Claudia Gonzaga-Jauregui, Carlos Salazar, Jennifer MacDonald, Juergen K.V. Reichardt, Stephen C. Groft
The importance of establishing programs to address the challenges of patients living with rare diseases has been recognized internationally, yet many countries, especially in low- and middle-income regions, are lagging in the recognition of the challenges and needs of patients and families. To improve this situation, the Enfermedades Raras en el Caribe y America Latina (ERCAL) initiative was established in 2020 with the vision of bringing together patients, patient representatives, organizations, researchers, clinicians, regulators, and all interested stakeholders in the rare diseases ecosystem under a common collaborative platform to sum efforts to improve the lives of patients and families living with rare diseases in the Latin American and the Caribbean region. Over the last three years, we have been working consistently to establish an agenda of priorities and objectives to guide the work of the initiative and address the major challenges faced by the rare disease community in the region.
{"title":"ERCAL, a regional initiative for rare diseases in Latin America and the Caribbean","authors":"Claudia Gonzaga-Jauregui, Carlos Salazar, Jennifer MacDonald, Juergen K.V. Reichardt, Stephen C. Groft","doi":"10.20517/rdodj.2023.48","DOIUrl":"https://doi.org/10.20517/rdodj.2023.48","url":null,"abstract":"The importance of establishing programs to address the challenges of patients living with rare diseases has been recognized internationally, yet many countries, especially in low- and middle-income regions, are lagging in the recognition of the challenges and needs of patients and families. To improve this situation, the Enfermedades Raras en el Caribe y America Latina (ERCAL) initiative was established in 2020 with the vision of bringing together patients, patient representatives, organizations, researchers, clinicians, regulators, and all interested stakeholders in the rare diseases ecosystem under a common collaborative platform to sum efforts to improve the lives of patients and families living with rare diseases in the Latin American and the Caribbean region. Over the last three years, we have been working consistently to establish an agenda of priorities and objectives to guide the work of the initiative and address the major challenges faced by the rare disease community in the region.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"59 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140424182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
N. Venugopal, G. Naik, Krishnamurthy Jayanna, Archisman Mohapatra, F. J. Sasinowski, Reena V. Kartha, Harsha K. Rajasimha
One of the main challenges in rare diseases is the unavailability of reliable estimates of prevalence and incidence. The lack of epidemiological data makes planning for therapeutic and management options challenging. Methods for estimating the prevalence and incidence of rare and genetic diseases primarily rely on the availability of accurate national patient registries or databases of birth defects. This gap is wider in Low- and Middle-Income countries (LMICs) such as India, where currently, the estimates of prevalence and incidence are either unknown or data from developed countries have to be used as a proxy. Here, we analyzed the current methods used to estimate the prevalence and incidence of rare genetic diseases to provide recommendations in the form of a decision tree to select the most feasible method, particularly in resource-constrained environments such as India. We selected ten rare diseases of shared importance to the Indo US Organization for Rare Diseases (IndoUSrare) and its Patients Alliance members for analysis. Our analysis suggests that retrospective study designs are the most commonly used method to estimate the prevalence and incidence of rare diseases. We propose a generalized decision tree or flowchart to aid epidemiology researchers during the selection of methods for estimating the prevalence and incidence of a rare or genetic disease.
