X-连锁肾上腺脑白质营养不良(X-linked adrenoleukodystrophy,X-ALD)是一种罕见的过氧化物酶体疾病,发病率约为1/17000[1]。其主要病因是位于X染色体Xq28上ATP结合盒亚家族D成员1(ATP binding cassette subfamily D member 1,ABCD1)基...X-连锁肾上腺脑白质营养不良(X-linked adrenoleukodystrophy,X-ALD)是一种罕见的过氧化物酶体疾病,发病率约为1/17000[1]。其主要病因是位于X染色体Xq28上ATP结合盒亚家族D成员1(ATP binding cassette subfamily D member 1,ABCD1)基因突变,呈X-连锁隐性遗传[2],该基因突变导致极长链脂肪酸(very-long-chain fatty acid,VLCFA)跨膜转入过氧化物酶体降解失败致使VLCFA在组织液及体液中大量蓄积,尤其在血浆、大脑白质、神经系统及肾上腺等组织异常沉积,引发中枢神经系统脱髓鞘和原发性肾上腺皮质功能不全[3-4]。展开更多
This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),an...This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),and multi-site injection was performed.The injection dose increased from 200 to 1600 lL(vector titer:1×10^(9) transduction units per mL(TU/mL)),and the average dose per kilogram body weight ranges from 8 to 63.6 lL/kg.The primary endpoint was safety,dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein.A total of 7 patients participated in this phase I study and were followed for 1 year.No injectionrelated serious adverse event or death occurred.Common adverse events associated with the injection were irritability(71%,5/7)and fever(37.2-38.5℃,57%,4/7).Adverse events were mild and selflimited,or resolved within 3 d of symptomatic treatment.The maximal tolerable dose is 1600 lL.In 5 cases(83.3%,5/6),no lentivirus associated antibodies were detected.The overall survival at 1-year was 100%.The ABCD1 protein expression was detected in neutrophils,monocytes and lymphocytes.This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo;even the maximal dose did not increase the risk of adverse events.Furthermore,the direct LV-ABCD1 injection displayed low immunogenicity.In addition,the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed.This study has been registered in the Chinese Clinical Trial Registry(https://www.chictr.org.cn/,registration number:ChiCTR1900026649).展开更多
Background:X-linked adrenoleukodystrophy(X-ALD)is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1(ABCD1)gene.This study aimed to retrospectively investigate the ...Background:X-linked adrenoleukodystrophy(X-ALD)is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1(ABCD1)gene.This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees,to analyze ABCD1 gene mutations,the effect of gene novel variants on ALD protein(ALDP)structure and function,and to expand gene mutation spectrum of Chinese patients.Methods:Twenty-five male patients diagnosed with X-ALD were enrolled in this study.The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation.ABCD1 gene mutations were analyzed.The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool,polymorphism phenotyping,sorting intolerant from tolerant,Align-Grantham variation and Grantham deviation,and Swiss-Program Database Viewer 4.04 software,respectively.Results:Childhood cerebral form ALD(CCALD)is the most common phenotype(64%)in the 25 patients with X-ALD.The progressive deterioration of neurological and cognitive functions is the main clinical feature.The demyelination of the brain white matter and elevated plasma very long chain fatty acids(VLCFAs)were found in all patients.Different phenotypes were also presented within family members of the patients.Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identifi ed in the 25 patients.Of the mutations,63.6%were missense mutations and 34.8%located in exon 1.The amino acid residues of three novel missense mutations in eight species were highly conserved,and were predicted to be"probably"damaging to ALDP function.The other five novel mutations were splice,nonsense,deletion or duplication mutations.Conclusions:CCALD is the most common phenotype(64%)in our patients with X-ALD.Eight novel mutations in the ABCD1 gene identifi ed are disease-causing mutations.Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.展开更多
Adrenomyeloneuropathy(AMN)is a kind of varied disease caused by ABCD1 gene mutation and characterized by very-long-chain fatty acids(VLCFA)accumulation.It is diag-nosed by clinical features,high VLCFAs levels and ABCD...Adrenomyeloneuropathy(AMN)is a kind of varied disease caused by ABCD1 gene mutation and characterized by very-long-chain fatty acids(VLCFA)accumulation.It is diag-nosed by clinical features,high VLCFAs levels and ABCD1 gene mutation.AMN is rarely reported in Chinese population.In this study,we report the genetic and clinical features of a Chinese pure AMN patient.Meanwhile,we conducted a literature review of AMN cases to summarize the characteristics of AMN.We report a rare Chinese pure AMN case with slowly progressive weakness of the lower extremities,caused by a novel c.1202G>A mutation in ABCD1 gene.The literature review indicates that spastic paraplegia is the mainly clinical manifestation in patients with AMN.VLCFAs and ABCD1 gene test should be performed in patients with spastic paraplegia of the lower limbs to diagnose AMN.展开更多
文摘X-连锁肾上腺脑白质营养不良(X-linked adrenoleukodystrophy,X-ALD)是一种罕见的过氧化物酶体疾病,发病率约为1/17000[1]。其主要病因是位于X染色体Xq28上ATP结合盒亚家族D成员1(ATP binding cassette subfamily D member 1,ABCD1)基因突变,呈X-连锁隐性遗传[2],该基因突变导致极长链脂肪酸(very-long-chain fatty acid,VLCFA)跨膜转入过氧化物酶体降解失败致使VLCFA在组织液及体液中大量蓄积,尤其在血浆、大脑白质、神经系统及肾上腺等组织异常沉积,引发中枢神经系统脱髓鞘和原发性肾上腺皮质功能不全[3-4]。
基金supported by the Capital’s Funds for Health Improvement and Research(2022-1-5081)the National Key Research and Development Program of China(2023YFC2706304)+1 种基金Shenzhen Geno-Immune Medical InstituteBeijing Meikang Biotechnology Co.,LTD.
