Thalassaemia major(TM) and Friedreich's ataxia(FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the...Thalassaemia major(TM) and Friedreich's ataxia(FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients.Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.展开更多
Friedreich's ataxia(FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical ma...Friedreich's ataxia(FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify.The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and(less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life.However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length(i.e.,markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.展开更多
Introduction: Friedreich ataxia (FRDA) is a multi-system autosomal-recessive disease, the most common one of the genetically inherited ataxias. FRDA occurs as a consequence of mutations in the frataxin gene, with an e...Introduction: Friedreich ataxia (FRDA) is a multi-system autosomal-recessive disease, the most common one of the genetically inherited ataxias. FRDA occurs as a consequence of mutations in the frataxin gene, with an expansion of a GAA trinucleotide. Ataxia with vitamin E deficiency (AVED) is characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich’s ataxia (FA) but serum concentrations of vitamin E are low. Aim of study: To study clinical and genetic features of the Friedreich’s ataxia and AVED patients in 44 Moroccan families. Patients and Methods: Retrospective series of 72 Moroccan patients displaying Friedreich’s ataxia syndrome was recruited over a period of 22 years (1987-2009). All patients had a clinical and ophtalmological examinations, 30 patients underwent electromyography, and CT scan was performed in 29 patients. GAA repeats in the frataxin gene and the 744 del A mutation α-TTP gene were performed in all patients. Results: 17 patients (24% of cases) had the 744 del A mutation in the α-TTP gene responsible of ataxia with vitamin E deficiency (AVED) phenotype. 55 patients ?(76% of cases) had GAA expanded allele in the first intron of the frataxin gene. Phenotype-genotype correlation revealed a high frequency of head titubation, decreased visual acuity and slower disease progression in AVED than in Friedreich’s ataxia phenotype (p Our study represents a large series which highlight the clinical and genetic differences between AVED and Friedreich’s ataxia. AVED patients have a better prognosis after alpha-tocopherol treatment.展开更多
We report a patient with severe ataxia due to Dandy-Walker malformation, who showed functional recovery over 10 months corresponding to a change in a cerebellar peduncle lesion. A 20-month-old female patient who was d...We report a patient with severe ataxia due to Dandy-Walker malformation, who showed functional recovery over 10 months corresponding to a change in a cerebellar peduncle lesion. A 20-month-old female patient who was diagnosed with Dandy-Walker syndrome and six age- and sex-matched healthy control subjects were enrolled. The superior cerebellar peduncle, the middle cerebellar peduncle, and the inferior cerebellar peduncle were evaluated using fractional anisotropy and the apparent diffusion coefficient. The patients＇ functional ambulation category was 0 at the initial visit, but improved to 2 at the follow-up evaluation, and Berg＇s balance scale score also improved from 0 to 7. Initial diffusion tensor tractography revealed that the inferior cerebellar peduncle was not detected, that the fractional anisotropy of the superior cerebellar peduncle and middle cerebellar peduncle decreased by two standard deviations below, and that the apparent diffusion coefficient increased by two standard deviations over normal control values. However, on follow-up diffusion tensor tractography, both inferior cerebellar peduncles could be detected, and the fractional anisotropy of superior cerebellar peduncle increased to within two standard deviations of normal controls. The functional improvement in this patient appeared to correspond to changes in these cerebellar peduncles. We believe that evaluating cerebellar peduncles using diffusion tensor imaging is useful in cases when a cerebellar peduncle lesion is suspected.展开更多