{"title":"Review of methods for estimating the prevalence of rare diseases","authors":"N. Venugopal, G. Naik, Krishnamurthy Jayanna, Archisman Mohapatra, F. J. Sasinowski, Reena V. Kartha, Harsha K. Rajasimha","doi":"10.20517/rdodj.2023.39","DOIUrl":"https://doi.org/10.20517/rdodj.2023.39","url":null,"abstract":"One of the main challenges in rare diseases is the unavailability of reliable estimates of prevalence and incidence. The lack of epidemiological data makes planning for therapeutic and management options challenging. Methods for estimating the prevalence and incidence of rare and genetic diseases primarily rely on the availability of accurate national patient registries or databases of birth defects. This gap is wider in Low- and Middle-Income countries (LMICs) such as India, where currently, the estimates of prevalence and incidence are either unknown or data from developed countries have to be used as a proxy. Here, we analyzed the current methods used to estimate the prevalence and incidence of rare genetic diseases to provide recommendations in the form of a decision tree to select the most feasible method, particularly in resource-constrained environments such as India. We selected ten rare diseases of shared importance to the Indo US Organization for Rare Diseases (IndoUSrare) and its Patients Alliance members for analysis. Our analysis suggests that retrospective study designs are the most commonly used method to estimate the prevalence and incidence of rare diseases. We propose a generalized decision tree or flowchart to aid epidemiology researchers during the selection of methods for estimating the prevalence and incidence of a rare or genetic disease.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"9 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139959781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite recent advances, there is still much to be learned about the pathogenesis of Fabry disease. The categorization of GLA gene missense mutations has been complicated by the fact that some missense variants may fall into more than one category. For instance, the A143T variant may cause late-onset Fabry disease in some subjects and not result in Fabry disease in others (pseudo-deficient). Efforts to mitigate the pathobiology of α-galactosidase A deficiency should differentiate between damaging (maladaptive) consequences and compensatory (adaptive) changes. Current therapy leaves a significant unmet need, especially concerning cardiovascular complications and cardiological clinical outcomes. Non-Fabry-specific therapy is necessary and quite beneficial and must be utilized. Its contribution should be considered when trying to assess the net effect of Fabry-specific therapy. Enzyme replacement therapy (ERT) can be administered to patients independently of their GLA genotype, as it slows the decline of kidney function in most patients if initiated sufficiently early in the disease course. Migalastat has better tissue penetration than ERT, but its usefulness is restricted to patients with amenable missense GLA variants. However, it is important to realize that in a substantial proportion of common amenable mutations, migalastat increases α-galactosidase A activity level beyond the disease threshold and thus eliminates the metabolic disturbance that is at the center of Fabry disease. Substrate reduction therapy and gene therapy approaches are being developed, but these therapeutic modalities have their own limitations and difficulties.
{"title":"Investigating Fabry disease - some lessons learned","authors":"Raphael Schiffmann","doi":"10.20517/rdodj.2023.50","DOIUrl":"https://doi.org/10.20517/rdodj.2023.50","url":null,"abstract":"Despite recent advances, there is still much to be learned about the pathogenesis of Fabry disease. The categorization of GLA gene missense mutations has been complicated by the fact that some missense variants may fall into more than one category. For instance, the A143T variant may cause late-onset Fabry disease in some subjects and not result in Fabry disease in others (pseudo-deficient). Efforts to mitigate the pathobiology of α-galactosidase A deficiency should differentiate between damaging (maladaptive) consequences and compensatory (adaptive) changes. Current therapy leaves a significant unmet need, especially concerning cardiovascular complications and cardiological clinical outcomes. Non-Fabry-specific therapy is necessary and quite beneficial and must be utilized. Its contribution should be considered when trying to assess the net effect of Fabry-specific therapy. Enzyme replacement therapy (ERT) can be administered to patients independently of their GLA genotype, as it slows the decline of kidney function in most patients if initiated sufficiently early in the disease course. Migalastat has better tissue penetration than ERT, but its usefulness is restricted to patients with amenable missense GLA variants. However, it is important to realize that in a substantial proportion of common amenable mutations, migalastat increases α-galactosidase A activity level beyond the disease threshold and thus eliminates the metabolic disturbance that is at the center of Fabry disease. Substrate reduction therapy and gene therapy approaches are being developed, but these therapeutic modalities have their own limitations and difficulties.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"42 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139603592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sleep problems are more common in people with autism spectrum disorder (ASD) as compared to the general population, and may contribute to worsening social functioning, emotional symptoms, and lower quality of life. To support healthcare professionals and researchers in the field, we provide an updated overview of sleep problems in the context of autism across the lifespan and their evidence-based management, as derived from evidence-synthesis studies and the most recent randomized controlled trials. Most studies to date have been conducted in children and adolescents with autism. Several studies suggest that behavioral interventions aiming at improving sleep hygiene and environment may be beneficial, especially when actively involving parents. Furthermore, there is an increasing body of literature showing that melatonin is an effective pharmacological option for improving sleep quality in children and adolescents with autism, in line with reports showing a reduced endogenous synthesis of this hormone. Unfortunately, studies in adults are more limited, and thus, the evidence base around non-pharmacological and pharmacological interventions remains mixed. Finally, there is a growing interest towards the use of complementary interventions or food supplements, but further studies are needed to test their effectiveness. In sum, most studies to date support the use of behavioral interventions and melatonin, especially in children and adolescents with autism. However, findings need to be validated in large-scale, rigorous and blinded trials and extended to the adult population. Non-pharmacological interventions remain the first treatment option and should adopt an individualized approach, considering individual characteristics and needs, including comorbidities, family dynamics, and sleep environment.
