Background Megalencephalic leukoencephalopathy with subcortical cysts(MLC)is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inherit...Background Megalencephalic leukoencephalopathy with subcortical cysts(MLC)is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis,characterized by macrocephaly,delayed motor and cognitive development,and bilateral abnormal signals in cerebral white matter(WM)with or without cysts on magnetic resonance imaging(MRI).This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance.Methods Clinical information and peripheral venous blood were collected from six families.Genetic analysis was performed by Sanger sequencing of GLIALCAM.Glialcam^(Arg92Trp/+)and Glialcam^(Lys68Met/Thr132Asn)mouse models were generated based on mutations from patients(c.274C>T(p.Arg92Trp)(c.203A>T(p.Lys68Met),and c.395C>A(p.Thr132Asn))).Brain pathologies of the mouse models at different time points were analyzed.Results Six patients were clinically diagnosed with MLC.Of the six patients,five(Pt1-Pt5)presented with a heterozygous mutation in GLIALCAM(c.274C>T(p.Arg92Trp)or c.275G>C(p.Arg92Pro))and were diagnosed with MLC2B;the remaining patient(Pt6)with two compound heterozygous mutations in GLIALCAM(c.203A>T(p.Lys68Met)and c.395C>A(p.Thr132Asn))was diagnosed with MLC2A.The mutation c.275C>G(p.Arg92Pro)has not been reported before.Clinical manifestations of the patient with MLC2A(Pt6)progressed with regression,whereas the course of the five MLC2B patients remained stable or improved.The Glialcam^(Arg92Trp/+)and Glialcam^(Lys68Met/Thr132Asn)mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months,respectively.At 9 months,the vacuolization of the GlialcamiLys68Met/Thr132Asn mouse model was heavier than that of the Glialcam^(Arg92Trp/+)mouse model.Decreased expression of Glialcam in Glialcam^(Arg92Trp/+)and Glialcam^(Lys68Met/Thr132Asn)mice may contribute to the vacuolization.Conclusions Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation,expanding the spectrum of GLIALCAM mutations.The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated.The two mouse models with different modes of inheritance showed different degrees of brain pathological features,which were consistent with the patients'phenotype and further confirmed the pathogenicity of the corresponding mutations.展开更多
Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rate...Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rates of behavioral and cognitive problems,the treatment and outcomes of NR2F1-related epilepsy have rarely been described.Here,we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.Methods We identified six new Chinese cases of BBSOAS with epilepsy.Five different de novo heterozygous NR2F1 mutations were identified in these cases,including two novel mutations c.365G>T,p.Cys122Phe and c.449G>T,p.Gly150Val.By combining the six cases and 14 previously reported cases,we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.Results Twelve of the 20 patients(60%)had infantile epileptic spasms,while the other patients had generalized tonic/tonic-clonic,focal,myoclonic,absence,or unclassified seizures.Several anti-seizure medications,steroids,and a ketogenic diet were administered in these cases.However,seizures were controlled in only 50%of previously reported cases,while all of the six new cases became seizure-free after perampanel as an add-on treatment.The average time from the addition of perampanel to seizure control was 7.33±4.59 months(range,1–12 months).The median time to seizure freedom was 14 months(1–32 months,>19 months in 3 cases).The average dosage of perampanel needed for epilepsy control was 0.22±0.17 mg/kg per day.Conclusions In this paper,we comprehensively summarized the clinical characteristics,treatments and outcomes of NR2F1-related epilepsy for the first time.Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy.This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms.The two novel mutations expand the genotype spectrum of this disease.展开更多
基金funded by the National Natural Science Foundation of China(Grant Number:81741053,81501123)the Beijing Natural Science Foundation(Grant Number:7151010,7172217)+5 种基金the Bejing Municipal Science&Technology Commission(Grant Number:Z161100000216133,Z161100004916169)the Beijing Institute for Brain Disorders Foundation(Grant Number:BIBDPXM2014_014226_000016)the Beijing Municipal Natural Science Key Project(Grant Number 15G10050)Bejing key laboratory of molecular diagnosis and study on pediatric genetic discases(Grant Number BZ0317)the National Key Rescarch and Development Program of China(Grant Number:2016YFC1306201,2016YFC0901505)the Fundamental Research Funds for the Central Universities(Grant Number:BMU2017JI002).
