-ethnic pattern, which means it changes substantially among different ethnic groups. According to a study published in early 1999, one child for every 57,000 live births worldwide has GD. While in the Jewish Ashkenazi population, GD showed an incidence of 1 for every 2500 individuals. Data regarding the prevalence of GD in the kingdom of Saudi Arabia are not available in the literature, however, based on our clinical practice, we think the prevalence of GD in Saudi Arabia is much higher than in western countries.
Clinical presentation of GD varies according to patient phenotype and onset of presentation. GD is formed of three major phenotypes that can be distinguished clinically from each other. Type-1 GD is the most common phenotype and it can be distinguished from the other types by the absence of any neurological involvement. Patients with Type-1 GD usually presented with fatigue, splenomegaly, hepatomegaly, a focal lesion in the liver or spleen (Gaucheromas), gall stones, and acute painful limbs (bone crisis). On the other hand, Type-2 GD and Type-3 GD are manifested by neurological impairment. Patients with Type-2 GD commonly presented with severe and early neurological manifestations. Neck rigidity (opisthotonus), swallowing disorder (bulbar signs), and oculomotor paralysis are very suggestive neurological triad for Type-2 GD. Type-3 GD is usually manifested in patients <20 years of age, so it is commonly called juvenile GD. Type-3 GD is further classified into three categories (a, b, and c). GD Type-3a patients are usually manifested by mild visceral symptoms and a variety of neurological manifestations (such as cognitive impairment, muscle weakness, and ataxia), however, life-threatening myoclonic seizures can occur.,, On the other hand, patients with Type-3b usually presented with severe systemic manifestations including hepatosplenomegaly, anemia, thrombocytopenia, and bone manifestations (such as kyphosis). Type-3c GD is characterized by eye involvement in the form of corneal opacities and valvular heart disease with progressive calcification.,,
Complications of GD include hepatic and splenic infarction which manifested as pseudo surgical abdominal pain, a splenic rupture in severe cases of splenomegaly, cancer of the liver and spleen (such as hepatocellular carcinoma [HCC] and lymphoma), pulmonary hypertension, delayed growth, and puberty in children, gynecological and obstetric problems (such as heavy menstruation, first-trimester abortions, and infertility), epilepsy and dementia (if severe neurological involvement), and Skeletal complications.
The treatment of GD depends mainly on the phenotype and the symptoms of the patient, however, enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) is considered the standard treatment that is prescribed for all GD patients. Other treatment options include bone marrow transplantation, gene therapy, molecular proteins, and symptomatic treatment. However, published data on the characteristics and treatment protocols of GD patients in the Saudi Arabia are still lacking. Therefore, the present manuscript aimed to present an overview of the GD clinical practice in Saudi Arabia by bringing together a panel of Saudi experts to share their views on the current trends, practice, diagnosis, and management of GD in Saudi Arabia.
| Methodology|| |
The present manuscript was developed as a part of the Saudi hematology expert's efforts to address the current situation, clinical implications, diagnosis, and best care management regarding GD in Saudi Arabia. The authors aim to discuss diagnosis, and management of GD to be adopted by Saudi hematologists and other practitioners.
| Gaucher Disease Patient's Journey in Saudi Arabia|| |
Patients with Gaucher Disease have usually exhibited variable symptoms in their initial presentation; thus, they pass through different ways in their diagnosing journey. GD patients are commonly presented with splenomegaly, hepatomegaly, bone problems (such as bony ache, fractures, and arthritis), or bleeding symptoms of thrombocytopenia with unknown etiology or coagulation factors deficiencies (such as bruising, epistaxis, bleeding tendency), and avascular necrosis in severe cases).,
Gaucher disease patients' journey
The patient referral system relies mainly on the initial presenting symptom of the patients. The majority of the cases were referred to the hematologists from the gastrointestinal (GI) physician (due to the splenomegaly and hepatomegaly) or the pediatrician (due to the early onset of the disease). Most of the experts' groups agreed that the general pediatrician and the primary care physicians are usually the first to encounter the GD patient. The key element in the diagnosis and referral of a patient with GD to the specialist is to increase awareness to suspect the disease clinically as early as possible. Due to the rare cases of the disease, Gaucher's diagnosis is a challenging process and needs a physician with a basic knowledge of LSD. Referral of GD patients in Saudi Arabia differs from city to city.