{"title":"Management of sleep problems in people with autism: an updated review","authors":"Alessio Bellato, V. Parlatini, S. Cortese","doi":"10.20517/rdodj.2023.36","DOIUrl":"https://doi.org/10.20517/rdodj.2023.36","url":null,"abstract":"Sleep problems are more common in people with autism spectrum disorder (ASD) as compared to the general population, and may contribute to worsening social functioning, emotional symptoms, and lower quality of life. To support healthcare professionals and researchers in the field, we provide an updated overview of sleep problems in the context of autism across the lifespan and their evidence-based management, as derived from evidence-synthesis studies and the most recent randomized controlled trials. Most studies to date have been conducted in children and adolescents with autism. Several studies suggest that behavioral interventions aiming at improving sleep hygiene and environment may be beneficial, especially when actively involving parents. Furthermore, there is an increasing body of literature showing that melatonin is an effective pharmacological option for improving sleep quality in children and adolescents with autism, in line with reports showing a reduced endogenous synthesis of this hormone. Unfortunately, studies in adults are more limited, and thus, the evidence base around non-pharmacological and pharmacological interventions remains mixed. Finally, there is a growing interest towards the use of complementary interventions or food supplements, but further studies are needed to test their effectiveness. In sum, most studies to date support the use of behavioral interventions and melatonin, especially in children and adolescents with autism. However, findings need to be validated in large-scale, rigorous and blinded trials and extended to the adult population. Non-pharmacological interventions remain the first treatment option and should adopt an individualized approach, considering individual characteristics and needs, including comorbidities, family dynamics, and sleep environment.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":" 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139618671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children. Methods: Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment. Results: These observations raise important debates on whether treating only a % of children with ASD is acceptable. Discussion: It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.
{"title":"Bumetanide to treat autism spectrum disorders: are complex administrative regulations fit to treat heterogeneous disorders?","authors":"Yehezkel Ben-Ari","doi":"10.20517/rdodj.2023.22","DOIUrl":"https://doi.org/10.20517/rdodj.2023.22","url":null,"abstract":"Introduction: Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children.\u0000 Methods: Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment.\u0000 Results: These observations raise important debates on whether treating only a % of children with ASD is acceptable.\u0000 Discussion: It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"13 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139388613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Light chain (AL) amyloidosis is a complex and rare disease characterized by low incidence and diverse clinical manifestations. At the time of diagnosis, most patients exhibit involvement of multiple organs or tissues, leading to severe illness and a poor prognosis. Therefore, early diagnosis, active treatment, and a comprehensive assessment of the disease hold paramount importance. The initial presentation of this rare condition often manifests as gastrointestinal symptoms, posing challenges in clinical identification and differential diagnosis. In this case report, we describe a 70-year-old man with AL amyloidosis, initially misdiagnosed as irritable bowel syndrome and colon polyps. Subsequently, he experienced a series of complications including renal function impairment, pulmonary nodule, pleural effusion, mediastinal lymph node enlargement, spleen enlargement, reduction of white blood cells, red blood cells and platelets, and small intestinal obstruction. Despite multiple pulmonary nodule biopsy and lymph node biopsy, as well as concurrent splenectomy and partial resection of the small intestine, a clear diagnosis remained elusive. Before admission, diarrhea was aggravated, accompanied by emaciation and fatigue. Following the completion of serum immunofixed protein electrophoresis, renal biopsy, bone marrow and rectal biopsy, a conclusive diagnosis of AL amyloidosis involving multiple organs (Mayo 2012 revision stage III) was finally confirmed after a 12-year period. Treatment with proteasome inhibitors, immunomodulators, and glucocorticoids was recommended. The patient underwent methylprednisolone treatment and was discharged after symptom improvement. However, eight months into the follow-up, the patient succumbed to multiple organ failure. The repeated misdiagnoses over the past 12 years were attributed to limited perspectives among some specialists who did not conduct a systematic and detailed medical history analysis or comprehensive physical examinations. Additionally, they did not strictly follow the principle of "monism" in diagnosis. On the contrary, early diagnosis and active treatment of the disease are of great significance to improve the prognosis.
