The phenotypic and genetic spectrum of colony-stimulating factor 1 receptor gene-related leukoencephalopathy in China / 中华神经科杂志

Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.

Application of skin biopsy in neurological disorders / 中华神经科杂志

The skin is the largest organ comprised of three main layers: epidermis, dermis and subcutaneous tissue. Characteristic microscopic and ultrastructural alterations are present in certain skin structures, such as nerve fibers, blood vessels and sweat glands, not only in vasculitis, but in several other metabolic neurologic diseases. In recent years, advances in immunohistochemistry and electron microscopy have made these dermatopathological changes identifiable and clear-cut. It was then recognized that such pathological feature could be present in many tissues in addition to those nerve systems clinically affected. Skin biopsy has become a recognized diagnostic procedure for peripheral neuropathy and central nervous system diseases. This article reviews the dermatopathology in neurological disorders under light and electron microscope to promote application of skin biopsy in clinical diagnosis for neurologist.

Pathologic and genetic features in 6 Chinese X-linked Charcot-Marie-Tooth disease type 1 families / 中华神经科杂志

ObjectivesTo report pathological and genetic features of 6 Chinese families with Xlinked Charcot-Marie-Tooth disease type 1 ( CMTX1 ).Methods The index cases from 6 families with CMTX1 are males with onset of disease between 11 and 24 years old.All of them had distal leg muscle weakness,accompanied with areflexia and sensory loss in the feet.Additionally,the index 1 presented with recurrent encephalopathy and the index case 5 with cerebellar ataxia.Peripheral neuropathy was found in 12 family members,while other 7 members showed talipescavus and hyporeflexia.Sural nerve biopsies were performed in all index cases.Connexin 32(Cx32) gene was analyzed in the index cases,8 affected and 10unaffected family members as well as 50 healthy women control subjects.ResultsMild to moderate loss of myelinated fiber with axonal degeneration and regeneration clusters were found in all index cases. Thin myelin fibers were found in 5,small onion bulbs in 3 and inflammatory infiltrates in 2.Five novel mutations (I20T,I127F,D178G,A197V,403_404insT) and one L10L synonymous mutation were detected in the 6index cases and their affected family members.The same mutations,in heterozygous state,were detected in 4 female family members without clinical symptoms,but not found in 6 male unaffected family members.The same mutations were not found in healthy control subjects.ConclusionsThe CMTX1 patients in our study present predominantly axonal lesions.Frequent novel Cx32 gene mutations indicated that private mutations may be common in Chinese CMTX1 patients.

Mutant connexin 32 abnormally distributed in the vascular endothelial cells of X-linked Charcot-Marie-Tooth disease type 1 patients / 中华神经科杂志

ObjectiveTo investigate expression distribution of mutant connexin 32 (Cx32) protein in human endothelial cells in patients with X-linked Charcot-Marie-Tooth disease type 1 ( CMTX1 ) .MethodsNerve biopsies were performed in 3 patients with CMTX1 and in 3 non-CMTX1 controls. Cx32 mutations of c. 379A ＞ T( I127F), c. 533A ＞ G(D178G) and c. 590C ＞ T(A197V) were identified in these 3 patients respectively.Immunofluorescent (IMF) staining of nerve blood vessel was processed with antibodies against Cx32, Yon Willebrand factor and Cx40. The mutant Cx32 was constructed in pEGFP-N plasmid (pEGFP-N1-Cx32) and was transfected in HeLa cells. Cx32 and GRP78, a marker of endoplasmic reticulum ( ER), were stained by IMF in HeLa cells to investigate expression of mutant Cx32. ResultsIn 3 control cases, Cx32 was visualized by IMF staining as dots along gap junction of vascular endothelial cells,and it was coexisted with Cx40.However, immunoreactivity of Cx32 in 3 patients was predominantly decreased and was not located in endothelial gap junction. The transfection of 3 Cx32 mutants into HeLa cells demonstrated thepathogenic changes.The cells withthemutationc. 379A ＞T found Cx32 accumulations in the cytoplasm; the cells with mutation c. 533A ＞G showed few staining positive dots surrounding the nuclear and the cells with c. 590C ＞ T showed dot-like expression of Cx32 both in the cytoplasmicand cell membrane. The mutant Cx32 was not overlapped with expression of the marker of ER.ConclusionsMutant Cx32 might cause dysfunction of endothelial gap-junctions due to the abnormal expression of Cx32 in level and location in the vascular endothelial cells of CMTX1 patients.

