Michael L. West, Laurette Geldenhuys, Daniel G. Bichet
Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate and thus accumulates Gb3 throughout life. Podocytes are injured by Gb3, leading to their detachment from the glomerular basement membrane and subsequent loss in the urine. Albuminuria starts in childhood and progresses to overt proteinuria in the teens and 20 s. CKD ensues with adults starting dialysis at an average age of 42 years. Patients have a high prevalence of stroke and cardiomyopathy with hypertrophic change, heart failure, and dysrhythmias. Patient survival is limited in both genders. Diagnosis is based on the demonstration of a low α-Gal activity and a pathogenic GLA mutation. Clinical features are highly variable, which makes recognition of this condition difficult. Treatment with intravenous recombinant human enzyme replacement therapy (ERT) and oral pharmacologic chaperone are available. Control of proteinuria to 0.5 g/day or less is of critical importance to limit progression to end-stage renal disease. Early initiation of treatment gives the best results, but the optimal age to start is uncertain. Fabry nephropathy remains a challenge due to its multisystem nature, difficult diagnosis, and complicated management. It is important as a treatable cause of CKD.
法布里病是一种罕见的 X 连锁先天性代谢错误，是慢性肾脏病（CKD）和肾衰竭的高发疾病。它是由于溶酶体中缺乏α-半乳糖苷酶A（α-Gal），从而导致溶酶体中积累球糖基甘油三酯（Gb3）。在肾脏中，荚膜细胞是这种疾病的主要目标，尽管所有类型的细胞都会受累。荚膜细胞是终末分化的细胞，不会复制，因此终生都会积累 Gb3。荚膜细胞受到 Gb3 的损伤，导致其从肾小球基底膜上脱落，并随尿液流失。白蛋白尿从儿童时期开始，到十几岁和二十几岁时发展为明显的蛋白尿，随后出现慢性肾功能衰竭，成人平均在 42 岁时开始透析。患者中风和心肌病的发病率很高，并伴有肥厚性改变、心力衰竭和心律失常。男女患者的存活率均有限。诊断依据是α-gal活性低和致病性GLA突变。临床特征变化很大，因此很难识别这种疾病。可采用静脉注射重组人酶替代疗法（ERT）和口服药物合剂进行治疗。将蛋白尿控制在 0.5 克/天或更低水平对于限制病情恶化至终末期肾病至关重要。早期开始治疗效果最佳，但最佳治疗年龄尚不确定。法布里肾病具有多系统性、诊断困难、治疗复杂等特点，因此仍然是一项挑战。作为慢性肾功能衰竭的一种可治疗病因，法布里肾病非常重要。
{"title":"Fabry nephropathy: a treatable cause of chronic kidney disease","authors":"Michael L. West, Laurette Geldenhuys, Daniel G. Bichet","doi":"10.20517/rdodj.2023.61","DOIUrl":"https://doi.org/10.20517/rdodj.2023.61","url":null,"abstract":"Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate and thus accumulates Gb3 throughout life. Podocytes are injured by Gb3, leading to their detachment from the glomerular basement membrane and subsequent loss in the urine. Albuminuria starts in childhood and progresses to overt proteinuria in the teens and 20 s. CKD ensues with adults starting dialysis at an average age of 42 years. Patients have a high prevalence of stroke and cardiomyopathy with hypertrophic change, heart failure, and dysrhythmias. Patient survival is limited in both genders. Diagnosis is based on the demonstration of a low α-Gal activity and a pathogenic GLA mutation. Clinical features are highly variable, which makes recognition of this condition difficult. Treatment with intravenous recombinant human enzyme replacement therapy (ERT) and oral pharmacologic chaperone are available. Control of proteinuria to 0.5 g/day or less is of critical importance to limit progression to end-stage renal disease. Early initiation of treatment gives the best results, but the optimal age to start is uncertain. Fabry nephropathy remains a challenge due to its multisystem nature, difficult diagnosis, and complicated management. It is important as a treatable cause of CKD.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"97 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141657389","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}
C. Di Berardino, L. Massimino, F. Ungaro, G. Colasante
Dravet syndrome is a severe epileptic syndrome that begins during the first year of life of otherwise healthy babies. Over the years, the seizure burden changes, and pathology evolves in strong association with behavioral alterations, including cognitive delay and autistic traits. Initially, this aspect was considered a direct consequence of epilepsy severity, and DS was defined as an epileptic encephalopathy. Increasing evidence suggests that these two aspects of the disease, epilepsy and behavioral impairment, might not be so strictly connected. DS is mostly caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes for the alpha-subunit of the voltage-gated sodium channel Nav1.1, responsible for GABAergic interneuron excitability. Interneuron dysfunction is evident at symptom onset in Dravet murine models, but their activity appears to recover in the chronic phase of the disease, when a series of secondary modifications arise and likely drive the phenotype. Given that the genetic basis of the disease is clear, innovative therapies based on the restoration of sufficient expression levels of Nav1.1 to re-establish functional neuronal activity are being developed. In this work, we review such therapeutic approaches, with a specific focus on the existing evidence of their ability to address not only epilepsy but also behavioral alterations, and to recover secondary modifications.