Some GD patients can be referred to more than one specialist simultaneously during their disease journey. They may be referred to an orthopedic surgeon due to their bone abnormalities symptoms, a GI specialist for hepatomegaly, and GI symptoms, a pediatrician due to growth retardation, and to a hematologist due to symptoms of bleeding or anemia. The hematology experts notice in their clinical practice that; the direct referrals of GD patients from family medicine doctors or general physicians are rare and hepatosplenomegaly cases are usually referred to the GI physician.
General practitioners sometimes diagnose and refer GD patients as Immune thrombocytopenic purpura (ITP) cases as they cannot exactly differentiate what type of thrombocytopenia it is. Some patients have organomegaly (hepatosplenomegaly) along with thrombocytopenia from the start, therefore experts recommend starting the examination from the abdomen.
This manuscript stipulates the following points regarding GD patients journey in Saudi Arabia:
- The most prevalent presenting symptom usually indicates where the patient is initially referred to. Patients with thrombocytopenia are usually referred to a hematologist, whereas patients with prominent GI symptoms (such as hepatosplenomegaly) are referred to GI physicians. Pediatricians also receive several cases due to growth retardation problems and the early onset of the symptoms
- Some hematologists erroneously diagnose Gaucher as ITP, which can add to the diagnostic delay
- It is imperative to emphasize the two most common symptoms of GD (thrombocytopenia and hepatosplenomegaly) to primary care physicians to curb diagnostic delay
- The diagnostic timeline for GD could be in years due to the rarity and variety of presentations associated with the disease
- It is necessary to increase the awareness of primary care physicians about the common symptoms associated with GD.
| Barriers of Early Diagnosis of Gaucher Disease|| |
In clinical practice, a lot of barriers encounter the early diagnosis of GD in Saudi Arabia. The awareness of the primary care physicians and hematologists about the common and possible symptoms and presentation of GD patients is one of the most important problems that hamper the early diagnosis of GD. In a survey conducted by Mistry et al. on hematology specialists from variable countries, only 20% of the specialists considered GD in their differential diagnosis after presenting a hypothetical case with all of the common symptoms of GD (thrombocytopenia, hepatosplenomegaly, anemia, and bony aches). The percentage was much lower (4% and 16%–17%) when fewer symptoms were presented. This shows that GD is underdiagnosed even among hematology specialty physicians. Other causes for the diagnostic delays include variability of clinical manifestations.
Outcomes of the diagnostic delay
The diagnostic delay of GD exposes patients to a higher risk of complications and dozens of unnecessary investigations. This delay may reach up to 10 years or more in some rural areas. Furthermre, the risk of severe complications increases with the onset of the disease. These complications include malignancy (myeloma, leukemia, pituitary adenoma, and lymphoma), hepatic disorders (cirrhosis and HCC), portal hypertension, frozen shoulder, pathological bone fractures, growth failure, bleeding tendencies, or hemochromatosis.,
Awareness of Gaucher should be increased in areas with a high rate of consanguinity and blood disorders. Physicians in these remote areas should be more aware of Gaucher to be able to suspect patients early and refer them to specialists during the early stages of the disease. In the era of virtual meetings, it is more viable to host nationwide meetings for all physicians to increase the awareness of GD and rare diseases in general. This will help to alert the physicians' minds when they observe these findings and they may even suspect rare diseases other than GD.
Diagnostic tests availability
Availability of diagnostic tests is another reason for the diagnostic delay that occurs in GD in Saudi Arabia. Laboratory workup for GD diagnosis consists of routine complete blood count, blood film morphology to confirm the thrombocytopenia both the prothrombin time (PT) and the activated partial thromboplastin time to detect factor deficiency, beta-glucosidase leukocyte test to measure β-GBA enzyme activity, and genotype testing to detect genes mutations especially in Ashkenazi patients. Some common laboratory markers for GD are still not available in some areas of Saudi Arabia. Some experts recommend taking more than one blood sample from the patient, for potential DNA testing if required in the future. This is because it is usually difficult to summon the patient for multiple visits. Moreover, some diagnostic tests give false-positive results due to the similarity with other blood disorders.