Sequence similarities were found between protein and DNA sequences encoding certain part of conserved variable immunoglobulin domains (i.e. conserved IgV) and phosphorylation sites. Hypermutation motifs were then indi...Sequence similarities were found between protein and DNA sequences encoding certain part of conserved variable immunoglobulin domains (i.e. conserved IgV) and phosphorylation sites. Hypermutation motifs were then indicated in the majority of the corresponding non-IgV nucleotide sequences. According to database confirmations or double prediction of phosphorylation sites, 80% of the selected human and mouse IgV-related phosphorylation sites or their highly probable candidates exhibited substrate relationship to ataxia-telangiectasia-mutated kinase known as ATM. In accordance with literature data, inactivation of ATM by mutations can participate in the mechanisms of carcinogenesis, neurodegeneration and possibly also in aging. In agreement with this relationship, some of the selected IgV-/ATM-related segments formed molecules specifically involved in carcinogenesis. The selected IgV-related sequence segments were also similar to certain segments of higher plants containing immunoglobulin-like repeats and related regions. Bioinformatic analysis of some selected plant sequences then indicated the presence of catalytic domains composing serine/threonine/tyrosine receptor/receptor-like kinases, which are considered important structures for evolution of very early and part of later Ig-domain-related immunity. The analyzed conserved domain similarities also suggested certain interesting structural and phylogenic relationships, which need to be further investigated. This review in fact briefly summarizes the findings on the subject from the last twenty years.展开更多
目的:探讨多系统萎缩(multiple system atrophy,MSA)患者的临床表现和诊断方法。方法:回顾性分析近3年来郑州大学第一附属医院收治的68例MSA患者的临床资料并结合文献复习。结果:MSA患者自主神经功能障碍57例(83.8%),其中46例患者(67.6%...目的:探讨多系统萎缩(multiple system atrophy,MSA)患者的临床表现和诊断方法。方法:回顾性分析近3年来郑州大学第一附属医院收治的68例MSA患者的临床资料并结合文献复习。结果:MSA患者自主神经功能障碍57例(83.8%),其中46例患者(67.6%)出现泌尿生殖功能障碍;以帕金森综合征为主的MSA-P亚型23例占总人数33.8%,以小脑性共济失调为主的MSA-C亚型45例占总人数66.2%;头部MRI可见T2信号典型改变:壳核背外侧条带样低信号、外侧缘裂隙样高信号、小脑萎缩、小脑中脚高信号、脑桥基底部"十字征"。结论:MSA是多系统受累的神经变性疾病,其症状复杂多样。临床诊断需详细病史及神经系统检查,并以磁共振成像等辅助手段加以支持。展开更多
Friedreich ataxia(FRDA)is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene.The numerous drawbacks of historical cellular and rodent models of FRDA have ca...Friedreich ataxia(FRDA)is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene.The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease.The recent discovery and subsequent development of induced pluripotent stem cell(iPSC)technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases.Utilising iPSCs,researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA.These models enable studies of the molecular mechanisms underlying GAA-induced pathology,as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies.This review explores how the use of iPSCs to study FRDA has developed over the past decade,as well as discussing the enormous therapeutic potentials of iPSC-derived models,their current limitations and their future direction within the field of FRDA research.展开更多
文摘Thalassaemia major(TM) and Friedreich's ataxia(FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients.Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.
文摘Friedreich's ataxia(FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify.The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and(less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life.However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length(i.e.,markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
文摘Introduction: Friedreich ataxia (FRDA) is a multi-system autosomal-recessive disease, the most common one of the genetically inherited ataxias. FRDA occurs as a consequence of mutations in the frataxin gene, with an expansion of a GAA trinucleotide. Ataxia with vitamin E deficiency (AVED) is characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich’s ataxia (FA) but serum concentrations of vitamin E are low. Aim of study: To study clinical and genetic features of the Friedreich’s ataxia and AVED patients in 44 Moroccan families. Patients and Methods: Retrospective series of 72 Moroccan patients displaying Friedreich’s ataxia syndrome was recruited over a period of 22 years (1987-2009). All patients had a clinical and ophtalmological examinations, 30 patients underwent electromyography, and CT scan was performed in 29 patients. GAA repeats in the frataxin gene and the 744 del A mutation α-TTP gene were performed in all patients. Results: 17 patients (24% of cases) had the 744 del A mutation in the α-TTP gene responsible of ataxia with vitamin E deficiency (AVED) phenotype. 55 patients ?(76% of cases) had GAA expanded allele in the first intron of the frataxin gene. Phenotype-genotype correlation revealed a high frequency of head titubation, decreased visual acuity and slower disease progression in AVED than in Friedreich’s ataxia phenotype (p Our study represents a large series which highlight the clinical and genetic differences between AVED and Friedreich’s ataxia. AVED patients have a better prognosis after alpha-tocopherol treatment.