轻链（AL）淀粉样变性是一种复杂而罕见的疾病，其特点是发病率低、临床表现多样。确诊时，大多数患者表现为多个器官或组织受累，导致病情严重，预后不良。因此，早期诊断、积极治疗和全面评估病情至关重要。这种罕见疾病的初期症状通常表现为胃肠道症状，给临床鉴别和鉴别诊断带来了挑战。在本病例报告中，我们描述了一名 70 岁男性 AL 淀粉样变性患者，起初被误诊为肠易激综合征和结肠息肉。随后，他出现了一系列并发症，包括肾功能损害、肺结节、胸腔积液、纵隔淋巴结肿大、脾脏肿大、白细胞、红细胞和血小板减少以及小肠梗阻。尽管进行了多次肺结节活检和淋巴结活检，并同时进行了脾脏切除术和小肠部分切除术，但仍无法明确诊断。入院前，腹泻加重，伴有消瘦和乏力。在完成血清免疫固定蛋白电泳、肾活检、骨髓和直肠活检后，历时 12 年，最终确诊为累及多器官的 AL 淀粉样变性（梅奥 2012 修订版 III 期）。建议使用蛋白酶体抑制剂、免疫调节剂和糖皮质激素进行治疗。患者接受了甲基强的松龙治疗，症状改善后出院。然而，随访八个月后，患者死于多器官衰竭。在过去的 12 年中，患者屡次被误诊，究其原因是一些专科医生的视野有限，没有进行系统、详细的病史分析或全面的体格检查。此外，他们也没有严格遵循 "一元论 "的诊断原则。相反，疾病的早期诊断和积极治疗对改善预后具有重要意义。
{"title":"Light chain (AL) amyloidosis following gastrointestinal symptoms that involve multiple organs: a case report","authors":"Yeqing Chen, Zhenxiang Wang, Xiaofang Pi, Shuai Yuan, Xueyu Tang, Yong Liao, Xing Wen, Hongyu Zhou","doi":"10.20517/rdodj.2023.45","DOIUrl":"https://doi.org/10.20517/rdodj.2023.45","url":null,"abstract":"Light chain (AL) amyloidosis is a complex and rare disease characterized by low incidence and diverse clinical manifestations. At the time of diagnosis, most patients exhibit involvement of multiple organs or tissues, leading to severe illness and a poor prognosis. Therefore, early diagnosis, active treatment, and a comprehensive assessment of the disease hold paramount importance. The initial presentation of this rare condition often manifests as gastrointestinal symptoms, posing challenges in clinical identification and differential diagnosis. In this case report, we describe a 70-year-old man with AL amyloidosis, initially misdiagnosed as irritable bowel syndrome and colon polyps. Subsequently, he experienced a series of complications including renal function impairment, pulmonary nodule, pleural effusion, mediastinal lymph node enlargement, spleen enlargement, reduction of white blood cells, red blood cells and platelets, and small intestinal obstruction. Despite multiple pulmonary nodule biopsy and lymph node biopsy, as well as concurrent splenectomy and partial resection of the small intestine, a clear diagnosis remained elusive. Before admission, diarrhea was aggravated, accompanied by emaciation and fatigue. Following the completion of serum immunofixed protein electrophoresis, renal biopsy, bone marrow and rectal biopsy, a conclusive diagnosis of AL amyloidosis involving multiple organs (Mayo 2012 revision stage III) was finally confirmed after a 12-year period. Treatment with proteasome inhibitors, immunomodulators, and glucocorticoids was recommended. The patient underwent methylprednisolone treatment and was discharged after symptom improvement. However, eight months into the follow-up, the patient succumbed to multiple organ failure. The repeated misdiagnoses over the past 12 years were attributed to limited perspectives among some specialists who did not conduct a systematic and detailed medical history analysis or comprehensive physical examinations. Additionally, they did not strictly follow the principle of \"monism\" in diagnosis. On the contrary, early diagnosis and active treatment of the disease are of great significance to improve the prognosis.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"107 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carmencita D. Padilla, Michelle E. Abadingo, Katherine V. Munda, B. Therrell
Newborn screening (NBS) was introduced in the Philippines in 1996, and the Newborn Screening Act of 2004 mandated its provision to all Filipino newborns. The program initially covered five conditions and has expanded to the current panel of 29 conditions. This report focuses on the steps taken for successful NBS implementation and the challenges that must be overcome to make NBS sustainable. While often considered a public health program, NBS is really a system of interacting parts that must be carefully considered and planned prior to embarking on their implementation. The basic challenges are the same in both high-income and low-middle-income countries (LMICs), but they are more difficult to overcome in LMICs. In addition to the technical aspects of screening, including supplies and maintenance, considerations must include human resources, professional and public education, and government support. Challenges may occur at any point in implementation and continuation, and it is important to learn from the experiences of others in order to make the process more efficient. Here, we report on the experiences in one LMIC, the Philippines, in creating and sustaining a NBS system so that others may gain from these experiences.
