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1.
M. Luigetti MD G.M. Fabrizi MD F. Madia MD PhD M. Ferrarini PhD A. Conte MD A. Delgrande MD P.A. Tonali MD M. Sabatelli MD 《Muscle & nerve》2010,42(3):448-451
Heterozygous mutations in the Berardinelli–Seip congenital lipodystrophy (BSCL2) gene have been associated with different clinical phenotypes including Silver syndrome/spastic paraplegia 17, distal hereditary motor neuropathy type V, and Charcot–Marie–Tooth disease type 2 (CMT2) with predominant hand involvement. We studied an Italian family with a CMT2 phenotype with pyramidal signs that had subclinical sensory involvement on sural nerve biopsy. Direct sequencing analysis of the BSCL2 gene in the three affected siblings revealed an S90L mutation. This report confirms the variability of clinical phenotypes associated with a BSCL2 Ser90Leu mutation and describes the first Italian family with this mutation. Muscle Nerve, 2010 相似文献
2.
Satoshi Ishihara Yuji Okamoto Hajime Tanabe Akiko Yoshimura Yujiro Higuchi Jun‐Hui Yuan Akihiro Hashiguchi Hiroyuki Ishiura Jun Mitsui Shugo Suwazono Yasushi Oya Masayuki Sasaki Masanori Nakagawa Shoji Tsuji Yusuke Ohya Hiroshi Takashima 《Journal of the peripheral nervous system : JPNS》2020,25(2):125-131
Heterozygous mutations in the Berardinelli‐Seip congenital lipodystrophy 2 (BSCL2) gene have been reported with different clinical phenotypes including Silver syndrome (SS)/spastic paraplegia 17 (SPG17), distal hereditary motor neuropathy type V (dHMN‐V), and Charcot‐Marie‐Tooth (CMT) disease type 2. We screened 407 Japanese patients who were clinically suspected of having CMT by exome sequencing and searched mutations in BSCL2. As a result, we identified five patients with heterozygous mutations in BSCL2. We confirmed three cases of known mutations (p.N88S and p.S90L) and two cases of novel mutations (p.N88T and p.S141A). The clinical features of the cases with known mutations in Japan were similar to those previously reported in other countries. In particular, there were many cases with sensory disturbance. The case with p.N88T mutation showed severe phenotype such as early onset age and prominent vocal cord paresis. The case with p.S141A mutation showed characteristics of demyelinating neuropathy such as CMT disease type 1 by electrophysiological examination. In this article, we report the clinical features and spread of cases with BSCL2 mutation in a Japanese cohort. 相似文献
3.
In 2004, heterozygous mutations (N88S, S90L) in the Seipin/BSCL2 gene were identified in two autosomal dominant motor neuron diseases, distal hereditary motor neuropathy type V (OMIM #182960) and Silver syndrome (OMIM #270685). The Seipin/BSCL2 gene was originally identified as a candidate gene for congenital generalized lipodystrophy type 2 (CGL2) (OMIM #269700). Individuals with homozygous null mutations in seipin have severe lipoatrophy, insulin resistance, hypertriglyceridemia, and mental retardation without any abnormality of the motor neurons. Recent phenotype analyses of the N88S and S90L mutations have revealed a wide spectrum of Seipin/BSCL2-related motor neuron diseases, including Silver syndrome, distal hereditary motor neuropathy type V, variants of Charcot-Marie-Tooth disease type 2, and spastic paraplegia 17; therefore, these diseases should be termed "seipinopathies". Seipin is a transmembrane protein that is localized in the endoplasmic reticulum (ER). Interestingly, the N88S and S90L mutations both disturb the N-glycosylation motif, suggesting that improper glycosylation of seipin is closely associated with the pathogenesis of motor neuron diseases. Our recent study demonstrated that seipin is proteolytically cleaved into N and C-terminal fragments and then polyubiquitinated. The N88S and S90L mutations enhance ubiquitination and degradation by UPS, and N88S and S90L mutants appear to be improperly folded, resulting in their accumulation in the ER. Furthermore, expression of mutant seipin in cultured cells activates UPR stress and induces ER stress-mediated apoptosis. Our findings suggest that seipin-related motor neuron diseases, seipinopathies are novel conformational diseases, and we propose that the pathological process of these diseases is tightly associated with ER stress-mediated cell death. 相似文献
4.