基金supported by the Basic Scientific Research Program of National Research Foundation of Korea Funded by Ministry of Education, Science and Technology, No.2011-0003426
文摘We report a patient with severe ataxia due to Dandy-Walker malformation, who showed functional recovery over 10 months corresponding to a change in a cerebellar peduncle lesion. A 20-month-old female patient who was diagnosed with Dandy-Walker syndrome and six age- and sex-matched healthy control subjects were enrolled. The superior cerebellar peduncle, the middle cerebellar peduncle, and the inferior cerebellar peduncle were evaluated using fractional anisotropy and the apparent diffusion coefficient. The patients＇ functional ambulation category was 0 at the initial visit, but improved to 2 at the follow-up evaluation, and Berg＇s balance scale score also improved from 0 to 7. Initial diffusion tensor tractography revealed that the inferior cerebellar peduncle was not detected, that the fractional anisotropy of the superior cerebellar peduncle and middle cerebellar peduncle decreased by two standard deviations below, and that the apparent diffusion coefficient increased by two standard deviations over normal control values. However, on follow-up diffusion tensor tractography, both inferior cerebellar peduncles could be detected, and the fractional anisotropy of superior cerebellar peduncle increased to within two standard deviations of normal controls. The functional improvement in this patient appeared to correspond to changes in these cerebellar peduncles. We believe that evaluating cerebellar peduncles using diffusion tensor imaging is useful in cases when a cerebellar peduncle lesion is suspected.
文摘Sequence similarities were found between protein and DNA sequences encoding certain part of conserved variable immunoglobulin domains (i.e. conserved IgV) and phosphorylation sites. Hypermutation motifs were then indicated in the majority of the corresponding non-IgV nucleotide sequences. According to database confirmations or double prediction of phosphorylation sites, 80% of the selected human and mouse IgV-related phosphorylation sites or their highly probable candidates exhibited substrate relationship to ataxia-telangiectasia-mutated kinase known as ATM. In accordance with literature data, inactivation of ATM by mutations can participate in the mechanisms of carcinogenesis, neurodegeneration and possibly also in aging. In agreement with this relationship, some of the selected IgV-/ATM-related segments formed molecules specifically involved in carcinogenesis. The selected IgV-related sequence segments were also similar to certain segments of higher plants containing immunoglobulin-like repeats and related regions. Bioinformatic analysis of some selected plant sequences then indicated the presence of catalytic domains composing serine/threonine/tyrosine receptor/receptor-like kinases, which are considered important structures for evolution of very early and part of later Ig-domain-related immunity. The analyzed conserved domain similarities also suggested certain interesting structural and phylogenic relationships, which need to be further investigated. This review in fact briefly summarizes the findings on the subject from the last twenty years.
文摘目的:探讨多系统萎缩(multiple system atrophy,MSA)患者的临床表现和诊断方法。方法:回顾性分析近3年来郑州大学第一附属医院收治的68例MSA患者的临床资料并结合文献复习。结果:MSA患者自主神经功能障碍57例(83.8%),其中46例患者(67.6%)出现泌尿生殖功能障碍;以帕金森综合征为主的MSA-P亚型23例占总人数33.8%,以小脑性共济失调为主的MSA-C亚型45例占总人数66.2%;头部MRI可见T2信号典型改变:壳核背外侧条带样低信号、外侧缘裂隙样高信号、小脑萎缩、小脑中脚高信号、脑桥基底部"十字征"。结论:MSA是多系统受累的神经变性疾病,其症状复杂多样。临床诊断需详细病史及神经系统检查,并以磁共振成像等辅助手段加以支持。
基金supported in part by LifeArc Project 10312,and partly by the Friedreich’s Ataxia Research Alliance,Ataxia UK and EndFA.G.V.-Esupported by the Ecuadorian government through Secretaría Nacional de Educación Superior,Ciencia,Tecnología e Innovación Act 063-CIBAE-2015.
文摘Friedreich ataxia(FRDA)is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene.The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease.The recent discovery and subsequent development of induced pluripotent stem cell(iPSC)technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases.Utilising iPSCs,researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA.These models enable studies of the molecular mechanisms underlying GAA-induced pathology,as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies.This review explores how the use of iPSCs to study FRDA has developed over the past decade,as well as discussing the enormous therapeutic potentials of iPSC-derived models,their current limitations and their future direction within the field of FRDA research.
