Xu J Chu, Kang Du, Ling C Meng, Zhi Y Xie, Ying Zhu, Wei Zhang, Zhao X Wang, Yun Yuan
Background and aims: The early growth response 2 gene (EGR2) mutations are associated with a group of hereditary neuropathy, including axonal neuropathy and hypomyelinating neuropathy or Charcot-Marie-Tooth disease (CMT) type 1D. We aim to perform an electrodiagnostic, nerve imaging, and histological study of EGR2-associated neuropathy.
Materials and methods: We performed a retrospective analysis of two patients with EGR2-related neurology at our hospital. The neuropathy was confirmed by the nerve conduction study. Nerve imaging and sural biopsies were performed in two patients.
Results: Two unrelated boys exhibited early-onset length-dependent neuropathy. Next generation sequencing identified EGR2 gene with previously described E412K mutation in the third zine finger domain in patient 1 and a previously undescribed variant D355N mutation in the first zinc finger domain in patient 2. The magnetic resonance imaging of the lumbosacral plexus showed no abnormalities in patient 1 and thickened lumbosacral plexuses in patient 2. Electrophysiology and nerve biopsies showed a prominent axonal neuropathy, accompanied with demyelinating involvement.
Conclusion: Therefore, it seemed that the EGR2 mutations could cause not only the known demyelinating type and axonal type but also mixed-type CMT. Our findings expanded the phenotypic heterogeneities of EGR2-associated neuropathy.
背景和目的:早期生长反应2基因(EGR2)突变与一组遗传性神经病变有关,包括轴索神经病变、低髓鞘神经病变或charco - marie - tooth病(CMT) 1D型。我们的目标是对egr2相关的神经病变进行电诊断、神经成像和组织学研究。材料和方法:我们对我院2例egr2相关神经病学患者进行回顾性分析。神经传导检查证实神经病变。2例患者行神经显像和腓肠活检。结果:两名无亲缘关系的男孩表现出早发性长度依赖性神经病变。下一代测序发现EGR2基因在患者1的第三锌指结构域具有先前描述的E412K突变,在患者2的第一锌指结构域具有先前描述的D355N突变。1例腰骶神经丛磁共振成像未见异常,2例腰骶神经丛增厚。电生理和神经活检显示明显的轴索神经病,并伴有脱髓鞘受累。结论:因此,EGR2突变不仅可能导致已知的脱髓鞘型和轴突型CMT,还可能导致混合型CMT。我们的发现扩大了egr2相关神经病的表型异质性。
{"title":"EGR2-related mixed demyelinating and axonal Charcot-Marie-Tooth disease: An electrodiagnostic, nerve imaging, and histological study.","authors":"Xu J Chu, Kang Du, Ling C Meng, Zhi Y Xie, Ying Zhu, Wei Zhang, Zhao X Wang, Yun Yuan","doi":"10.5414/NP301460","DOIUrl":"https://doi.org/10.5414/NP301460","url":null,"abstract":"<p><strong>Background and aims: </strong>The early growth response 2 gene <i>(EGR2)</i> mutations are associated with a group of hereditary neuropathy, including axonal neuropathy and hypomyelinating neuropathy or Charcot-Marie-Tooth disease (CMT) type 1D. We aim to perform an electrodiagnostic, nerve imaging, and histological study of EGR2-associated neuropathy.</p><p><strong>Materials and methods: </strong>We performed a retrospective analysis of two patients with EGR2-related neurology at our hospital. The neuropathy was confirmed by the nerve conduction study. Nerve imaging and sural biopsies were performed in two patients.</p><p><strong>Results: </strong>Two unrelated boys exhibited early-onset length-dependent neuropathy. Next generation sequencing identified <i>EGR2</i> gene with previously described E412K mutation in the third zine finger domain in patient 1 and a previously undescribed variant D355N mutation in the first zinc finger domain in patient 2. The magnetic resonance imaging of the lumbosacral plexus showed no abnormalities in patient 1 and thickened lumbosacral plexuses in patient 2. Electrophysiology and nerve biopsies showed a prominent axonal neuropathy, accompanied with demyelinating involvement.</p><p><strong>Conclusion: </strong>Therefore, it seemed that the <i>EGR2</i> mutations could cause not only the known demyelinating type and axonal type but also mixed-type CMT. Our findings expanded the phenotypic heterogeneities of EGR2-associated neuropathy.</p>","PeriodicalId":55251,"journal":{"name":"Clinical Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40410284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenbo Wang, Yunkun Zhang, Yang Dong, Shen Li, Huamin Qin