Phenotypic and genotypic studies in 6 Chinese Han families with oculopharyngeal muscular dystrophy / 中华神经科杂志

Objective To explore phenotypes and genotypes in 6 Chinese Han families with oculopharyngeal muscular dystrophy (OPMD).Methods There were 28 OPMD patients in 6 Chinese Han families, aged between 32 and 70 years old.The initial symptom was dysphagia in 13 patients, ptosis in 4 patients,lower limb weakness in 1 patient.Most OPMD patients displayed dysphagia and ptosis in 3-20 years after the initial symptom appeared.Biceps brachii biopsies were made in the 6 OPMD probands.The specimens were examined with histological, histochemical stainings and ultrastructural examination.The exon 1 of PABPN1 gene was sequenced in all probands of OPMD and some of their family members.Haplotype analysis was executed in the 6OPMD probands.Results Mild hypertrophy and hypotrophy of fibers and rimmed vacuoles were found in each probands of OPMD muscle biopsies.Intranuclear palisading filamentous inclusions only appeared in 4OPMD probands.Gene analysis identified (GCG)9 in exon 1 of PA BPN 1 gene was detected in 3OPMD families, while (GCG) 6 (GCA) 1 (GCG) 3, (GCG) 10 and (GCG) 8were in one family respectively.Two families with (GCG) 9 expansion shared a common rs2239579 (C) -(GCG) 9-SNP2622 (C) haplotype.Conclusions Dysphagia and ptosis may be the common initial symptoms in Chinese Han OPMD patients.Rimmed vacuoles and intranuclear inclusions may be the common pathological feature in the muscle fibers.Both (GCG) expansions and (GCA) insertion of PABPN1 gene could be detected in Chinese patients.The genetic heterogeneity and the haplotype of three (GCG)9 families in our patients indicate that OPMD arises from different origin within the Han population.Some families with the same (GCG)9 expansions probably come from a common ancestor.

Filaminopathy caused by a novel deletion-insertion mutation in filamin C gene / 中华神经科杂志

Objective To report filaminopathy with novel insertion mutation in a Chinese family.Methods Total 19 patients from successive 5 generations involved in an autosomal dominant family. The detailed clinical manifestations had been described (Chinese Journal of Neurology, 2008, 41:751-755).The filamin C gene sequencing was performed in 3 patients, 5 family members without symptoms and 50 normal persons. The amplified fragments of the exon 18 in filamin C gene were cloned into pBluesripts vectors, then sequenced and identified with capillary electrophoresis. Results 18-nucleotide deletion and 6-nucleotide insertion were identified in the exon 18 of filamin C gene. The mutation caused the disturbance of the seventh immunoglobulin-like domain in filamin C, leading to the instability of dimmers of filamin C.Another 2 patients in the family had same mutation while 5 family members without symptoms and 50 normal controls were normal. Conclusion The novel nucleotide deletion-insertion in exon 18 of filamin C gene causes filaminopathy. This disease can appear in non-Nordic race.

Notch3 gene mutation results in hypoplasia of arterial smooth muscle cells / 中华神经科杂志

Objective To describe the changes of cell development associated contracture and structure proteins in vascular smooth muscle cells (VSMCs) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods The clinical manifestation of probands in 6 families showed the recurrent cerebral ischemic event. A part of patients showed dementia. The genetic analysis in all probands showed Notch3 gene mutation. All probands received the sural nerve biopsy. The primary antibodies against α-smooth muscle actin, smooth muscle myosin heavy chain, desmin and vimenfin were used in immunohistochemistry staining on all of them. Results VSMCs showed hypertrophy or atrophy in the arterioles with different caliber. The granular osmiophilic material (GOM) could be found within the basal lamina of arteriole VSMCs in all of the probands. The expressions of α-smooth muscle actin and smooth muscle myosin heavy chain were partly lost, negative or unevenly distributed in the VSMCs in the arteriole. The expression of desmin showed also unregular distribution or partial loss. The expression of vimentin was partly enhanced. Conclusions The VSMCs show the physiological features of synthetic configuration, indicating the hypoplasia of VSMCs in the arterioles of CADASIL. The VSMCs of the larger arteriole were more severely involved.

Transient white matter lesions in X-linked Charcot-Marie-Tooth disease type 1 with novel I20T mutation of gap junction protein beta 1 gene / 中华神经科杂志

Objective To describe the clinical, radiological and genetic features in a family with X-linked Charot-Marie-Tooth disease type 1 (CMT1X) with transient white matter lesions.Methods The proband is a 14-year-old boy who presented transient and recurrent dysarthria, mild numbness and weakness of the limbs for 2 years and 5 months.Later he developed leg weakness.His mother only presented pes cavus.MRI, electrophysiology and nerve biopsy were performed in the proband.Gap junction protein beta 1 (GJB1) gene was analyzed by PCR-sequencing on the proband, his parents and 50 non-illness control women.Results Electremyography showed marked reduced amplitude of the distal compound muscle action potentials and mild decrease of conduction velocities.MRI showed bilateral white matter lesions in centrum semiovale and corpus callnsum, which improved significantly after 6 months.Pathological examination revealed chronic axonal neuropathy and widened Schmidt-Lanterman incisures of myelinated fibers.I20T mutation in GJB1 gene was detected in the proband and his mother, but not in non-illness control women and his father.Conclusions Novel 120T mutation of GJBI maybe could result in CMT1X with predominant recurrent leucocncephalopathy.The white matter changes in MRI are reversibility.