{"title":"Overcoming challenges in sustaining newborn screening in low-middle-income countries: the Philippine newborn screening system","authors":"Carmencita D. Padilla, Michelle E. Abadingo, Katherine V. Munda, B. Therrell","doi":"10.20517/rdodj.2023.38","DOIUrl":"https://doi.org/10.20517/rdodj.2023.38","url":null,"abstract":"Newborn screening (NBS) was introduced in the Philippines in 1996, and the Newborn Screening Act of 2004 mandated its provision to all Filipino newborns. The program initially covered five conditions and has expanded to the current panel of 29 conditions. This report focuses on the steps taken for successful NBS implementation and the challenges that must be overcome to make NBS sustainable. While often considered a public health program, NBS is really a system of interacting parts that must be carefully considered and planned prior to embarking on their implementation. The basic challenges are the same in both high-income and low-middle-income countries (LMICs), but they are more difficult to overcome in LMICs. In addition to the technical aspects of screening, including supplies and maintenance, considerations must include human resources, professional and public education, and government support. Challenges may occur at any point in implementation and continuation, and it is important to learn from the experiences of others in order to make the process more efficient. Here, we report on the experiences in one LMIC, the Philippines, in creating and sustaining a NBS system so that others may gain from these experiences.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"16 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138980914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nadine Petitpain, Marie Lauren Antoine, Mathilde Beurrier, Joëlle Micallef, A. Fresse
Gene therapy medicinal products (GTMPs) may generate unexpected risks to public health and individual patients. Pharmacovigilance serves the purpose of detecting, assessing, understanding, and preventing adverse effects or any other medicine-related problems. This article aims to provide an overview of the significance of pharmacovigilance and particularities in the domain of gene therapy with a brief description of the European regulatory framework. Viral vectors, insertional mutagenesis, viral latency or reactivation, as well as duration and accuracy of the patient’s clinical follow-up, are some of the main concerns. Two recent examples of signals illustrate some of these safety issues. The first concerns onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy for treating spinal muscular atrophy. This GTMP initially raised safety concerns about hepatotoxicity, cardiotoxicity, and neurotoxicity, necessitating recommendations for close monitoring. During the post-marketing period, two fatal cases of acute liver failure led the European Medicine Agency (EMA) to strengthen the recommendations for liver function monitoring. The second example pertains to betibeglogene autotemcel, a genetically modified autologous CD34+ cell-enriched population that contains hematopoietic stem cells transduced with lentiviral vectors encoding the β A-T87Q-globin gene. After the report of a case of acute myeloid leukemia in a patient treated with an investigational product using the same lentiviral vector, the European Commission triggered a regulatory safety procedure. After careful assessment, the EMA’s ad hoc safety committees stated that the viral vector was unlikely to be the cause. However, due to commercial reasons, betibeglogene autotemcel was finally withdrawn from the market by the marketing authorization holder. Pharmacovigilance activities and systems continuously evolve to keep pace with advancements in new therapies and technologies. They must also address varied situations and adhere to evolving regulations. GTMPs likely stand out as one of the most demanding areas within pharmacovigilance. Therefore, their effective oversight requires the full commitment of pharmacological and clinical experts, as well as active involvement from patients, to ensure optimal outcomes.