Hye Jin Lee Jin Park Khriezanou Nakhro Jin Mo Park Yoon‐Mi Hur Byung‐Ok Choi Ki Wha Chung 《Journal of the peripheral nervous system : JPNS》2012,17(4):418-421
Glycyl‐tRNA synthetase (GARS), which encodes the enzyme responsible for charging tRNA(Gly) with glycine in both the cytoplasm and mitochondria, is implicated to Charcot‐Marie‐Tooth disease 2D (CMT2D) and distal hereditary motor neuropathy type V (dHMN‐V). We performed whole exome sequencing (WES) to identify the genetic defects in the two dHMN families. WES revealed several decades of non‐synonymous variants in the CMT and aminoacyl‐tRNA synthetase genes. The subsequent capillary sequencing for family members and controls revealed two novel causative mutations, c.598G>A (D200N) and c.794C>T (S265F), in the GARS gene in each dHMN family. Both mutations were cosegregated with affected individuals in each family, and were not found in the 200 controls. The mutation sites were well conserved between the different species and in silico analysis predicted that both mutations may affect protein function. Therefore, we believe that these two novel GARS mutations are the underlying causes of the dHMN phenotype. 相似文献
5.
Kochański A Dierick I Timmerman V Hausmanowa-Petrusewicz I 《Neurologia i neurochirurgia polska》2007,41(6):562-566
Silver syndrome (Silver spastic paraplegia syndrome) is a rare disorder of the peripheral nervous system that combines features of spastic paraparesis and peripheral neuropathy. The underlying genetic defects are two mutations in the BSCL2 gene which have been described in several families. Silver syndrome--related to the N88S mutation in the BSCL2 gene--is characterized by a spectrum of clinical findings. The coexistence of sensory fiber damage and motor deficit leads to the diagnosis of Charcot-Marie-Tooth disease in some patients, while others are diagnosed with spastic paresis due to predominant pyramidal symptoms. If the symptoms are limited to the motor deficit, hereditary motor neuropathy is diagnosed in some cases. In this report, we describe a case of the Silver syndrome in a Polish family that has been verified by genetic testing. Due to the lack of pyramidal symptoms and slightly expressed sensory fiber damage (in neurographic studies), motor neuropathy type of the Silver syndrome with minor sensory component was diagnosed. 相似文献
6.
van de Warrenburg BP Scheffer H van Eijk JJ Versteeg MH Kremer H Zwarts MJ Schelhaas HJ van Engelen BG 《Neuromuscular disorders : NMD》2006,16(2):122-125
Mutations in the BSCL2 gene have recently been identified in families with (SPG17-linked) Silver syndrome-type hereditary spastic paraparesis as well as in families with distal hereditary motor neuropathy (HMN). We describe the first two Dutch families with BSCL2 mutations and corroborate the phenotypic variability of this gene mutation, as features compatible with Silver syndrome, variant Silver syndrome (with predominant foot rather than hand muscle involvement), distal HMN type II, or distal HMN type V were all encountered. 相似文献
7.
Gianfranco Cafforio Rosanna Calabrese Nicola Morelli Michelangelo Mancuso Selina Piazza Andrea Martinuzzi Maria Teresa Bassi Francesco Crippa Gabriele Siciliano 《Neurological sciences》2008,29(3):189-191
Silver syndrome (SPG17) is a rare form of hereditary spastic paraparesis. Its relationship to distal hereditary motor neuropathy (dHMN) type V is underlined by the recent discovery of causative mutation in BSCL2 gene coding for a protein termed seipin, an integral membrane protein of endoplasmic reticulum, with unknown function. Here we report the third Italian family with dHMN and SPG17 in which two affected members harbor the heterozygous N88S mutation in the BSCL2 gene. The proband developed a severe paraparetic spastic gait, while, in the other Italian families reported so far, no signs of upper motor neuron involvement were observed. This family confirms the clinical heterogeneity associated with this specific mutation. Moreover, this is the first report in which neuroimaging seems to confirm the pyramidal alterations in dHMN associated to SPG17. 相似文献
8.