The experts recommended the following to support diagnosis
- Educating primary care physicians to include GD in their differential diagnosis when encountering thrombocytopenia, anemia and splenomegaly will help to reduce the diagnostic delay, especially in the remote areas of Saudi Arabia
- The diagnostic tests for GD are not available in some remote areas of the Kingdom
- Taking more than one blood sample from the patient may be viable in case of any future genetic testing is required. This will lessen the number of patient visits
- Consider adding a next-generation test for diagnosis of genetic disorders including GD
- Correct transportation of samples is key to limit the false-positive results in enzymatic tests
- The delay in the dried blood spots (DBS) test, which can take up to 6 weeks, greatly contributes to diagnostic delay
- Logistical hurdles can sometimes prevent or delay the shipment of whole blood samples outside the Kingdom.
| Impact of the Localized Algorithm on Gaucher Disease Diagnosis|| |
Developing a localized algorithm for GD diagnosis in Saudi Arabia is one of the Saudi hematology experts' panels goals. The experts' assent to that the general physicians, but not hematologists, are the ones who need further education on GD. The experts recommended the use of standard cut-off values for different diagnostic parameters. Recently established, platelet cut-off 140,000 platelets per microliter of blood. In anemia, the threshold according to WHO should be 12 g/dl for females and 13 g/dl for males
Obstacles facing the localized algorithm
Several obstacles will complicate developing the Saudi localized algorithm. One of these obstacles is the availability of GD patients' records and the hardships of getting the required data. Not all physicians will accept and usually depend on their clinical practice and the old guidelines in the management of GD patients.
The experts underlined the need for different hematology societies to get together and accept the suggested algorithm or adopt a unified algorithm for the diagnosis and treatment of GD patients. This algorithm will impact the diagnostic process of GD in many ways including:
- Developing unified diagnostic criteria for GD to be applied all over the kingdom of Saudi Arabia
- More Gaucher cases will be discovered and reported
- A systematic referral scheme for GD cases can be developed to be adopted by Saudi physicians
- Practical and easy algorithm to be recalled, thus it will be easier for primary care physicians to diagnose the GD cases based on the algorithm
- The presence of a national algorithm is likely to improve awareness of GD among physicians.
Diagnostic algorithm for Gaucher disease in Saudi Arabia
As GD is a rare metabolic disorder, so its diagnosis should start by the exclusion of the other common disorders sharing the same presentation. In any suspected GD patient presenting with hepatomegaly or splenomegaly; the clinician should exclude the presence of portal hypertension or hemoglobinopathies before reaching a diagnosis of GD.
If the bone marrow biopsy showed Gaucher cells, an exclusion of conditions that are associated with pseudo-Gaucher cells should be done before the establishment of the GD diagnosis. An enzyme assay revealed a deficiency of acid β-glucosidase activity, an initial screening with DBSs or whole blood sampling should be carried to confirm the diagnosis of GD. The full details of the diagnostic algorithm of GD in adults and pediatrics approved by the panel experts' group are is presented in [Figure 1] and [Figure 2].
|Figure 1: Diagnostic algorithm for Gaucher disease in adults in Saudi Arabia. MGUS = Monoclonal gammopathy of unknown significance; BM = Bone marrow; DBS = Dried blood spot|
Click here to view
|Figure 2: Diagnostic algorithm for Gaucher disease in pediatrics in Saudi Arabia. HDL = High-density lipoprotein; DBS = Dried blood spot|
Click here to view
The following diagnostics recommendations were done
- First- and second-degree family studies can play a role in the diagnosis of GD
- To suspect GD, the thrombocytopenia cut-off in Riyadh will be 140,000 platelets per microliter, whereas the anemia cut-off will be set at 12 g/dL for females and 13 g/dL for males
- The intense efforts from different societies in the Saudi Arabia to create a unified algorithm for GD diagnosis will undoubtedly facilitate the diagnosis, especially for nonhematologists
- An algorithm for GD diagnosis should include how to discern sickle-cell anemia and ITP presentations.
Software (like the one used in the USA) to assist in GD diagnosis can help primary care physicians to include GD in their differential diagnosis.
| High-risk Testing of Gaucher Disease|| |
Developing a screening program for the high-risk population in Saudi Arabia is one of the fundamental purposes of this manuscript. Establishing an initial diagnosis of GD in the high-risk population is very challenging, however, it is very beneficial for both patients and the Saudi community. The following cases are considered the primary targets for the GD screening program as they are at a high risk to develop GD:,
- Patients with unexplained thrombocytopenia and splenomegaly
- Patients diagnosed as ITP and are not responding to ITP treatment or with associated anemia and or bone symptoms
- Patients with splenomegaly, gammopathies, or multiple myeloma that developed at a young age
- Unexplained prolongation of PT and or PTT with bleeding symptoms
- Patients with isolated thrombocytopenia and diagnosed as immune thrombocytopenia (ITP), but not responding to treatment or associated with anemia or bone aches
- People with a family history of GD.