{"title":"Pharmacovigilance of gene therapy medicinal products","authors":"Nadine Petitpain, Marie Lauren Antoine, Mathilde Beurrier, Joëlle Micallef, A. Fresse","doi":"10.20517/rdodj.2023.19","DOIUrl":"https://doi.org/10.20517/rdodj.2023.19","url":null,"abstract":"Gene therapy medicinal products (GTMPs) may generate unexpected risks to public health and individual patients. Pharmacovigilance serves the purpose of detecting, assessing, understanding, and preventing adverse effects or any other medicine-related problems. This article aims to provide an overview of the significance of pharmacovigilance and particularities in the domain of gene therapy with a brief description of the European regulatory framework. Viral vectors, insertional mutagenesis, viral latency or reactivation, as well as duration and accuracy of the patient’s clinical follow-up, are some of the main concerns. Two recent examples of signals illustrate some of these safety issues. The first concerns onasemnogene abeparvovec, an adeno-associated virus-based gene replacement therapy for treating spinal muscular atrophy. This GTMP initially raised safety concerns about hepatotoxicity, cardiotoxicity, and neurotoxicity, necessitating recommendations for close monitoring. During the post-marketing period, two fatal cases of acute liver failure led the European Medicine Agency (EMA) to strengthen the recommendations for liver function monitoring. The second example pertains to betibeglogene autotemcel, a genetically modified autologous CD34+ cell-enriched population that contains hematopoietic stem cells transduced with lentiviral vectors encoding the β A-T87Q-globin gene. After the report of a case of acute myeloid leukemia in a patient treated with an investigational product using the same lentiviral vector, the European Commission triggered a regulatory safety procedure. After careful assessment, the EMA’s ad hoc safety committees stated that the viral vector was unlikely to be the cause. However, due to commercial reasons, betibeglogene autotemcel was finally withdrawn from the market by the marketing authorization holder. Pharmacovigilance activities and systems continuously evolve to keep pace with advancements in new therapies and technologies. They must also address varied situations and adhere to evolving regulations. GTMPs likely stand out as one of the most demanding areas within pharmacovigilance. Therefore, their effective oversight requires the full commitment of pharmacological and clinical experts, as well as active involvement from patients, to ensure optimal outcomes.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"29 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139243139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charli Ji, Michelle A. Farrar, Sarah Norris, Kaustuv Bhattacharya, Bruce Bennetts, A. Newson, Louise Healy, N. Millis, Didu S Kariyawasam
In Australia, over 300,000 newborns undergo newborn bloodspot screening (NBS) annually, with approximately 1 in 1,000 identified with a rare but actionable condition through this pathway. Prior to 2018, the inclusion criteria for adding conditions in NBS panels was inconsistent nationally, leading to the development of the Australian National Newborn Bloodspot Screening Policy Framework. This framework promotes systematic and evidence-based inclusion of conditions using criteria closely informed by traditional Wilson and Junger screening principles. Current policy initiatives are focused on achieving national consistency in the conditions screened. NBS programs, initiated in the 1960s, have used a variety of techniques, including but not limited to tandem mass spectrometry and immunological assays. The acceleration of genomic technologies has the potential to greatly increase the number of conditions screened and match affected newborns with innovative treatment options, including advanced (gene, immune modulation, and RNA) therapies. This review describes the evolution, current status quo, and outlook for Australian NBS programs with a focus on the implications of wider adoption of genomic newborn screening (gNBS) in our culturally, geographically, and genetically diverse population. We discuss the potential for transformative benefits for families with children identified by gNBS and how this must be balanced against the potential for a range of unintended negative consequences. We emphasise the importance of a nationally agreed, coordinated, and streamlined approach to the addition and removal of conditions from Australian NBS programs, which considers the utility, cost, ethical, and equity aspects of gNBS.