A novel mutation of SI2F in desmin causing desminopathy: a family report / 中华神经科杂志

Objective To report clinical and pathological features in a Chinese family with desminopathy caused by a novel mutation in desmin gene. Methods There were 8 patients (7 male and 1 female) in a family manifesting desminopathy in an autosomal dominant inheritance pattern. The onset age ranged from 20--50 years old. Heart disease appeared in 7 cases, diarrhea in 1 case and limb weakness in 3 patients. Muscle biopsies were carried out in proband and his elder brother. The histological, enzymhistochemicai staining, ultrastructural examination and immunohistochemical staining with desmin antibody were performed. The sequence of desmin gene was analyzed in DNA from 4 patients, 5 asymptomatic members and 50 healthy controls. Results Muscle pathology in the proband revealed wide variation in size of fibers. Some fibers had eosinophilic changes with rimmed vacuoles. Muscle pathology in the brother revealed multiple small and round eosinophilic inclusions in the fibers. Desmin staining was positive in the inclusions and in the sarcolemma. Electron microscopy revealed deposits of abnormal granulofilamentous materials. A novel S12F mutation in desmin gene has been identified in 4 affected family individuals, but not in unaffected family members and controls. Conclusions The desminopathy caused by desmiu SI2F mutation dominantly affected male individuals. Most of victims had cardiac abnormalities. The myopatholgical features can vary in the different patients in one family.

Clinical features of myopathy with tubular aggregates:6 cases / 中华神经科杂志

Objectives To report clinical,electrophysiological and pathological features of myopathy with tubular aggregates.Methods The onset of the disease was between 5-50 years old in the 6 sporadic male cases.Skeletal muscle biopsy was performed for all cases.Specimens were examined histochemically,enzymhistochemically and electromicroscopically.Results Case 1 and 2 presented with limb girdle myasthenic syndrome.The case 1 developed exercise-induced cramps in the late stage.Case 3 complained about persistent weakness and Dopa-responsive dystonia.Case 4 and 5 were characterized by periodic paralysis.Case 6 showed exercise-induced cramps.Serum potassium was normal in all patients. Slight elevation of serum creatine kinase appeared in 3 cases.Electromyography showed neurogenic pattern in case 1 and 6,myogenic changes in case 4 and 5,and no abnormality in other 2 cases.Marked decrement of active potential amplitude was noted with low frequency repetitive nerve stimuli in case 1 and 2.Four percent to forty percent of muscle fibers showed focal material accumulation in the fibers,which involved mainly type 2 fibers in all cases.The material was stained bright red material with modified gomori trichrome,intensive staining with nicotinamide adenine dinucleotide-tetrazolium reductase,lack activity of succinate dehydrogenase and ATPase.Electron microscopy confirmed bundles of parallel micro-tubular structure in the muscle fiber.Conclusions Myopathy with tubular aggregates has various clinical subtypes and electromyographic pattern.Dystonia or other systemic symptoms could be noted in this disease.The limb girdle myasthenic syndrome can also be accompanied with exercise-induced cramps.

Clinical characters correlate with cranial MRI lesion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy / 中华神经科杂志

Objective To assess retinal arteriole stenosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to evaluate the relationship between retinal arteriole stenosis with cranial MRI changes and clinical features. Methods Sixteen CADASIL patients (mean age was (43.4±8.1)years, mean duration was(4.7±3.4)years)and sixteen age matched healthy individuals were enrolled. Mini-Mental State Examination (MMSE) and modified Rankin scale scoring were performed in 16 patients. Cranial MRl with Coulthard scores was assessed on CADASIL patients as well. Retinal examinations for arteriole stenosis were done for each subject. Bivariate correlations (Kendall's tau-b) were used to assess the relationship among the grade of retinal stenosis, MMSE, modified Rankin seale, cranial MRI with Coulthard scores and age. Results Retinal arteriole stenosis presented in 15 cases. in whom 4 cases showed mild arterio-venous nicking. while it only presented in 2 controls. Grade 0.Ⅰ, and Ⅲ of retinal arteriole stenosis are noted in 1/16,4/16,7/16 and 4/16cases respectively. Coulthard scores of cerebral MRl were 6.0.19.0.25.1 and 29.8 respectively from Grade 0 toⅢ of retinal arteriole stenosis. The correlation coefficient of retinal arteriole stenosis and cranial MRI scores was 0.743(P＜0.001＝,MMSE-0.429(P＜0.05＝,modified Rankin scale 0.437(P＞0.05).and age 0.299(P＞0.05).Conclusion Retinal arteriole stenosis is significantly correlated with lesion in cranial MRI and dementia.