{"title":"Gene therapy for Dravet syndrome: promises and impact on disease trigger and secondary modifications","authors":"C. Di Berardino, L. Massimino, F. Ungaro, G. Colasante","doi":"10.20517/rdodj.2024.07","DOIUrl":"https://doi.org/10.20517/rdodj.2024.07","url":null,"abstract":"Dravet syndrome is a severe epileptic syndrome that begins during the first year of life of otherwise healthy babies. Over the years, the seizure burden changes, and pathology evolves in strong association with behavioral alterations, including cognitive delay and autistic traits. Initially, this aspect was considered a direct consequence of epilepsy severity, and DS was defined as an epileptic encephalopathy. Increasing evidence suggests that these two aspects of the disease, epilepsy and behavioral impairment, might not be so strictly connected. DS is mostly caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes for the alpha-subunit of the voltage-gated sodium channel Nav1.1, responsible for GABAergic interneuron excitability. Interneuron dysfunction is evident at symptom onset in Dravet murine models, but their activity appears to recover in the chronic phase of the disease, when a series of secondary modifications arise and likely drive the phenotype. Given that the genetic basis of the disease is clear, innovative therapies based on the restoration of sufficient expression levels of Nav1.1 to re-establish functional neuronal activity are being developed. In this work, we review such therapeutic approaches, with a specific focus on the existing evidence of their ability to address not only epilepsy but also behavioral alterations, and to recover secondary modifications.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"59 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141664781","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}
Fabry disease (FD) is a multiorgan lysosomal storage disorder caused by mutations in the alfa-galactosidase A (GLA ) gene. Pathogenic GLA mutations lead to impaired or even lost enzyme activity, which causes the accumulation of sphingolipids, e.g., globotriaosylceramide, in cells and tissues. The majority of FD patients experience triggerable pain, mainly acral and burning, which often begins in early childhood. While small fiber pathology is assumed to be the basis of FD pain, the underlying molecular mechanisms are not well understood. This review summarizes the clinical characteristics of neuropathy and neuropathic pain in FD, presents current treatment options, and gives an overview of the latest findings from experimental and human model systems on the pathomechanisms contributing to small fiber pathology and FD-associated pain.
{"title":"Neuropathy and pain in Fabry disease","authors":"Vijay Krishna Medala, Nurcan Üçeyler","doi":"10.20517/rdodj.2024.13","DOIUrl":"https://doi.org/10.20517/rdodj.2024.13","url":null,"abstract":"Fabry disease (FD) is a multiorgan lysosomal storage disorder caused by mutations in the alfa-galactosidase A (GLA ) gene. Pathogenic GLA mutations lead to impaired or even lost enzyme activity, which causes the accumulation of sphingolipids, e.g., globotriaosylceramide, in cells and tissues. The majority of FD patients experience triggerable pain, mainly acral and burning, which often begins in early childhood. While small fiber pathology is assumed to be the basis of FD pain, the underlying molecular mechanisms are not well understood. This review summarizes the clinical characteristics of neuropathy and neuropathic pain in FD, presents current treatment options, and gives an overview of the latest findings from experimental and human model systems on the pathomechanisms contributing to small fiber pathology and FD-associated pain.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"117 36","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141666666","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}
P. J. Brooks, Alice Chen Grady, Stephen Groft, Linda Ho, Joanne M Lumsden, Meera Shah, E. Sid, Yanji Xu, Ainslie Tisdale, Jim Dickens, Dominique Pichard, Tiina K Urv
The mission of the NCATS Division of Rare Diseases Research Innovation (DRDRI), formerly known as the Office of Rare Diseases Research, is to advance rare diseases research to benefit patients. DRDRI is part of the National Center for Advancing Translational Sciences, one of the 27 components of the US National Institutes of Health. DRDRI facilitates and coordinates NIH-wide activities involving rare diseases research, as well as directly supporting rare diseases research activities. These activities include the development and maintenance of a centralized database on rare diseases; collaboration and coordination with organizations focused on orphan products development and rare diseases research across the globe, advising the Office of the NIH Director on matters related to NIH-sponsored research involving rare diseases; and responding to information and policy requests about rare diseases within the NIH. DRDRI also supports various rare diseases research activities, including the Rare Diseases Clinical Research Network, rare disease-related conference grants, and assessment of the costs of untreated rare diseases. In addition, several of the projects DRDRI is supporting are “many diseases at a time” translational approaches for rare diseases, which emphasize leveraging commonalities across multiple rare diseases. These include the support of “basket trials” based on shared molecular etiologies across multiple rare diseases, as well as therapeutic platforms for the treatment of monogenic diseases, such as gene therapy and genome editing. This Perspective will provide an overview and summary of these various activities, noting where relevant our collaborative partnerships within the U.S. and internationally.
