Novel AARS2 gene mutations encoding mitochondrial alanyl-tRNA synthetase are important in the spectrum of different phenotypes expressed in the nervous system. Leukodystrophy and ovarian failure in females are common ...Novel AARS2 gene mutations encoding mitochondrial alanyl-tRNA synthetase are important in the spectrum of different phenotypes expressed in the nervous system. Leukodystrophy and ovarian failure in females are common phenotypes. Peripheral demyelination is not a recognized aspect of the AARS2 phenotype. A patient with preceding Lyme neuroborreliosis developed progressive leukodystrophy and peripheral demyelinating motor polyneuropathy. Serial magnetic resonance imaging showed progressive inflammatory demyelination extending to the corticospinal tracts. Treatment with a standard of care of antibiotics and immune-modulatory therapy employing intravenous immune globulin was employed. The contribution of neuroborreliosis is not well understood in the expression of the AARS2 phenotype.展开更多
Metachromatic leukodystrophy(MLD)is an inherited disease caused by a deficiency of the enzyme arylsulfatase A(ARSA).Lentivirus-modified autologous hematopoietic stem cell gene therapy(HSCGT)has recently been approved ...Metachromatic leukodystrophy(MLD)is an inherited disease caused by a deficiency of the enzyme arylsulfatase A(ARSA).Lentivirus-modified autologous hematopoietic stem cell gene therapy(HSCGT)has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity.Unfortunately,this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis.Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system,whereas those with early onset infantile MLD die within a few years of symptom onset.We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results.The safety profile of HSCGT was favorable in this long-term follow-up over 9 years.The most common adverse events(AEs)within 2 months of HSCGT were related to busulfan conditioning,and all AEs resolved.No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years.Importantly,to date,patients have maintained remarkably improved ARSA activity with a stable disease state,including increased Functional Independence Measure(FIM)score and decreased magnetic resonance imaging(MRI)lesion score.This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.展开更多
Importance:Aicardi-Goutières syndrome(AGS)is a rare genetic disorder mainly affecting the central nervous system and autoimmunity.However,research on AGS among Chinese patients is limited.Objective:To summarize t...Importance:Aicardi-Goutières syndrome(AGS)is a rare genetic disorder mainly affecting the central nervous system and autoimmunity.However,research on AGS among Chinese patients is limited.Objective:To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients,providing insights for early recognition and diagnosis in the Chinese population.Methods:Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children’s Hospital between January 2018 and January 2022 were collected.Whole exome sequencing was used for genetic analysis.Results:A total of 15 patients was included,all presenting with various neurological symptoms,including developmental delay(100%),motor skill impairment(100%),language disability(78.6%),dystonia(93.3%),microcephaly(73.3%),sleep disorders(26.7%),regression(20.0%),vessel disease(6.7%),and epilepsy(6.7%).Neuroimaging revealed intracranial calcification(86.7%),cerebral atrophy(73.3%),and leukodystrophy(73.3%).Seven genes were identified,with TREX1 being the most common(40.0%,6/15),followed by IFIH1(20.0%,3/15).Variant c.294dupA(p.C99Mfs*3)was detected in four unrelated patients,accounting for 66.7%(4/6)patients with the TREX1 variant.A literature review showed that TREX1 gene mutations in 35.6%(21/59)of AGS patients among the Chinese population.Interpretation:Neurological symptoms are the most prevalent and severe presentation of AGS.Diagnosis may be considered when symptoms such as developmental delay,dystonia,microcephaly,brain calcification,and leukodystrophy emerge.TREX1 mutations are predominant in the Chinese population.展开更多
文摘Novel AARS2 gene mutations encoding mitochondrial alanyl-tRNA synthetase are important in the spectrum of different phenotypes expressed in the nervous system. Leukodystrophy and ovarian failure in females are common phenotypes. Peripheral demyelination is not a recognized aspect of the AARS2 phenotype. A patient with preceding Lyme neuroborreliosis developed progressive leukodystrophy and peripheral demyelinating motor polyneuropathy. Serial magnetic resonance imaging showed progressive inflammatory demyelination extending to the corticospinal tracts. Treatment with a standard of care of antibiotics and immune-modulatory therapy employing intravenous immune globulin was employed. The contribution of neuroborreliosis is not well understood in the expression of the AARS2 phenotype.
基金supported in part by Poland Fundacja SiepomagaJS Foundation (Hong Kong)+1 种基金Shenzhen Li Weibo Charity FoundationTaiwan Rare Disease Foundation。
文摘Metachromatic leukodystrophy(MLD)is an inherited disease caused by a deficiency of the enzyme arylsulfatase A(ARSA).Lentivirus-modified autologous hematopoietic stem cell gene therapy(HSCGT)has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity.Unfortunately,this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis.Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system,whereas those with early onset infantile MLD die within a few years of symptom onset.We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results.The safety profile of HSCGT was favorable in this long-term follow-up over 9 years.The most common adverse events(AEs)within 2 months of HSCGT were related to busulfan conditioning,and all AEs resolved.No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years.Importantly,to date,patients have maintained remarkably improved ARSA activity with a stable disease state,including increased Functional Independence Measure(FIM)score and decreased magnetic resonance imaging(MRI)lesion score.This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
文摘Importance:Aicardi-Goutières syndrome(AGS)is a rare genetic disorder mainly affecting the central nervous system and autoimmunity.However,research on AGS among Chinese patients is limited.Objective:To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients,providing insights for early recognition and diagnosis in the Chinese population.Methods:Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children’s Hospital between January 2018 and January 2022 were collected.Whole exome sequencing was used for genetic analysis.Results:A total of 15 patients was included,all presenting with various neurological symptoms,including developmental delay(100%),motor skill impairment(100%),language disability(78.6%),dystonia(93.3%),microcephaly(73.3%),sleep disorders(26.7%),regression(20.0%),vessel disease(6.7%),and epilepsy(6.7%).Neuroimaging revealed intracranial calcification(86.7%),cerebral atrophy(73.3%),and leukodystrophy(73.3%).Seven genes were identified,with TREX1 being the most common(40.0%,6/15),followed by IFIH1(20.0%,3/15).Variant c.294dupA(p.C99Mfs*3)was detected in four unrelated patients,accounting for 66.7%(4/6)patients with the TREX1 variant.A literature review showed that TREX1 gene mutations in 35.6%(21/59)of AGS patients among the Chinese population.Interpretation:Neurological symptoms are the most prevalent and severe presentation of AGS.Diagnosis may be considered when symptoms such as developmental delay,dystonia,microcephaly,brain calcification,and leukodystrophy emerge.TREX1 mutations are predominant in the Chinese population.