Primary histiocytic sarcoma of the central nervous system is a rare lymphohematopoietic tumor originating from histiocytes. Here we report such a case with somatic NF2 mutation. Based on imaging studies, a 24-year-old woman presented with a homogeneously enhancing lesion in the right parietal lobe region and without other organ involvement. Histological analysis showed that the pleomorphic tumor cells were loosely arranged, and the neoplastic cells are characterized by abundant eosinophilic cytoplasm, highly atypical nuclei, and prominent nucleoli. The lesional cells were immunoreactive with antibodies against -CD68KP1, CD163 focally, lysozyme, and BRAF V600E. NGS-based genetic profiling revealed a pathogenic somatic NF2 (p.R196*) mutation. Additionally, BRAF (p.V600E), PDGFRA (p.V561D), BRCA1 (p.H437Q, VUS), and BRCA2 (p.E2343A, VUS) mutations were detected. However, the tumor did not respond to apatinib and anlotinib treatment, and the patient died 10 months after the initial diagnosis.
{"title":"Primary central nervous system histiocytic sarcoma with somatic <i>NF2</i> mutation: Case report and review of literature.","authors":"Wenbo Wang, Yunkun Zhang, Yang Dong, Shen Li, Huamin Qin","doi":"10.5414/NP301473","DOIUrl":"https://doi.org/10.5414/NP301473","url":null,"abstract":"<p><p>Primary histiocytic sarcoma of the central nervous system is a rare lymphohematopoietic tumor originating from histiocytes. Here we report such a case with somatic <i>NF2</i> mutation. Based on imaging studies, a 24-year-old woman presented with a homogeneously enhancing lesion in the right parietal lobe region and without other organ involvement. Histological analysis showed that the pleomorphic tumor cells were loosely arranged, and the neoplastic cells are characterized by abundant eosinophilic cytoplasm, highly atypical nuclei, and prominent nucleoli. The lesional cells were immunoreactive with antibodies against -CD68KP1, CD163 focally, lysozyme, and BRAF V600E. NGS-based genetic profiling revealed a pathogenic somatic <i>NF2</i> (p.R196*) mutation. Additionally, <i>BRAF</i> (p.V600E), <i>PDGFRA</i> (p.V561D), <i>BRCA1</i> (p.H437Q, VUS), and <i>BRCA2</i> (p.E2343A, VUS) mutations were detected. However, the tumor did not respond to apatinib and anlotinib treatment, and the patient died 10 months after the initial diagnosis.</p>","PeriodicalId":55251,"journal":{"name":"Clinical Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10376604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To report a new genetic cause of distal hereditary motor neuropathy (dHMN), which is likely associated with worsening during pregnancy. We collected the clinical data of a patient with severe weakness of the lower limbs induced by repeated pregnancy and performed relevant experimental examinations, including neuromuscular electrophysiological examination, neuromuscular biopsy, and genetic testing. The patient reported weakness of the right lower extremity after delivery of the first child. Initially, the right foot was weak during lifting, and symptoms gradually progressed to weakness when landing on the toe during walking. She then developed weakness of the right lower extremity and thinning of the right leg. After an interval of 2.5 years, after delivery of the second child, her left lower extremity developed asthenia, with the same symptoms as previously reported for the right lower extremity. Subsequently, weakness of both lower extremities became progressively worse, and she developed difficulty sitting up, getting out of bed, and walking. Physical examination showed that both upper limb vertebral tracts were damaged and both lower extremity motor nerves were damaged. Electrophysiology suggested motor axonal neurogenic damage. Brain magnetic resonance imaging demonstrated leukodystrophy. Sural nerve biopsy suggested mild axonal damage. Skeletal muscle biopsy suggested neurogenic skeletal muscle damage. Genetic testing suggested that there was a heterozygous mutation at the shear site of the AARS gene. An AARS mutation may cause dHMN associated with pyramidal tract signs.