文摘This was a single-arm,multicenter,open-label phase I trial.Lentiviral vectors(LV)carrying the ABCD1 gene(LV-ABCD1)was directly injected into the brain of patients with childhood cerebral adrenoleukodystrophy(CCALD),and multi-site injection was performed.The injection dose increased from 200 to 1600 lL(vector titer:1×10^(9) transduction units per mL(TU/mL)),and the average dose per kilogram body weight ranges from 8 to 63.6 lL/kg.The primary endpoint was safety,dose-exploration and immunogenicity and the secondary endpoint was initial evaluation of efficacy and the expression of ABCD1 protein.A total of 7 patients participated in this phase I study and were followed for 1 year.No injectionrelated serious adverse event or death occurred.Common adverse events associated with the injection were irritability(71%,5/7)and fever(37.2-38.5℃,57%,4/7).Adverse events were mild and selflimited,or resolved within 3 d of symptomatic treatment.The maximal tolerable dose is 1600 lL.In 5 cases(83.3%,5/6),no lentivirus associated antibodies were detected.The overall survival at 1-year was 100%.The ABCD1 protein expression was detected in neutrophils,monocytes and lymphocytes.This study suggests that the intracerebral injection of LV-ABCD1 for CCALD is safe and can achieve successful LV transduction in vivo;even the maximal dose did not increase the risk of adverse events.Furthermore,the direct LV-ABCD1 injection displayed low immunogenicity.In addition,the effectiveness of intracerebral LV-ABCD1 injection has been preliminarily demonstrated while further investigation is needed.This study has been registered in the Chinese Clinical Trial Registry(https://www.chictr.org.cn/,registration number:ChiCTR1900026649).
基金supported by a grant from the National Key Technology R&D Program(2012BAI09B00).
文摘Background:X-linked adrenoleukodystrophy(X-ALD)is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1(ABCD1)gene.This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees,to analyze ABCD1 gene mutations,the effect of gene novel variants on ALD protein(ALDP)structure and function,and to expand gene mutation spectrum of Chinese patients.Methods:Twenty-five male patients diagnosed with X-ALD were enrolled in this study.The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation.ABCD1 gene mutations were analyzed.The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool,polymorphism phenotyping,sorting intolerant from tolerant,Align-Grantham variation and Grantham deviation,and Swiss-Program Database Viewer 4.04 software,respectively.Results:Childhood cerebral form ALD(CCALD)is the most common phenotype(64%)in the 25 patients with X-ALD.The progressive deterioration of neurological and cognitive functions is the main clinical feature.The demyelination of the brain white matter and elevated plasma very long chain fatty acids(VLCFAs)were found in all patients.Different phenotypes were also presented within family members of the patients.Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identifi ed in the 25 patients.Of the mutations,63.6%were missense mutations and 34.8%located in exon 1.The amino acid residues of three novel missense mutations in eight species were highly conserved,and were predicted to be"probably"damaging to ALDP function.The other five novel mutations were splice,nonsense,deletion or duplication mutations.Conclusions:CCALD is the most common phenotype(64%)in our patients with X-ALD.Eight novel mutations in the ABCD1 gene identifi ed are disease-causing mutations.Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.
基金The study was supported by the National key R&D Program of China[grant numbers 2017YFC1310300,2016YFC1306600]the National Natural Science Foun-dation of China[grant numbers 81301081,81601127]。
文摘Adrenomyeloneuropathy(AMN)is a kind of varied disease caused by ABCD1 gene mutation and characterized by very-long-chain fatty acids(VLCFA)accumulation.It is diag-nosed by clinical features,high VLCFAs levels and ABCD1 gene mutation.AMN is rarely reported in Chinese population.In this study,we report the genetic and clinical features of a Chinese pure AMN patient.Meanwhile,we conducted a literature review of AMN cases to summarize the characteristics of AMN.We report a rare Chinese pure AMN case with slowly progressive weakness of the lower extremities,caused by a novel c.1202G>A mutation in ABCD1 gene.The literature review indicates that spastic paraplegia is the mainly clinical manifestation in patients with AMN.VLCFAs and ABCD1 gene test should be performed in patients with spastic paraplegia of the lower limbs to diagnose AMN.