Auer-Grumbach M Schlotter-Weigel B Lochmüller H Strobl-Wildemann G Auer-Grumbach P Fischer R Offenbacher H Zwick EB Robl T Hartl G Hartung HP Wagner K Windpassinger C;Austrian Peripheral Neuropathy Study Group 《Annals of neurology》2005,57(3):415-424
Recently, two missense mutations (N88S, S90L) in the Berardinelli-Seip congenital lipodystrophy gene have been identified in autosomal dominant distal hereditary motor neuropathy and Silver syndrome. We report the phenotypic consequences of the N88S mutation in 90 patients of 1 large Austrian family and two unrelated German families. Variation in the clinical and electrophysiological phenotype enabled us to distinguish six subtypes. In 4.4%, the disorder was not penetrant. Twenty percent of the patients were subclinically affected; some of these patients could only be detected by pathological nerve conduction studies. A distal hereditary motor neuropathy type V phenotype characterized by predominant hand muscle involvement was found in 31.1%, whereas 14.5% showed typical Silver syndrome with amyotrophy of the small hand muscles and spasticity of the lower extremities. Moreover, the phenotype present in 20% was compatible with Charcot-Marie-Tooth disease. In 10%, the clinical diagnosis of pure or complicated hereditary spastic paraparesis was made. Electrophysiological studies showed an axonal neuropathy but also chronodispersion of compound motor action potentials and conduction blocks. Sensory nerve conduction studies were rarely pathological. Our study indicates that the dominant N88S mutation in the Berardinelli-Seip congenital lipodystrophy gene 2 leads to a broad spectrum of motor neuron disorders. 相似文献
9.
Mutations in the HSPB1 gene are associated with Charcot‐Marie‐Tooth (CMT) disease type 2F (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN2). More than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. Three family members with a novel p.P57S (c.169C>T) HSPB1 mutation resulting in a late onset axonal neuropathy with heterogeneous clinical and electrophysiological features are detailed. We systematically reviewed published case reports and case series on HSPB1 mutations. While a genotype‐phenotype correlation was not obvious, we identified a common phenotype, which included adult onset, male predominance, motor more frequently than sensory involvement, distal and symmetric distribution with preferential involvement of plantar flexors, and a motor and axonal electrophysiological picture. 相似文献
10.
Esther Brusse Danielle Majoor-Krakauer Bianca M. de Graaf Gerhard H. Visser Sigrid Swagemakers Agnita J.W. Boon Ben A. Oostra Aida M. Bertoli-Avella 《Neurogenetics》2009,10(4):289-297
We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy
(HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease
ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies
(NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower
(four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was
noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric
linkage analysis identified a novel locus on chromosome 16p (mLOD = 3.28) spanning 6 Mb (rs6500882–rs7192086). Direct sequencing
excluded mutations in the SIMPLE/LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12–q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype
with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological
muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected
person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance
of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype. 相似文献
11.
OBJECTIVE: Heterozygous mutations in the Seipin/BSCL2 gene have recently been identified in two autosomal dominant motor neuron diseases, distal hereditary motor neuropathy type V and Silver's syndrome. Seipin protein is reportedly a transmembrane protein localized in the endoplasmic reticulum (ER). N88S and S90L mutations of this protein disrupt its glycosylation, resulting in its aggregation, but the mechanism of neurodegeneration remains unclear. To clarify the molecular pathogenesis of seipin-related motor neuron diseases, we expressed wild-type and mutant seipin proteins in neuronal and nonneuronal cells. METHODS AND RESULTS: Coexpression of human seipin and ubiquitin showed that seipin is polyubiquitinated and its ubiquitination is enhanced by mutation. Treatment of cells with a proteasome inhibitor increased the amounts of mutant seipin in the cells, suggesting that they are degraded through the ER-associated degradation pathway. Immunoprecipitation studies showed that mutant seipin stably binds to the ER chaperone calnexin, indicating accumulation of unfolded mutant seipin in the ER. Furthermore, expression of mutant seipin increased the level of ER stress-mediated molecules and induced apoptosis in cultured cells. INTERPRETATION: These findings demonstrate that seipin/BSCL2-related motor neuron diseases are novel conformational diseases, and we suspect that they are tightly associated with ER stress-mediated cell death. 相似文献
12.