{"title":"Distal hereditary neuropathy associated with a novel mutation in alanyl-aminoacyl-tRNA synthetase.","authors":"Yuan Yuan, Daojun Hong, Xuguang Gao, Jun Zhang","doi":"10.5414/NP301489","DOIUrl":"https://doi.org/10.5414/NP301489","url":null,"abstract":"<p><p>To report a new genetic cause of distal hereditary motor neuropathy (dHMN), which is likely associated with worsening during pregnancy. We collected the clinical data of a patient with severe weakness of the lower limbs induced by repeated pregnancy and performed relevant experimental examinations, including neuromuscular electrophysiological examination, neuromuscular biopsy, and genetic testing. The patient reported weakness of the right lower extremity after delivery of the first child. Initially, the right foot was weak during lifting, and symptoms gradually progressed to weakness when landing on the toe during walking. She then developed weakness of the right lower extremity and thinning of the right leg. After an interval of 2.5 years, after delivery of the second child, her left lower extremity developed asthenia, with the same symptoms as previously reported for the right lower extremity. Subsequently, weakness of both lower extremities became progressively worse, and she developed difficulty sitting up, getting out of bed, and walking. Physical examination showed that both upper limb vertebral tracts were damaged and both lower extremity motor nerves were damaged. Electrophysiology suggested motor axonal neurogenic damage. Brain magnetic resonance imaging demonstrated leukodystrophy. Sural nerve biopsy suggested mild axonal damage. Skeletal muscle biopsy suggested neurogenic skeletal muscle damage. Genetic testing suggested that there was a heterozygous mutation at the shear site of the <i>AARS</i> gene. An <i>AARS</i> mutation may cause dHMN associated with pyramidal tract signs.</p>","PeriodicalId":55251,"journal":{"name":"Clinical Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10382664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The long-awaited 5th edition of the WHO brain tumor classification has put considerable emphasis on the importance of diagnostic DNA methylation profiling. In this article, the authors comparatively discuss selected practical aspects as well as general advantages and limitations of array- versus nanopore sequencing-based approaches to methylome profiling.
{"title":"Diagnostic DNA methylome profiling and the WHO 5th edition CNS tumor classification.","authors":"Stephan Frank, J. Hench","doi":"10.5414/NP301493","DOIUrl":"https://doi.org/10.5414/NP301493","url":null,"abstract":"The long-awaited 5th edition of the WHO brain tumor classification has put considerable emphasis on the importance of diagnostic DNA methylation profiling. In this article, the authors comparatively discuss selected practical aspects as well as general advantages and limitations of array- versus nanopore sequencing-based approaches to methylome profiling.","PeriodicalId":55251,"journal":{"name":"Clinical Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2022-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46735214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meige Liu, Yan Xu, D. Hong, L. Cong, Yangyi Fan, Jun Zhang
Distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (dSMA), comprises a group of inherited peripheral neuropathies with great clinical and genetic heterogeneity, mainly characterized by progressive atrophy and weakness of distal muscle without clinical or electrophysiological sensory abnormalities. Next-generation sequencing is widely applied as an effective diagnostic technique to discover pathogenic genes in patients with dHMN. To date, at least 23 causal genes have been identified to be associated with dHMN, several of which encode chaperones. Here, we report a dHMN patient due to a homozygous c.184C>T variant in the DNAJB2 gene with rare neuropathic and myopathic characteristics on pathological examination. These findings might broaden the mutational spectrum of DNAJB2 and expand the tissue involvement of DNAJB2-related presentations.