文摘Background Megalencephalic leukoencephalopathy with subcortical cysts(MLC)is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis,characterized by macrocephaly,delayed motor and cognitive development,and bilateral abnormal signals in cerebral white matter(WM)with or without cysts on magnetic resonance imaging(MRI).This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance.Methods Clinical information and peripheral venous blood were collected from six families.Genetic analysis was performed by Sanger sequencing of GLIALCAM.Glialcam^(Arg92Trp/+)and Glialcam^(Lys68Met/Thr132Asn)mouse models were generated based on mutations from patients(c.274C>T(p.Arg92Trp)(c.203A>T(p.Lys68Met),and c.395C>A(p.Thr132Asn))).Brain pathologies of the mouse models at different time points were analyzed.Results Six patients were clinically diagnosed with MLC.Of the six patients,five(Pt1-Pt5)presented with a heterozygous mutation in GLIALCAM(c.274C>T(p.Arg92Trp)or c.275G>C(p.Arg92Pro))and were diagnosed with MLC2B;the remaining patient(Pt6)with two compound heterozygous mutations in GLIALCAM(c.203A>T(p.Lys68Met)and c.395C>A(p.Thr132Asn))was diagnosed with MLC2A.The mutation c.275C>G(p.Arg92Pro)has not been reported before.Clinical manifestations of the patient with MLC2A(Pt6)progressed with regression,whereas the course of the five MLC2B patients remained stable or improved.The Glialcam^(Arg92Trp/+)and Glialcam^(Lys68Met/Thr132Asn)mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months,respectively.At 9 months,the vacuolization of the GlialcamiLys68Met/Thr132Asn mouse model was heavier than that of the Glialcam^(Arg92Trp/+)mouse model.Decreased expression of Glialcam in Glialcam^(Arg92Trp/+)and Glialcam^(Lys68Met/Thr132Asn)mice may contribute to the vacuolization.Conclusions Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation,expanding the spectrum of GLIALCAM mutations.The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated.The two mouse models with different modes of inheritance showed different degrees of brain pathological features,which were consistent with the patients'phenotype and further confirmed the pathogenicity of the corresponding mutations.
文摘Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rates of behavioral and cognitive problems,the treatment and outcomes of NR2F1-related epilepsy have rarely been described.Here,we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.Methods We identified six new Chinese cases of BBSOAS with epilepsy.Five different de novo heterozygous NR2F1 mutations were identified in these cases,including two novel mutations c.365G>T,p.Cys122Phe and c.449G>T,p.Gly150Val.By combining the six cases and 14 previously reported cases,we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.Results Twelve of the 20 patients(60%)had infantile epileptic spasms,while the other patients had generalized tonic/tonic-clonic,focal,myoclonic,absence,or unclassified seizures.Several anti-seizure medications,steroids,and a ketogenic diet were administered in these cases.However,seizures were controlled in only 50%of previously reported cases,while all of the six new cases became seizure-free after perampanel as an add-on treatment.The average time from the addition of perampanel to seizure control was 7.33±4.59 months(range,1–12 months).The median time to seizure freedom was 14 months(1–32 months,>19 months in 3 cases).The average dosage of perampanel needed for epilepsy control was 0.22±0.17 mg/kg per day.Conclusions In this paper,we comprehensively summarized the clinical characteristics,treatments and outcomes of NR2F1-related epilepsy for the first time.Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy.This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms.The two novel mutations expand the genotype spectrum of this disease.
基金supported by the National Natural Science Foundation of China (81925022, 31821091, 31327901, 91854112, and 91750203)the National Key Research and Development Program of China (SQ2016YFJC040028, 2016YFC1306201 and 2016YFC0901505)+1 种基金the Beijing Natural Science Foundation (L172003)the UMHSPUHSC Joint Institute for Translational and Clinical Research (BMU2019JI009)。