Impact of Gaucher disease screening program of high-risk population
The Saudi government is moving from blood testing for genetic disorders toward whole-genome testing to identify novel mutations. The experts recommend governmental partnerships with large software companies to pair Electronic Medical Records software with machine learning. This would greatly facilitate searching for patients that fit the high-risk criteria. The screening program will be beneficial for genetic disorders as well as rare diseases. The experts also agreed that national adoption of the high-risk testing project would reduce the efforts and the financial burden related to GD diagnosis.
The benefits of the early diagnosis of GD and the other LSDs through the screening program include:
- Early diagnosis of GD/rare disorders is likely to reduce the burden on the health service
- Early discovery of genetic disorders and rare diseases, thus more effective treatment
- Screening can reduce the risk of developing a GD or its future complications
- Reduction of the diagnostic delay of GD
- Genotype detection as some gene mutations associated with GD may lead to severe complications (e.g, N370S gene mutation)
- Reduction of the financial burden related to the GD diagnosis.
Impact of epidemiological studies and electronic medical records
- Saudi Arabia would benefit from an epidemiological study on GD and other rare diseases to increase government intervention, hone diagnostic acuity, and reduce delayed diagnosis
- Patients who had a common symptom of GD (especially splenomegaly) identified several years ago are sometimes averse to taking the “new” DBSs test
- Electronic Medical Records and machine learning have a place in facilitating diagnosis and recognizing new trends and high-risk patients.
| Social Stigma Facing Patients with Gaucher Disease|| |
Common psychological troubles among Gaucher disease patients
Patients with rare diseases and genetic disorders like GD suffer from various mental health problems during their disease journey. They usually encountered these different psychological troubles due to the harmful interaction with the surrounding society. In a study conducted by Wendy Packman et al. GD patients reported difficulty in coping with the GD diagnosis, hardship of daily work with pain crisis and its negative effect on their career, and the psychological stress (anxiety and mood changes) accompanying the disease.
In Saudi Arabia, some families' names are linked with GD and rare diseases in general, and it could create problems in marriage for example. Furthermore, children are known to have genetic disorders as GD suffers from psychological and communications troubles in their school life. The foreign residents in the Saudi Arabia who are diagnosed with GD face hardships during their disease journey, as they often cannot access the resources provided by the government for Saudi patients.
Patients with GD and other genetic disorders usually facing social stigma in the form of extreme disapproval during their daily interactions with the surrounding people. In a study conducted by Klitzman and Sweeney. Patients with genetic health problems (Huntington's disease and Alpha-1 antitrypsin deficiency) reported being socially excluded by their friends, work colleagues, and relatives. In addition, patients avoided expressing their feelings and emotions as they feared being rejected by the other partner. Most Arab countries neglect to form official groups capable of representing local GD patients. For instance, only 3 Arab countries (Jordan, Morocco, and Tunisia) are part of the intergovernmental agreement (IGA), which enables countries to share their information and cooperate to solve a common problem or mutual concern.
The experts agreed on the following points regarding the social stigma experienced by GD patients:
- There is a need for support groups (patients' associations) to help people with rare diseases coping with the associated stress and possible stigma
- There is a need for psychological health and coping strategies to suppress social stigma in patients with rare diseases
- There is a need for awareness campaigns (online and physical) to face public stigma to rare diseases.
| Management Algorithm of Gaucher disease|| |
We have created a stepwise management algorithm for Gaucher patients in Saudi Arabia. Our recommended management algorithm is formed of four major stages (diagnosis, assessment, treatment, and follow-up) [Figure 3]. The first step of the management is to confirm the diagnosis of GD by the clinical examination and investigations. The next step is to assess the disease severity and patient's condition. Gaucher patients' can be presented by asymptomatic/very mild, mild/moderate disease, severe/rapidly progressive, or severe/rapidly progressive disease accompanied by comorbidities. Diagnosis abreast with the assessment of the disease severity will set the type of treatment the patient will receive. The third step of the Gaucher management is to implement the previous data (examination and investigations) to determine the need for ERT use. The last step in the management plan is to follow-up with Gaucher patients to assess the disease progression, treatment safety, and effectiveness.