{"title":"The division of rare diseases research innovation at the national center for advancing translational sciences, NIH: mission, history, and current research activities","authors":"P. J. Brooks, Alice Chen Grady, Stephen Groft, Linda Ho, Joanne M Lumsden, Meera Shah, E. Sid, Yanji Xu, Ainslie Tisdale, Jim Dickens, Dominique Pichard, Tiina K Urv","doi":"10.20517/rdodj.2023.27","DOIUrl":"https://doi.org/10.20517/rdodj.2023.27","url":null,"abstract":"The mission of the NCATS Division of Rare Diseases Research Innovation (DRDRI), formerly known as the Office of Rare Diseases Research, is to advance rare diseases research to benefit patients. DRDRI is part of the National Center for Advancing Translational Sciences, one of the 27 components of the US National Institutes of Health. DRDRI facilitates and coordinates NIH-wide activities involving rare diseases research, as well as directly supporting rare diseases research activities. These activities include the development and maintenance of a centralized database on rare diseases; collaboration and coordination with organizations focused on orphan products development and rare diseases research across the globe, advising the Office of the NIH Director on matters related to NIH-sponsored research involving rare diseases; and responding to information and policy requests about rare diseases within the NIH. DRDRI also supports various rare diseases research activities, including the Rare Diseases Clinical Research Network, rare disease-related conference grants, and assessment of the costs of untreated rare diseases. In addition, several of the projects DRDRI is supporting are “many diseases at a time” translational approaches for rare diseases, which emphasize leveraging commonalities across multiple rare diseases. These include the support of “basket trials” based on shared molecular etiologies across multiple rare diseases, as well as therapeutic platforms for the treatment of monogenic diseases, such as gene therapy and genome editing. This Perspective will provide an overview and summary of these various activities, noting where relevant our collaborative partnerships within the U.S. and internationally.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"39 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141268763","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}
Mara Parellada, Mónica Burdeus-Olavarrieta, David Fraguas, Antonia San José Cáceres, Constancio Medrano, María de los Desamparados Rodríguez
Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.
{"title":"Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report","authors":"Mara Parellada, Mónica Burdeus-Olavarrieta, David Fraguas, Antonia San José Cáceres, Constancio Medrano, María de los Desamparados Rodríguez","doi":"10.20517/rdodj.2023.53","DOIUrl":"https://doi.org/10.20517/rdodj.2023.53","url":null,"abstract":"Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"54 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141009234","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}
Major organ involvement in Anderson-Fabry disease (FD) is clinically silent for a long period and clinically heterogeneous; thus, it is difficult to identify the patients at increasing risk of a progressive disorder. Moreover, accumulating evidence suggests that early disease-specific treatment (DST) is safe and effective in preventing the progression of heart and kidney damage, with poorer results in patients with extensive myocardial fibrosis, advanced glomerulosclerosis, and/or heavy proteinuria. Therefore, biomarkers defining preclinical involvement, with a prognostic value and a correlation with response to treatment, are an urgent need in FD. Several types of biomarkers are recognized in FD, pertaining to total disease burden and specific organ involvement (central nervous system, heart, and kidney). Currently, plasma globotriaosylsphingosine (lyso-Gb3), cardiac and brain imaging, and albuminuria are recognized as the “gold standard” biomarkers of total disease burden or specific organ involvement in FD. However, severe globotriaosylceramide (Gb3) storage and organ damage may occur within the affected organs with minimal changes in these standard tests. Given the heterogeneity and rarity of the disease, the identification of new biomarkers is challenging. Several ways may be used to identify new biomarkers in FD, namely “omic” medicine, biomarkers identified in other pathological models similar to FD, and biomarkers linked to the pathophysiological pathways involved in FD. This article aims to review the clinical value of the available biomarkers in FD and give an overview of the research on new biomarkers.