{"title":"The Australian landscape of newborn screening in the genomics era","authors":"Charli Ji, Michelle A. Farrar, Sarah Norris, Kaustuv Bhattacharya, Bruce Bennetts, A. Newson, Louise Healy, N. Millis, Didu S Kariyawasam","doi":"10.20517/rdodj.2023.30","DOIUrl":"https://doi.org/10.20517/rdodj.2023.30","url":null,"abstract":"In Australia, over 300,000 newborns undergo newborn bloodspot screening (NBS) annually, with approximately 1 in 1,000 identified with a rare but actionable condition through this pathway. Prior to 2018, the inclusion criteria for adding conditions in NBS panels was inconsistent nationally, leading to the development of the Australian National Newborn Bloodspot Screening Policy Framework. This framework promotes systematic and evidence-based inclusion of conditions using criteria closely informed by traditional Wilson and Junger screening principles. Current policy initiatives are focused on achieving national consistency in the conditions screened. NBS programs, initiated in the 1960s, have used a variety of techniques, including but not limited to tandem mass spectrometry and immunological assays. The acceleration of genomic technologies has the potential to greatly increase the number of conditions screened and match affected newborns with innovative treatment options, including advanced (gene, immune modulation, and RNA) therapies. This review describes the evolution, current status quo, and outlook for Australian NBS programs with a focus on the implications of wider adoption of genomic newborn screening (gNBS) in our culturally, geographically, and genetically diverse population. We discuss the potential for transformative benefits for families with children identified by gNBS and how this must be balanced against the potential for a range of unintended negative consequences. We emphasise the importance of a nationally agreed, coordinated, and streamlined approach to the addition and removal of conditions from Australian NBS programs, which considers the utility, cost, ethical, and equity aspects of gNBS.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139246010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Rare diseases (RDs) are serious often chronic progressive diseases that affect a smaller number of individuals. RDs can manifest in any region of the body and have systemic effects that are detrimental to individual health. Although RDs are individually rare, there are various debilitating disorders arising from RDs. One of the disorders that have been shown to have a negative impact on the health of RD patients is temporomandibular disorders (TMD). There is a dearth of data on the rare diseases and potential manifestations of TMD. The objective of this systematic review is to provide an overview of rare diseases and temporomandibular joint (TMJ) manifestations. Method: The criterion for analysis of a rare disease and temporomandibular manifestations was inclusion in the Orphanet Classification of Rare Diseases and/or the National Organization for Rare Disorders (NORD)/The Genetic and Rare Diseases (GARD) databases. Only rare diseases with TMJ manifestations were recorded. Results: A total of 54 RDs with TMJ manifestations and different TMD diagnoses were recorded. There were thirty-five studies derived from the Pubmed search, and the Orphanet input had 19 results. Overall, 13 different types of TMJ manifestations and TMD diagnoses were recorded in rare diseases. Conclusion: TMJ manifestations associated with rare diseases are not uncommon. Healthcare professionals can play an important role in diagnosing and managing the complexity of RDs with TMJ manifestations. A multidisciplinary approach to TMD patients with rare diseases is advisable.
{"title":"Rare diseases with temporomandibular joint manifestations: a systematic review","authors":"Mayank Shrivastava, Gabriel Tian, Liang Ye","doi":"10.20517/rdodj.2023.32","DOIUrl":"https://doi.org/10.20517/rdodj.2023.32","url":null,"abstract":"Background: Rare diseases (RDs) are serious often chronic progressive diseases that affect a smaller number of individuals. RDs can manifest in any region of the body and have systemic effects that are detrimental to individual health. Although RDs are individually rare, there are various debilitating disorders arising from RDs. One of the disorders that have been shown to have a negative impact on the health of RD patients is temporomandibular disorders (TMD). There is a dearth of data on the rare diseases and potential manifestations of TMD. The objective of this systematic review is to provide an overview of rare diseases and temporomandibular joint (TMJ) manifestations. Method: The criterion for analysis of a rare disease and temporomandibular manifestations was inclusion in the Orphanet Classification of Rare Diseases and/or the National Organization for Rare Disorders (NORD)/The Genetic and Rare Diseases (GARD) databases. Only rare diseases with TMJ manifestations were recorded. Results: A total of 54 RDs with TMJ manifestations and different TMD diagnoses were recorded. There were thirty-five studies derived from the Pubmed search, and the Orphanet input had 19 results. Overall, 13 different types of TMJ manifestations and TMD diagnoses were recorded in rare diseases. Conclusion: TMJ manifestations associated with rare diseases are not uncommon. Healthcare professionals can play an important role in diagnosing and managing the complexity of RDs with TMJ manifestations. A multidisciplinary approach to TMD patients with rare diseases is advisable.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"66 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139254121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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