Objective Mutations in polymerase gamma gene(POLG)are believed to be an important cause of early and juvenile onset of non-syndromic intractable epilepsy.The aim of this study is to investigate the incidence/prevalenc...Objective Mutations in polymerase gamma gene(POLG)are believed to be an important cause of early and juvenile onset of non-syndromic intractable epilepsy.The aim of this study is to investigate the incidence/prevalence of POLG pathogenic variants in epilespy patients of Han population through sequencing it.Methods Han Chinese patients with seizures prior valproic acid(VPA)exposure at Shanghai Children\Hospital were collected from 2015 to 2019.The clinical diagnosis was based on the 2014 Consensus Statement of Epilepsy by the International League against Epilepsy(ILAE).Blood sampling were performed before VPA treatment.The POLG gene DNA was sequenced by either the first or the next generation sequencing(NGS).The POLG variant burden was illustrated.Liver functions were tested to describe whether they experienced VPA toxicity.Results Ibtally 216 Han Chinese patients were included,aged from 1 month to IS years old,102 were male and 114 were female.The onset age was 1 month old to 13 years old,and the epilepsy course ranged from 2 weeks to about 3 years.VPA treatment was delivered for the generalized or intractable partial seizures at standard dosage.No patient experienced hepatic toxicity following VPA exposure.DNA sequencing data showed no patient had either a homozygous mutation or compound heterozygous mutation of POLG.Single heterozygous mutations of c.1150G>T and p.D384Y were found in 2 patients,and single heterozygous mutation of c.l56_158dupGCA was found in 1 patient.None of these variants showed clinical significance.Conclusions Functional modifying POLG homozygous mutations and compound heterozygous mutations were not detected and VPA toxicity was not seen in the current study.POLG mutation frequency might be rare in Han Chinese,and standard VPA.therapeutic dosage might be safe for Han Chinese patients.展开更多
Described are six patients with Alpers syndrome from four unrelated families. Affected individuals harbored the following combinations of POLG mutations: 1) A 467T/W1020X, 2) W748S-E1143G/G848S, 3) A467T/A467T, and 4)...Described are six patients with Alpers syndrome from four unrelated families. Affected individuals harbored the following combinations of POLG mutations: 1) A 467T/W1020X, 2) W748S-E1143G/G848S, 3) A467T/A467T, and 4)A467T/G848S. Homozygo sity for the A467T allele in one patient was associated with a later age at onse t. Mitochondrial respiratory chain studies in skeletal muscle were normal in eac h case. Nine combinations of mutant POLG alleles that cause Alpers syndrome are summarized.展开更多
Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European fami...Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors con ducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analy zed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long range PCR. Results: Ataxia occurred in combination with various CNS features,i ncluding myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions onMRI, and neuronal loss in discrete gray n uclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate induced hepatotoxicity occurred less frequently. Two patients died w ithout preceding signs of progressive external ophthalmoplegia. In muscle, typic al findings of mitochondrial disease, such as ragged red fibers and Southern blo t mtDNA abnormalities, were absent. POLG mutations were present in eight patient s, including two isolated cases, and one Finnish and two unrelated Belgian famil ies contained in total six patients. All POLG mutations were recessive, occurrin g in a homozygous state in seven patients and in a compound heterozygous state i n one patient. The novel W748S mutation was identified in five patients from thr ee unrelated families. Conclusions: The clinical spectrum of recessive POLG muta tions is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, my opathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondri al DNA also are not mandatory features associated with POLG mutations.展开更多
文摘Objective Mutations in polymerase gamma gene(POLG)are believed to be an important cause of early and juvenile onset of non-syndromic intractable epilepsy.The aim of this study is to investigate the incidence/prevalence of POLG pathogenic variants in epilespy patients of Han population through sequencing it.Methods Han Chinese patients with seizures prior valproic acid(VPA)exposure at Shanghai Children\Hospital were collected from 2015 to 2019.The clinical diagnosis was based on the 2014 Consensus Statement of Epilepsy by the International League against Epilepsy(ILAE).Blood sampling were performed before VPA treatment.The POLG gene DNA was sequenced by either the first or the next generation sequencing(NGS).The POLG variant burden was illustrated.Liver functions were tested to describe whether they experienced VPA toxicity.Results Ibtally 216 Han Chinese patients were included,aged from 1 month to IS years old,102 were male and 114 were female.The onset age was 1 month old to 13 years old,and the epilepsy course ranged from 2 weeks to about 3 years.VPA treatment was delivered for the generalized or intractable partial seizures at standard dosage.No patient experienced hepatic toxicity following VPA exposure.DNA sequencing data showed no patient had either a homozygous mutation or compound heterozygous mutation of POLG.Single heterozygous mutations of c.1150G>T and p.D384Y were found in 2 patients,and single heterozygous mutation of c.l56_158dupGCA was found in 1 patient.None of these variants showed clinical significance.Conclusions Functional modifying POLG homozygous mutations and compound heterozygous mutations were not detected and VPA toxicity was not seen in the current study.POLG mutation frequency might be rare in Han Chinese,and standard VPA.therapeutic dosage might be safe for Han Chinese patients.
文摘Described are six patients with Alpers syndrome from four unrelated families. Affected individuals harbored the following combinations of POLG mutations: 1) A 467T/W1020X, 2) W748S-E1143G/G848S, 3) A467T/A467T, and 4)A467T/G848S. Homozygo sity for the A467T allele in one patient was associated with a later age at onse t. Mitochondrial respiratory chain studies in skeletal muscle were normal in eac h case. Nine combinations of mutant POLG alleles that cause Alpers syndrome are summarized.
文摘Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors con ducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analy zed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long range PCR. Results: Ataxia occurred in combination with various CNS features,i ncluding myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions onMRI, and neuronal loss in discrete gray n uclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate induced hepatotoxicity occurred less frequently. Two patients died w ithout preceding signs of progressive external ophthalmoplegia. In muscle, typic al findings of mitochondrial disease, such as ragged red fibers and Southern blo t mtDNA abnormalities, were absent. POLG mutations were present in eight patient s, including two isolated cases, and one Finnish and two unrelated Belgian famil ies contained in total six patients. All POLG mutations were recessive, occurrin g in a homozygous state in seven patients and in a compound heterozygous state i n one patient. The novel W748S mutation was identified in five patients from thr ee unrelated families. Conclusions: The clinical spectrum of recessive POLG muta tions is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, my opathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondri al DNA also are not mandatory features associated with POLG mutations.