B.-O. Choi M.-H. Park K. W. Chung H.-M. Woo H. Koo H.-K. Chung K.-G. Choi K. D. Park H. J. Lee Y. S. Hyun S. K. Koo 《Neurogenetics》2013,14(1):35-42
The objective of the study was to investigate the disease-causing mutation in an autosomal dominant Charcot-Marie-Tooth disease type 2 family and examine the clinical and histopathological evaluation. We enrolled a family of Korean origin with axonal Charcot-Marie-Tooth disease neuropathy (FC305; 13 males, six females) and applied genome-wide linkage analysis. Whole exome sequencing was performed for two patients. In addition, sural nerve biopsies were obtained from two patients. Through whole exome sequencing, we identified an average of 20,336 coding variants from two patients. We also found evidence of linkage mapped to chromosome 11p11-11q13.3 (LOD score of 3.6). Among these variants in the linkage region, we detected a novel p.S90W mutation in the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) gene, after filtering 31 Korean control exomes. Our p.S90W patients had frequent sensory disturbances, pyramidal tract signs, and predominant right thenar muscle atrophy in comparison with reported p.S90L patients. The phenotypic spectra were wide and demonstrated intrafamilial variability. Two patients with different clinical features underwent sural nerve biopsies; the myelinated fiber densities were increased slightly in both patients, which differed from two previous case reports of BSCL2 mutations (p.S90L and p.N88S). This report expands the variability of the clinical spectrum associated with the BSCL2 gene and describes the first family with the p.S90W mutation. 相似文献
13.
Clinical and genetic features of Charcot‐Marie‐Tooth disease 2F and hereditary motor neuropathy 2B in Japan
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Hajime Tanabe Yujiro Higuchi Jun‐Hui Yuan Akihiro Hashiguchi Akiko Yoshimura Satoshi Ishihara Satoshi Nozuma Yuji Okamoto Eiji Matsuura Hiroyuki Ishiura Jun Mitsui Ryotaro Takashima Norito Kokubun Kengo Maeda Yuri Asano Yoko Sunami Yu Kono Yasunori Ishigaki Shosaburo Yanamoto Jiro Fukae Hiroshi Kida Mitsuya Morita Shoji Tsuji Hiroshi Takashima 《Journal of the peripheral nervous system : JPNS》2018,23(1):40-48
Mutations in small heat shock protein beta‐1 (HspB1) have been linked to Charcot‐Marie‐Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1‐related disorders. 相似文献
14.
Small heat shock protein B3 (HSPB3) mutation in an axonal Charcot‐Marie‐Tooth disease family
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Da E. Nam Soo H. Nam Ah J. Lee Young B. Hong Byung‐Ok Choi Ki W. Chung 《Journal of the peripheral nervous system : JPNS》2018,23(1):60-66
Heat shock protein B3 (HSPB3) gene encodes a small heat‐shock protein 27‐like protein which has a high sequence homology with HSPB1. A mutation in the HSPB3 was reported as the putative underlying cause of distal hereditary motor neuropathy 2C (dHMN2C) in 2010. We identified a heterozygous mutation (c.352T>C, p.Tyr118His) in the HSPB3 from a Charcot‐Marie‐Tooth disease type 2 (CMT2) family by the method of targeted next generation sequencing. The mutation was located in the well conserved alpha‐crystalline domain, and several in silico predictions indicated a pathogenic effect of the mutation. Clinical and electrophysiological features of the patients indicated the axonal type of CMT. Clinical symptoms without sensory involvements were similar between the present family and the previous family. Mutations in the HSPB1 and HSPB8 genes have been reported to be relevant with both types of CMT2 and dHMN. Our findings will help in the molecular diagnosis of CMT2 by expanding the phenotypic range due to the HSPB3 mutations. 相似文献
15.
Mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been identified in families with distal hereditary motor neuropathy (dHMN) and in families with SPG17-linked Silver syndrome. We studied the first Korean families with clinical features resembling classic Silver syndrome and dHMN type V. Direct sequencing analysis of the BSCL2 gene revealed a Ser90Leu mutation in the proband, a younger sister, and one of two sons of the proband. The clinical patterns in this family include presentation with lower-limb and hand-muscle involvement early in the disease course as well as the presence of Babinski signs with nonprogressive mild spastic paraparesis, resembling classic Silver syndrome and dHMN type V. This study reaffirms the clinical phenotype of the disorders associated with a BSCL2 Ser90Leu mutation and describes a genetically proven family with Silver syndrome and dHMN type V in Asia. 相似文献
16.
Rossor AM Davidson GL Blake J Polke JM Murphy SM Houlden H Innes A Kalmar B Greensmith L Reilly MM 《Journal of the peripheral nervous system : JPNS》2012,17(2):201-205
Mutations in the gene HSPB1, encoding the small heat shock protein 27 (HSP27), are a cause of distal hereditary motor neuropathy (dHMN) and axonal Charcot-Marie-Tooth disease (CMT2). dHMN and CMT2 are differentiated by the presence of a sensory neuropathy in the latter although in the case of HSPB1 this division is artificial as CMT2 secondary to HSPB1 mutations is predominantly a motor neuropathy with only minimal sensory involvement. A recent study in mice has suggested that mutations in the C-terminus result in a motor only phenotype resembling dHMN, whereas mutations at the N-terminus result in a CMT2-like phenotype. However, we present a family with a novel mutation in the C-terminus of HSP27 (p.Glu175X) with a motor predominant distal neuropathy but with definite sensory involvement compatible with CMT2. This case highlights the artificial distinction between patients with motor predominant forms of CMT2 and dHMN and argues against the hypothesis that mutations in the C-terminus have no sensory involvement. 相似文献
17.
Thomas?Musacchio Ann-Kathrin?Zaum Nurcan?ü?eyler Claudia?Sommer Nora?Pfeifroth Karlheinz?Reiners Erdmute?Kunstmann Jens?Volkmann Simone?Rost Stephan?Klebe
Silver syndrome/SPG17 is a motor manifestation of mutations in the BSCL2 gene and usually presents as a complicated form of hereditary spastic paraplegia (HSP). We present clinical data, follow-up, and genetic results of seven patients with Silver syndrome/SPG17 including a family with a variable intrafamilial phenotype ranging from subclinical signs to a severe and rapidly progressing amyotrophic lateral sclerosis (ALS)-like phenotype. For molecular diagnosis of the family, we used the TruSight Exome sequencing panel consisting of 2761 genes. We filtered for variants common to affected family members and for exclusive variants in the ALS-like index patient to find possible modifier mutations. We found that de novo mutations and/or incomplete penetrance in BSCL2 has been taken into account for Silver syndrome/SPG17 and confirm the large phenotypical heterogeneity of BSCL2 mutations. Our findings broaden the reported spectrum of the disease to an ALS-like and multifocal motor neuropathy phenotype and underline the need for further research for genetic modifiers due to the striking interindividual and intrafamilial variability. 相似文献
18.
Moritz Oberstadt Diana Mitter Joseph Classen Petra Baum 《Journal of the peripheral nervous system : JPNS》2016,21(2):111-113
Distal hereditary motor neuropathy (dHMN) type II is genetically heterogeneous. We report three siblings of a German family with late onset distal motor neuropathy due to the c.404C>G mutation in heat‐shock 27‐kDa protein 1 gene (HSPB1/HSP27). A 36‐year‐old mutation carrier, daughter of one sibling, did not present any clinical or electrophysiological abnormalities. The index patient (oldest brother) developed weakness of the distal lower limbs and nocturnal muscle cramps at the age of 54. After 5 years this patient developed an l ‐DOPA‐responsive hypokinetic rigid syndrome, establishing a diagnosis of Parkinson's disease. Although none of the three other mutation carriers displayed Parkinsonian signs, a pathogenic relationship with Parkinson's disease remains a possibility, based on the known molecular pathology of HSPB1. The rare pathogenic HSPB1 c.404C>G mutation may predispose for late‐onset of dHMN type II. 相似文献
19.
Paola Saveri Micaela Milani Claudia Ciano Laura Farina Davide Pareyson 《Journal of the peripheral nervous system : JPNS》2017,22(1):47-50
Charcot‐Marie‐Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N‐Myc downstream‐regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38‐year‐old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT. 相似文献