{"title":"Biomarkers in anderson-Fabry disease: what should we use in the clinical practice?","authors":"Patrício Aguiar","doi":"10.20517/rdodj.2023.56","DOIUrl":"https://doi.org/10.20517/rdodj.2023.56","url":null,"abstract":"Major organ involvement in Anderson-Fabry disease (FD) is clinically silent for a long period and clinically heterogeneous; thus, it is difficult to identify the patients at increasing risk of a progressive disorder. Moreover, accumulating evidence suggests that early disease-specific treatment (DST) is safe and effective in preventing the progression of heart and kidney damage, with poorer results in patients with extensive myocardial fibrosis, advanced glomerulosclerosis, and/or heavy proteinuria. Therefore, biomarkers defining preclinical involvement, with a prognostic value and a correlation with response to treatment, are an urgent need in FD. Several types of biomarkers are recognized in FD, pertaining to total disease burden and specific organ involvement (central nervous system, heart, and kidney). Currently, plasma globotriaosylsphingosine (lyso-Gb3), cardiac and brain imaging, and albuminuria are recognized as the “gold standard” biomarkers of total disease burden or specific organ involvement in FD. However, severe globotriaosylceramide (Gb3) storage and organ damage may occur within the affected organs with minimal changes in these standard tests. Given the heterogeneity and rarity of the disease, the identification of new biomarkers is challenging. Several ways may be used to identify new biomarkers in FD, namely “omic” medicine, biomarkers identified in other pathological models similar to FD, and biomarkers linked to the pathophysiological pathways involved in FD. This article aims to review the clinical value of the available biomarkers in FD and give an overview of the research on new biomarkers.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"5 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140661646","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}
The high variability in clinical features and outcomes observed in monogenic diseases like Fabry disease suggests the presence of additional pathogenetic pathways beyond the lysosomal deposition of Gb3 and Lyso-GB3. Research indicates that the deposition of Gb3 and Lyso-Gb3 can stimulate the inflammatory processes. Mononuclear immune-competent cells exposed to Gb3 deposition exhibit surface adhesion molecules and release pro-inflammatory and fibrotic cytokines such as IL β, TNFα, and TGFβ, culminating in the activation of inflammatory cascades associated with oxidative stress, apoptotic mechanisms maintained by renal residents and infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, in another avenue of inquiry (termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alpha-galactosidase A enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response (UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of pro-inflammatory cytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstrated that the pathogenetic mechanisms activated by Gb3 and Lyso Gb3 deposition can become independent from the initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-therapy or gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifest in the absence of Gb3 in the Zebrafish experimental model. This review endeavors to describe the role of these processes in Fabry nephropathy and aims to synthesize the available evidence on the pathogenesis of renal damage.
{"title":"The inflammatory pathogenetic pathways of Fabry nephropathy","authors":"Sandro Feriozzi, Paula Rozenfeld","doi":"10.20517/rdodj.2023.37","DOIUrl":"https://doi.org/10.20517/rdodj.2023.37","url":null,"abstract":"The high variability in clinical features and outcomes observed in monogenic diseases like Fabry disease suggests the presence of additional pathogenetic pathways beyond the lysosomal deposition of Gb3 and Lyso-GB3. Research indicates that the deposition of Gb3 and Lyso-Gb3 can stimulate the inflammatory processes. Mononuclear immune-competent cells exposed to Gb3 deposition exhibit surface adhesion molecules and release pro-inflammatory and fibrotic cytokines such as IL β, TNFα, and TGFβ, culminating in the activation of inflammatory cascades associated with oxidative stress, apoptotic mechanisms maintained by renal residents and infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, in another avenue of inquiry (termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alpha-galactosidase A enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response (UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of pro-inflammatory cytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstrated that the pathogenetic mechanisms activated by Gb3 and Lyso Gb3 deposition can become independent from the initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-therapy or gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifest in the absence of Gb3 in the Zebrafish experimental model. This review endeavors to describe the role of these processes in Fabry nephropathy and aims to synthesize the available evidence on the pathogenesis of renal damage.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":" 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140689680","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}
David Moreno-Martínez, Luciana León-Cejas, Ricardo Reisin
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding for alpha-galactosidase A. Renal, cardiac, and cerebrovascular involvement are the leading complications in early adulthood and are associated with severe morbidity and mortality. Cerebrovascular manifestations in FD manifest as ischemic stroke and transient ischemic attack and less frequently as hemorrhagic strokes. Many patients may develop their stroke not only before other major complications but also before the diagnosis of FD is made. This review will describe the frequency and characteristics of cerebrovascular disease in FD, the complex pathophysiological mechanisms, the neuroimaging findings, the value of screening studies in young patients with stroke, and the controversies regarding the beneficial effect of ERT for the prevention of cerebrovascular disease in FD.