{"title":"DNAJB2 c.184C>T mutation associated with distal hereditary motor neuropathy with rimmed vacuolar myopathy.","authors":"Meige Liu, Yan Xu, D. Hong, L. Cong, Yangyi Fan, Jun Zhang","doi":"10.5414/NP301466","DOIUrl":"https://doi.org/10.5414/NP301466","url":null,"abstract":"Distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (dSMA), comprises a group of inherited peripheral neuropathies with great clinical and genetic heterogeneity, mainly characterized by progressive atrophy and weakness of distal muscle without clinical or electrophysiological sensory abnormalities. Next-generation sequencing is widely applied as an effective diagnostic technique to discover pathogenic genes in patients with dHMN. To date, at least 23 causal genes have been identified to be associated with dHMN, several of which encode chaperones. Here, we report a dHMN patient due to a homozygous c.184C>T variant in the DNAJB2 gene with rare neuropathic and myopathic characteristics on pathological examination. These findings might broaden the mutational spectrum of DNAJB2 and expand the tissue involvement of DNAJB2-related presentations.","PeriodicalId":55251,"journal":{"name":"Clinical Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2022-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42817696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amyotrophic lateral sclerosis (ALS) is a disorder with strong clinical and genetic heterogeneity, and its pathogenic mechanism has not been completely clarified. Proximal myopathy is rare in clinical manifestations of ALS. Here, we describe a 34-year-old woman with a 1-year history of symmetrical, proximal limb weakness, and muscle atrophy, with slow progression and no upper motor neuron (UMN) signs. The clinical phenotype was similar to myopathy and was initially misdiagnosed as proximal myopathy. Electromyography (EMG) and muscle and nerve biopsy were performed. The genomic DNA from the patient's peripheral blood lymphocytes was analyzed. The EMG and pathologic examinations revealed chronic neurogenic changes and mild mixed peripheral neuropathy. DNA analysis revealed a heterozygous missense mutation in exon 1 at codon 50 (c.50G>C) of SOD1, and a heterozygous missense mutation in exon 11 at codon 1013 (c.1013G>A) of CPT1C that has not been reported previously. The patient was diagnosed as familial ALS (FALS) type 1, and the patient had a family history of autosomal dominant (AD) pattern. This report expands the knowledge of the clinical phenotype of FALS. For patients with clinical manifestations mimicking proximal myopathy, the possibility of underlying ALS should be considered.
{"title":"Clinical phenotype of familial amyotrophic lateral sclerosis with SOD1 gene mutation mimicking proximal myopathy: A case report and literature review.","authors":"Jingjing Sun, Chengning Zhang, Lin Wang, H. Bi","doi":"10.5414/NP301459","DOIUrl":"https://doi.org/10.5414/NP301459","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a disorder with strong clinical and genetic heterogeneity, and its pathogenic mechanism has not been completely clarified. Proximal myopathy is rare in clinical manifestations of ALS. Here, we describe a 34-year-old woman with a 1-year history of symmetrical, proximal limb weakness, and muscle atrophy, with slow progression and no upper motor neuron (UMN) signs. The clinical phenotype was similar to myopathy and was initially misdiagnosed as proximal myopathy. Electromyography (EMG) and muscle and nerve biopsy were performed. The genomic DNA from the patient's peripheral blood lymphocytes was analyzed. The EMG and pathologic examinations revealed chronic neurogenic changes and mild mixed peripheral neuropathy. DNA analysis revealed a heterozygous missense mutation in exon 1 at codon 50 (c.50G>C) of SOD1, and a heterozygous missense mutation in exon 11 at codon 1013 (c.1013G>A) of CPT1C that has not been reported previously. The patient was diagnosed as familial ALS (FALS) type 1, and the patient had a family history of autosomal dominant (AD) pattern. This report expands the knowledge of the clinical phenotype of FALS. For patients with clinical manifestations mimicking proximal myopathy, the possibility of underlying ALS should be considered.","PeriodicalId":55251,"journal":{"name":"Clinical Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.1,"publicationDate":"2022-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46121015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}