|Figure 3: Management algorithm for adults with Gaucher disease in Saudi Arabia. Hb = Hemoglobin, WBCs = White blood cells, MRI = Magnetic resonance imaging, DEXA = dual energy X-ray absorptiometry, ECG = Electrocardiogram, ECHO = Echocardiogram, ERT = Enzyme replacement therapy|
Click here to view
Once the diagnosis of GD is established, a comprehensive evaluation of all disease aspects (hematology lab findings, splenomegaly, bone, lungs, brain, and biochemical markers) should be performed to recognize the patient baseline characteristics and the ERT possibility. Complete blood tests including platelet count, hemoglobin (Hb) level, white blood cells, and coagulation profile should be obtained at the baseline. Also, biochemical markers as serum Fe, ferritin, and B12 level should be obtained for the follow-up. Spleen and liver state are assessed by liver function tests, hepatitis markers, computed tomography scan, and magnetic resonance imaging (MRI) scan. Additionally, chest X-ray, electrocardiogram, and echocardiogram are performed to assess the integrity of cardiothoracic functions (heart and lungs).
Evaluation, assessment, and serial monitoring of the skeletal system (bone mainly) is a vital step in the GD management plan since irreversible disabling complications of GD are mostly skeletal in nature. Experts recommend evaluation of bone condition annually by X-rays, Dual-energy X-ray absorptiometry scan, and MRI scan. The skeletal complications of GD include osteopenia, osteosclerosis, osteonecrosis, pathological fractures, and bone marrow infiltration.,
Follow-up of Gaucher patients is an imperative step to ensure achieving management goals. We are recommending using short-term and long-term management goals set by members of the European Working Group on GD for the patients' follow-up. Management goals of GD include eliminating the blood transfusion dependency, increasing Hb level within the first 1 or 2 years of the treatment, increasing the platelet count or normalize it in case of splenectomy in the 1st year of the treatment, and reaching platelet count of ≥100,000 mm3 during the 1st 3 years of treatment., Other goals related to patients' mobility encompass decreasing bony ache, increasing the bone mineral density, and normalizes the growth curve within 2 years of treatment. Also, decreasing the risk of visceral complication is one of the management goals such as avoiding splenectomy (except in life-threatening conditions), alleviating splenomegaly-related symptoms, and decrease hepatosplenomegaly depending on the baseline volume. The listed goals aim to restore the normal values, maintain the reserve functions, decrease the risk of complication, and improve the patients' quality of life (QoL).
As mentioned above, the treatment of GD depends on the type of the disease, the patient's condition, and disease severity. For instance, type-2 Gaucher patients may only be treated with supportive therapy. Current available treatment options for Gaucher patients include symptomatic/supportive therapy,, ERT,,,, and SRT.,, ERT is considered as the standard treatment for GD Type-1.
ERT and SRT can improve/reverse hematological (e.g, hypersplenism) and visceral (e.g, hepatosplenomegaly) manifestations within 2–4 years of treatment, however, they cannot help if fibrosis occurs. Current and potential treatment options for GD are shown in [Figure 4].
The treatment of hematological manifestations of GD is achieved by ERT mainly, SRT, or supportive therapy. Hepatosplenomegaly and secondary hypersplenism are mostly improved in the first 2 years of treatment with ERT (such as Imiglucerase, Velaglucerase, and Taliglucerase) or SRT (such as Eliglustat and Miglustat)., The bleeding tendency of Gaucher patients is one of the hematological manifestations that need close monitoring and regular follow-up. Patients with bleeding tendency can be treated by tranexamic acid, desmopressin, platelet transfusion, or clotting factors concentrates. Since its emergence, ERT has replaced splenectomy as the standard treatment for cases of splenomegaly. Splenectomy was performed for most of the cases of hypersplenism, however, it has decreased markedly and rarely performed nowadays as recent data showed it worsens the patient's condition and carries a higher risk of pulmonary hypertension and HCC.,,
Other potential treatment options for GD are shown in [Figure 4] which include gene therapy, pharmacological chaperone therapies, and histone deacetylase inhibitors. Currently, clinical trials are being conducted to study the efficacy of efficacy and safety profile of lentiviral vector gene therapy (NCT04145037) and chaperone (NCT03950050) on Gaucher Type-1 patients.