法布里病（FD）是由编码α-半乳糖苷酶 A 的 GLA 基因中的致病变体引起的一种 X 连锁溶酶体储积症。肾脏、心脏和脑血管受累是成年早期的主要并发症，并与严重的发病率和死亡率相关。FD 的脑血管表现为缺血性中风和短暂性脑缺血发作，出血性中风较少见。许多患者不仅可能在出现其他主要并发症之前就发生中风，也可能在确诊 FD 之前就发生中风。本综述将介绍 FD 脑血管疾病的发病频率和特点、复杂的病理生理机制、神经影像学发现、对年轻卒中患者进行筛查研究的价值，以及 ERT 对预防 FD 脑血管疾病的有益作用的争议。
{"title":"Cerebrovascular disorders and Fabry disease","authors":"David Moreno-Martínez, Luciana León-Cejas, Ricardo Reisin","doi":"10.20517/rdodj.2023.51","DOIUrl":"https://doi.org/10.20517/rdodj.2023.51","url":null,"abstract":"Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding for alpha-galactosidase A. Renal, cardiac, and cerebrovascular involvement are the leading complications in early adulthood and are associated with severe morbidity and mortality. Cerebrovascular manifestations in FD manifest as ischemic stroke and transient ischemic attack and less frequently as hemorrhagic strokes. Many patients may develop their stroke not only before other major complications but also before the diagnosis of FD is made. This review will describe the frequency and characteristics of cerebrovascular disease in FD, the complex pathophysiological mechanisms, the neuroimaging findings, the value of screening studies in young patients with stroke, and the controversies regarding the beneficial effect of ERT for the prevention of cerebrovascular disease in FD.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":" 50","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140384354","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}
Helen L. Malherbe, Jim Bonham, Michelle Carrihill, Karmani Chetty, E. H. Conradie, Marli Dercksen, Hilary Goeiman, Marianne C. M. Gomes, Brenda Klopper, Neil McKerrow, Carmencita Padilla, Tahir S. Pillay, Bronwyn Roussot, Tumelo M. Satekge, Michael Urban, George van der Watt, Helena Vreede, Dianne Webster, Marco Zampoli, B. C. Vorster
Worldwide, comprehensive newborn screening (NBS) now includes a clinical examination at birth, hearing screening, pulse oximetry measurement for congenital heart defects, and biochemical screening to identify congenital disorders early in life, preventing irreversible damage, early mortality and enhancing overall health outcomes. This article provides a comprehensive overview of biochemical NBS in South Africa, outlining the history, current status, and future plans for NBS expansion. In South Africa, NBS is fragmented, with some investigations included in neonatal health assessments. Historically, biochemical NBS pilot projects in the country in the 1960s and 1980s focused on phenylketonuria and congenital hypothyroidism (CH). Despite showing initial promise, these programmes were discontinued, largely due to competing health priorities. The current status of biochemical NBS in South Africa is discussed, both for the state and private healthcare sectors, which collectively screen approximately 0.5% of births annually. While recent clinical guidelines provide for a national biochemical NBS programme, implementation has been limited, and guideline adherence remains a challenge. A brief report of a two-day meeting held in Cape Town in February 2023 focusing on biochemical NBS for South Africa is provided. The meeting addressed the importance of NBS, technology requirements, and the need for a comprehensive demonstration project for biochemical CH NBS. Key challenges identified included early newborn post-delivery discharge, technical, logistical, and infrastructure issues, as well as limited financial and human resources. Meeting recommendations included the establishment of a National Advisory Panel for Biochemical NBS, and the development and implementation of a demonstration project for CH biochemical NBS in two provinces.