Oculopharyngeal muscular dystrophy,the clinical,electrophysiologic,myopathological and genetic study in a family / 中华神经科杂志

Objective To report clinical,myopathological and genetic features in a family with oculopharyngeal muscular dystrophy(OPMD).Methods The proband,a 60 year-old man,presented proximal weakness of both lower limbs since 50 years old.He developed dysphagia and dysarthria after 53 years old and mild exophthalmos with ptosis after 57 years old.The serum creatine kinase was mildly elevated.Electromyography showed neurogenic involvement and the nerve conduction velocity decreased 20%-143%.Other 5 members in 3 generations developed also dysathria after 45 years old.followed by ptosis 4-20 years afterwards.Three of them showed mild limb weakness.Muscle was biopsied in the proband and specimen was examined with histological,enzymhistochemical,immunohistochemical stainings (first antibody were anti.desmin and ubiquitin antibedies) and ultrastructural examination.PABPN1 gene was sequenced in the proband and 18 family members.Results Rimmed vacuoles with ubiquitin positive material appeared in the muscle fibers.Additionally.there were a few angular atrophic fibers in small groups,COX negative fibers and desmin positive regenerative fibers.Intranuclear palisading filamentous inclusions were observed electromicroscopically in 3% of the nuclears.(GCG)6in PABPN1 was expanded to (GCG)9 in the proband and 11 members.Conclusions The onset symptoms is pharyngeal weakness in OPMD due to heterozygous expanding of PABPNl(GCG)9,accompanied with demyelinating neuropathy.Intranuclear inclusions are also identified in Chinese patient.

Distal hereditary motor neuropathy type Ⅴ :a report of a Chinese family / 中华神经科杂志

Objective To report the clinical, pathological and genetic features in a Chinese family with distal hereditary motor ueuropathy type Ⅴ (dHMN-Ⅴ). Methods Four men and 5 women in 4 generations were involved. The onset of disease was from 13 to 40 years old. Six of them showed predominantly weakness of low extremities. Two women had only weakness and atrophy of hand muscle and 1 woman presented additionally pyramidal signs. The proband, a 20 year-old girl, presented asymmetrical atrophy and weakness of both hands since 13 years old. She had weakness of low extremities after 15 years old. Neurogenic changes were observed in the electromyography. Amplitude of compound muscle action potentials were markedly reduced, while the motor nerve conduction velocity were mildly decreased. Sensory nerve conduction velocity and amplitude of action potential were within the normal range. Sural nerve biopsy was performed in the proband. Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene were sequenced in the proband and other 4 patients. Results Nerve biopsy showed mild loss of myelinated fibers with a few regeneration cluster of myelinated fibers. DNA analysis revealed a heterozygons 263A→G mutation in exon 3 of BSCL2 gene. Conclusions dHMN-V has been genetically and clinically confirmed in this family. The phynotype is obviously heterogeneous in onset time and clinical symptoms within the same family. The patients present mild pyramidal tract signs and axonal lesions in the sensory nerve.

Myofibrillar myopathy with cytoplasmatic.spheroid bodies: a report of a Chinese family / 中华神经科杂志

Objective To report the clinical, myopathological and genetic features in myofibrillar myopathy (MFM) with numerous cytoplasmatic-spheroid bodies. Methods Ten patients in 5 successive generations began to present progressive proximal limbs weakness at 35 to 40 years old. Additionally, 4 cases manifested diarrhea and 6 cases accompanied with cardiorespiratory symptoms. An open biopsy was performed on the proband. In addition to histological, enzymhistochemical staining and ultrastructural examination, immunohistochemical staining with antibody against tau, desmin, ubiquitin, dysferlin, dystrophin-C', dystrophin-N' and dystrophin-R were done. All the exons of the MYOT, CRYAB, DESMIN, LDB3, LMNA, SEPNI gene and the FLNC exon 48 were analysed. Results Cytoplasmatic bodies and spheroid bodies were found in the fibers. The deposited material were positive for tau, desmin, ubiquitin, dysferlin and dystrophin-R, dystrophin-C'. Electron microscope showed granular dense Z-disc material in the inclusions which were surrounded by thin filament. There was no mutation in the above exons of the 7 candidate genes. Conclusions Myofibrillar myopathy involves multiple system impairment. Cytoplasmatic and spheroid bodies contain microtubule and membrane associated protein. The disease might be induced by some unknown genetic abnormities.