| Unmet Medical Needs for Gaucher disease|| |
Although we are trying to follow most of the guidelines related to GD diagnosis and management in Saudi Arabia, yet there are some challenges and patients' needs remain unmet due to the limited sources and unavailability of the data. The unmet medical needs agreed by all experts are presented in [Table 1].
|Table 1: Unmet medical needs for diagnosis and treatment of Gaucher diseasez|
Click here to view
| Social Stigma and the Unmet Medical Needs of Gaucher Disease Patients in Saudi Arabia|| |
The experts agreed on the following points regarding social stigma and the unmet medical needs of GD patients in Saudi Arabia:
- Patients can be hesitant to get help for a condition due to the social stigma surrounding it
- Some family names can be associated with particular rare diseases, which creates societal issues (e.g, difficulty to get married)
- Arab nations should exert more efforts to form local GD support groups and join international groups such as the IGA
- Multidisciplinary teams can be useful for ameliorating patient management and care; however, the challenge lies in keeping the team enthusiastic and motivated
- One of the biggest barriers in a multidisciplinary team is the fear of managing GD. Sometimes general practitioners will not have the judgment to refer the patient to a hematologist once a diagnosis is established
- Unmet medical needs include limited data on how GD treatment affects the QoL and its lifetime benefit to the patient, the poorly understood link between GD and Parkinson's disease, and limited understanding of the bone disease that responds slowly (or not at all) to treatment
- The experts suggested having someone coordinate the filter paper (DBSs) test for both the inpatient and outpatient settings.
| Discussion|| |
GD is carrying an increasing concern in Saudi Arabia as the actual number of cases is not reported due to the high number of underdiagnosed/misdiagnosed cases. To obtain the actual number of the GD and other rare metabolic disorders cases, a national registry for confirmed cases in Saudi Arabia must be developed. GD is not considered in the differential diagnosis of most physicians, even among hematology specialists. The experts' efforts to educate the general physicians and family medicine doctors on the common presentations of Gaucher patients will lessen the diagnostic delay and accelerate the management process. In addition, the application of machine learning techniques and Electronic Medical Records will add more value to the diagnosis and treatment of GD patients.
The management strategy of GD should be established on decisions from a multidisciplinary team. Management of Gaucher patients may require cooperation between hematologist, orthopedic specialist, hepatologist, GI specialist, and pediatrician (if early symptoms of the disease). Also, due to the high risk of the psychological problems associated with GD (including depression, anxiety, and hysteria), a competent psychologist should be part of the treatment team. Currently, ERT and SRT are the only Food and Drug Administration-approved treatment options for Gaucher patients. The treatment of Gaucher patients consists mainly of enzyme replacement by intravenous GBA. ERT is an effective therapeutic option that lowers the frequency of symptoms, decreases the risk of complications, and improves patients' QoL. Life-long treatment with ERT is needed as the enzymatic activity is deficient permanently and the patients will be at high risk of complications if the treatment is not provided. Also, SRT can be used alone or in combination with ERT for Gaucher in certain conditions such as in children, pregnancy, breastfeeding, and in patients with severe kidney or liver disease. SRT as eliglustat and Miglustat achieve their effects through an independent and different mechanism of action than ERT. They act by inhibition of the early steps of the anabolism of glycosphingolipids, thus decreasing glycolipids accumulation (Glucocerebroside) and their harmful effects.
GD has been linked with other genetic disorders in the literature. Several studies reported the association between GD and other diseases such as parkinsonism, dementia, rapid eye movement sleep behavior disorder, different types of cancer, and osteoporosis.,,, Most of these associated disorders have not been explained, however, some of these disorders share the same genetic abnormality with GD and their association has been explained in the literature.
The benefits of our nationwide algorithm will go beyond GD. It will encourage other Saudi experts from other specialties to share their expertise and put their recommendations into clinical practice guidelines.
| Conclusion|| |
There are no reliable data regarding the prevalence and incidence of GD in Saudi Arabia. In addition, GD is facing a state of underdiagnoses/misdiagnosis even among experienced specialists. Therefore, implementation of a nationwide screening program and establishing a national registry for Saudi Gaucher cases are essential for the accurate estimation of the burden of GD and early diagnosis of Gaucher patients. The experts recommend organizing awareness campaigns to familiarize hematologists and primary care physicians with GD and its common presentation. The availability of lab markers is imperative to lessen the diagnostic delay.