{"title":"Newborn screening in South Africa: the past, present, and plans for the future","authors":"Helen L. Malherbe, Jim Bonham, Michelle Carrihill, Karmani Chetty, E. H. Conradie, Marli Dercksen, Hilary Goeiman, Marianne C. M. Gomes, Brenda Klopper, Neil McKerrow, Carmencita Padilla, Tahir S. Pillay, Bronwyn Roussot, Tumelo M. Satekge, Michael Urban, George van der Watt, Helena Vreede, Dianne Webster, Marco Zampoli, B. C. Vorster","doi":"10.20517/rdodj.2023.49","DOIUrl":"https://doi.org/10.20517/rdodj.2023.49","url":null,"abstract":"Worldwide, comprehensive newborn screening (NBS) now includes a clinical examination at birth, hearing screening, pulse oximetry measurement for congenital heart defects, and biochemical screening to identify congenital disorders early in life, preventing irreversible damage, early mortality and enhancing overall health outcomes. This article provides a comprehensive overview of biochemical NBS in South Africa, outlining the history, current status, and future plans for NBS expansion. In South Africa, NBS is fragmented, with some investigations included in neonatal health assessments. Historically, biochemical NBS pilot projects in the country in the 1960s and 1980s focused on phenylketonuria and congenital hypothyroidism (CH). Despite showing initial promise, these programmes were discontinued, largely due to competing health priorities. The current status of biochemical NBS in South Africa is discussed, both for the state and private healthcare sectors, which collectively screen approximately 0.5% of births annually. While recent clinical guidelines provide for a national biochemical NBS programme, implementation has been limited, and guideline adherence remains a challenge. A brief report of a two-day meeting held in Cape Town in February 2023 focusing on biochemical NBS for South Africa is provided. The meeting addressed the importance of NBS, technology requirements, and the need for a comprehensive demonstration project for biochemical CH NBS. Key challenges identified included early newborn post-delivery discharge, technical, logistical, and infrastructure issues, as well as limited financial and human resources. Meeting recommendations included the establishment of a National Advisory Panel for Biochemical NBS, and the development and implementation of a demonstration project for CH biochemical NBS in two provinces.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140414997","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}
Ritu Jain, Chiuhui Mary Wang, Lisa Foster, Eileen Yangyang Li, Yukiko Nishimura, Kin Ping Tsang
The Asia-Pacific (APAC) region, home to 60% of the global population, has the highest number of Persons Living with a rare disease (PLWRD). To promote more equitable societies, the Asia Pacific rare disease Organization (APARDO), established in 2015, has been developing its regional position to promote collaboration, increase awareness among stakeholders, explore equitable and affordable diagnosis and treatment, and improve health outcomes and quality of life for all PLWRD. The APAC region’s heterogeneous population and complex healthcare environment pose distinctive challenges in addressing rare diseases. Through conferences, webinars, and contributions to global initiatives, APARDO is fostering connectivity and providing a platform as a part of the global rare disease (RD) community to address shared challenges. The development of APARDO to strengthen its global presence as the representative of the APAC RD region is vital for a more equitable world.
{"title":"Paradox of possibilities: the rare landscape in the Asia Pacific Region","authors":"Ritu Jain, Chiuhui Mary Wang, Lisa Foster, Eileen Yangyang Li, Yukiko Nishimura, Kin Ping Tsang","doi":"10.20517/rdodj.2023.42","DOIUrl":"https://doi.org/10.20517/rdodj.2023.42","url":null,"abstract":"The Asia-Pacific (APAC) region, home to 60% of the global population, has the highest number of Persons Living with a rare disease (PLWRD). To promote more equitable societies, the Asia Pacific rare disease Organization (APARDO), established in 2015, has been developing its regional position to promote collaboration, increase awareness among stakeholders, explore equitable and affordable diagnosis and treatment, and improve health outcomes and quality of life for all PLWRD. The APAC region’s heterogeneous population and complex healthcare environment pose distinctive challenges in addressing rare diseases. Through conferences, webinars, and contributions to global initiatives, APARDO is fostering connectivity and providing a platform as a part of the global rare disease (RD) community to address shared challenges. The development of APARDO to strengthen its global presence as the representative of the APAC RD region is vital for a more equitable world.","PeriodicalId":74638,"journal":{"name":"Rare disease and orphan drugs journal","volume":"2019 19","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140416010","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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