The authors would like to acknowledge the efforts of Sanofi Genzyme in providing logistical support for the development of this manuscript. Also, we would like to thank Dr. Ahmed Salah Hussein MBBS of RAY-CRO for his great efforts in medical writing and editorial support of the manuscript.
Financial support and sponsorship
Sanofi Genzyme has provided advisory board honoraria for authors, but no Honoria were paid to write the manuscript.
Conflicts of interest
Marwan ElBagoury and Sherif Roushdy are employees of Sanofi Genzyme and may hold shares and/or stock options in the company' for the Sanofi employees.
Other authors have nothing to declare.
| References|| |
Nalysnyk L, Rotella P, Simeone JC, Hamed A, Weinreb N. Gaucher disease epidemiology and natural history: A comprehensive review of the literature. Hematology 2017;22:65-73.
Mistry PK, Belmatoug N, vom Dahl S, Giugliani R. Understanding the natural history of Gaucher disease. Am J Hematol 2015;90 Suppl 1:S6-11.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA 1999;281:249-54.
Tylki-Szymańska A, Vellodi A, El-Beshlawy A, Cole JA, Kolodny E. Neuronopathic Gaucher disease: Demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis 2010;33:339-46.
Tantawy AA, Sherif EM, Adly AA, Hassanine S, Awad AH. Evoked potentials and neurocognitive functions in pediatric Egyptian Gaucher patients on enzyme replacement therapy: A single center experience. J Inherit Metab Dis 2013;36:1025-37.
Tylki-Szymańska A, Czartoryska B. Enzyme replacement therapy in type III Gaucher disease. J Inherit Metab Dis 1999;22:203-4.
Bohlega S, Kambouris M, Shahid M, Al Homsi M, Al Sous W. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC). Neurology 2000;54:261-3.
Schwartz IVD, Göker-Alpan Ö, Kishnani PS, Zimran A, Renault L, Panahloo Z, et al.
Characteristics of 26 patients with type 3 Gaucher disease: A descriptive analysis from the Gaucher Outcome Survey. Mol Genet Metab Rep 2018;14:73-9.
Rizk TM, Ariganjoye RO, Alsaeed GI. Gaucher disease. Unusual presentation and mini-review. Neurosciences (Riyadh) 2015;20:271-6.
Granovsky-Grisaru S, Aboulafia Y, Diamant YZ, Horowitz M, Abrahamov A, Zimran A. Gynecologic and obstetric aspects of Gaucher's disease: A survey of 53 patients. Am J Obstet Gynecol 1995;172:1284-90.
Platt FM, Jeyakumar M. Substrate reduction therapy. Acta Paediatr 2008;97:88-93.
Bennett LL, Mohan D. Gaucher disease and its treatment options. Ann Pharmacother 2013;47:1182-93.
Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al
. A review of gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18:441.
Thomas AS, Mehta A, Hughes DA. Gaucher disease: Haematological presentations and complications. Br J Haematol 2014;165:427-40.
Rosenbaum H. Hemorrhagic aspects of Gaucher disease. Rambam Maimonides Med J 2014;5:e0039.
Mistry PK, Sadan S, Yang R, Yee J, Yang M. Consequences of diagnostic delays in type 1 Gaucher disease: The need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention. Am J Hematol 2007;82:697-701.
Cox TM, Schofield JP. Gaucher's disease: Clinical features and natural history. Baillieres Clin Haematol 1997;10:657-89.
Mehta A, Kuter DJ, Salek SS, Belmatoug N, Bembi B, Bright J, et al.
Presenting signs and patient co-variables in Gaucher disease: Outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative. Intern Med J 2019;49:578-91.
Huang Y, Jia X, Tang C, Liu S, Sheng H, Zhao X, et al.
High risk screening for Gaucher disease in patients with splenomegaly and/or thrombocytopenia in China: 55 cases identified. Clin Chim Acta 2020;506:22-7.
Alhejazi A, AlMomen A, Tarawah AM, AlSuliman AM, Al Saeed HH, Saleh M, et al
. Management algorithms for gaucher disease. J Appl Hematol 2020;11:93-101. [Full text]
Alkuraya FS. Genetics and genomic medicine in Saudi Arabia. Mol Genet Genomic Med 2014;2:369-78.
Nunn R. “It's not all in my head!”- The complex relationship between rare diseases and mental health problems. Orphanet J Rare Dis 2017;12:29.
Packman W, Crosbie TW, Behnken M, Eudy K, Packman S. Living with Gaucher disease: Emotional health, psychosocial needs and concerns of individuals with Gaucher disease. Am J Med Genet A 2010;152A:2002-10.
Klitzman RL, Sweeney MM. “In sickness and in health”? Disclosures of genetic risks in dating. J Genet Couns 2011;20:98-112.
Stowens DW, Teitelbaum SL, Kahn AJ, Barranger JA. Skeletal complications of Gaucher disease. Medicine (Baltimore) 1985;64:310-22.
Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: A review. Br J Radiol 2002;75 Suppl 1:A2-12.
Biegstraaten M, Cox TM, Belmatoug N, Berger MG, Collin-Histed T, Vom Dahl S, et al.
Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease. Blood Cells Mol Dis 2018;68:203-8.
Bennett LL, Fellner C. Pharmacotherapy of Gaucher disease: Current and future options. P
Vellodi A, Tylki-Szymanska A, Davies EH, Kolodny E, Bembi B, Collin-Histed T, et al.
Management of neuronopathic Gaucher disease: Revised recommendations. J Inherit Metab Dis 2009;32:660-4.
Pena AH, Kaplan P, Ganesh J, Clevac E, Marie Cahill A. Partial splenic embolization in a child with Gaucher disease, massive splenomegaly and severe thrombocytopenia. Pediatr Radiol 2009;39:1006-9.
Hollak CE, vom Dahl S, Aerts JM, Belmatoug N, Bembi B, Cohen Y, et al.
Force majeure: Therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease. Blood Cells Mol Dis 2010;44:41-7.
Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC, et al.
Replacement therapy for inherited enzyme deficiency – Macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991;324:1464-70.
Weinreb NJ, Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, et al.
Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: A report from the Gaucher Registry. Am J Med 2002;113:112-9.
Zimran A, Brill-Almon E, Chertkoff R, Petakov M, Blanco-Favela F, Muñoz ET, et al.
Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood 2011;118:5767-73.
Schiffmann R, Fitzgibbon EJ, Harris C, DeVile C, Davies EH, Abel L, et al.
Randomized, controlled trial of miglustat in Gaucher's disease type 3. Ann Neurol 2008;64:514-22.
Shemesh E, Deroma L, Bembi B, Deegan P, Hollak C, Weinreb NJ, et al.
Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database Syst Rev 2015;CD010324.
Linari S, Castaman G. Hematological manifestations and complications of Gaucher disease. Expert Rev Hematol 2016;9:51-8.
Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al.
Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 2004;41:4-14.
Thomas AS, Mehta AB, Hughes DA. Diagnosing Gaucher disease: An on-going need for increased awareness amongst haematologists. Blood Cells Mol Dis 2013;50:212-7.
de Fost M, Vom Dahl S, Weverling GJ, Brill N, Brett S, Häussinger D, et al.
Increased incidence of cancer in adult Gaucher disease in Western Europe. Blood Cells Mol Dis 2006;36:53-8.
Elbagoury M, Qadi AI, Hejazi A, Alabbas F, Yamany GE, Saeed HH, et al.
Prevalence of gaucher disease in patients of unknown cause of splenomegaly and/or thrombocytopenia in Saudi Arabia. Blood 2020;136 Suppl 1:32-3.
Packman W, Wilson Crosbie T, Riesner A, Fairley C, Packman S. Psychological complications of patients with Gaucher disease. J Inherit Metab Dis 2006;29:99-105.
Balwani M, Burrow TA, Charrow J, Goker-Alpan O, Kaplan P, Kishnani PS, et al.
Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States. Mol Genet Metab 2016;117:95-103.
Riboldi GM, Di Fonzo AB. GBA
, Gaucher disease, and Parkinson's disease: From genetic to clinic to new therapeutic approaches. Cells 2019;8:364.
Hruska KS, Goker-Alpan O, Sidransky E. Gaucher disease and the synucleinopathies. J Biomed Biotechnol 2006;2006:78549.
Mucci JM, Rozenfeld P. Pathogenesis of bone alterations in gaucher disease: The role of immune system. J Immunol Res 2015;2015:192761.
Mistry PK, Taddei T, vom Dahl S, Rosenbloom BE. Gaucher disease and malignancy: A model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog 2013;18:235-46.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]