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1.
Fabrizi GM Taioli F Cavallaro T Rigatelli F Simonati A Mariani G Perrone P Rizzuto N 《Acta neuropathologica》2000,100(3):299-304
Charcot-Marie-Tooth disease type 1B (CMT1B) is a demyelinating neuropathy caused by mutations in the myelin protein zero
(P0) gene (MPZ). A few cases of CMT1B were recently found to be characterized by focally folded myelin sheaths in nerve biopsy specimens;
the significance of this association is unknown. Here, we describe two unrelated pedigrees harboring a heterozygous Ser49Leu
substitution in P0ex. In both pedigrees, the mutation caused a late-onset, relatively mild CMT1B; in one pedigree, two patients had atrophy
of peroneal muscles but hypertrophy of the gastrocnemius muscles. The sural nerve biopsy performed in the two index cases
revealed an identical chronic demyelinating and remyelinating neuropathy dominated by focal foldings of the myelin sheath
shaped either as tomacula or as out/infoldings. The report adds Ser49Leu to the mutations of P0ex associated with focally folded myelin and provides strong evidence that such a structural alteration of the myelin sheath
reflects a distinct pathogenetic mechanism in a subgroup of CMT1B.
Received: 18 August 1999 / Revised, accepted: 22 November 1999 相似文献
2.
Bolino A Lonie LJ Zimmer M Boerkoel CF Takashima H Monaco AP Lupski JR 《Neurogenetics》2001,3(2):107-109
Charcot-Marie-Tooth type 4B (CMT4B), an autosomal recessive demyelinating neuropathy characterized by focally folded myelin
sheaths in the peripheral nerve, has been associated with mutations in the gene encoding myotubularin-related protein 2, MTMR2, on chromosome 11q22. To investigate whether mutations in MTMR2 may also cause different forms of CMT, we screened 183 unrelated patients with a broad spectrum of CMT and related neuropathies
using denaturing high-performance liquid chromatography. We identified four frequent and three rare exonic variants; two of
the rare variants were identified in two unrelated patients with congenital hypomyelinating neuropathy and not in the normal
controls. Our results suggest that loss-of-function mutations in MTMR2 are preferentially associated with the CMT4B phenotype.
Electronic Publication 相似文献
3.
A. Kochaski H. Drac H. Jdrzejowska I. Hausmanowa-Petrusewicz 《European journal of neurology》2003,10(5):547-549
Charcot-Marie-Tooth disease type 1B (CMT1B) is a demyelinating neuropathy inherited as an autosomal dominant trait. The majority of CMT1B cases are caused by mutations in the myelin protein zero (P0) gene (MPZ). Only a few mutations in MPZ gene have been reported to be associated with focally folded myelin sheaths. We have studied five patients from one family with five generations, affected by CMT1B disease. The morphological studies of sural nerve biopsy performed in the proband revealed fibers with focally folded myelin. DNA sequencing analysis showed the Asn131Lys mutation in the MPZ gene in three members of the affected family. 相似文献
4.
Federica Taioli Laura Bertolasi Domenico Ajena Moreno Ferrarini Ilaria Cabrini Alberto Crestanello Gian Maria Fabrizi 《Journal of the peripheral nervous system : JPNS》2012,17(4):414-417
Genetic germinal and somatic mosaicisms of dominant Charcot‐Marie‐Tooth disease (CMT) mutations are rarely reported and/or recognized. We describe a novel heterozygous p.Trp39Cys missense mutation in the extracellular domain of the peripheral myelin protein 22 (PMP22) associated with an early‐onset demyelinating CMT type 1 E (CMT1E) in two siblings born from asymptomatic non‐consanguineous parents. The 29‐year‐old mother, harboring approximately 20% of the mutant PMP22 allele in blood, had minor signs of distal polyneuropathy (pes cavus, decreased ankle jerk reflexes and vibration sense in legs) and slight reduction of sural nerve action potentials (SNAPs). Authors suggest that mutations of CMT‐related genes which originate in post‐zygotic stages may be associated with mild phenotypes of peripheral neuropathy. 相似文献
5.
Hiroshi Takashima 《Clinical neurology》2006,46(11):760-767
6.
Nouioua S Hamadouche T Funalot B Bernard R Bellatache N Bouderba R Grid D Assami S Benhassine T Levy N Vallat JM Tazir M 《Neuromuscular disorders : NMD》2011,21(8):543-550
Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms. 相似文献
7.
Histopathological features of a patient with Charcot‐Marie‐Tooth disease type 2U/AD‐CMTax‐MARS
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Makito Hirano Nobuyuki Oka Akihiro Hashiguchi Shuichi Ueno Hikaru Sakamoto Hiroshi Takashima Yujiro Higuchi Susumu Kusunoki Yusaku Nakamura 《Journal of the peripheral nervous system : JPNS》2016,21(4):370-374
Charcot‐Marie‐Tooth (CMT) disease is a complex of peripheral nervous system disorders. CMT type 2U (CMT2U) is an autosomal dominant (AD) disease caused by mutations in the MARS gene encoding methionyl‐tRNA synthetase; this disease has thus been newly called AD‐CMTax‐MARS. A few families with mutations in the MARS gene have been reported, without detailed histopathological findings. We describe a 70‐year‐old woman who had bilateral dysesthesia of the soles since the age of 66 years. Sural nerve biopsy showed a decrease in the density of large myelinated nerve fibers. Increased clusters of regenerating myelinated nerve fibers were noted. Electron microscopic analyses revealed degeneration of unmyelinated nerves. There was no vasculitis or inflammatory cell infiltration. Genetic analysis identified a heterozygous p.P800T mutation, a reported mutation in the MARS gene. We report the detailed histopathological findings in a patient with CMT2U/AD‐CMTax‐MARS. The findings are similar to those found in CMT2D caused by mutations in the GARS gene, encoding glycyl‐tRNA synthetase. 相似文献
8.
9.
PMP22‐Related neuropathies and other clinical manifestations in Chinese han patients with charcot‐marie‐tooth disease type 1
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Yajing Zhan PhD Xiaohong Zi MD Zhengmao Hu PhD Ying Peng PhD Lingqian Wu PhD Xiaobo Li MS Mingming Jiang MS Lei Liu MS Yongzhi Xie MS Kun Xia PhD Beisha Tang PhD Ruxu Zhang MD 《Muscle & nerve》2015,52(1):69-75
Introduction: Most cases of Charcot‐Marie‐Tooth (CMT) disease are caused by mutations in the peripheral myelin protein 22 gene (PMP22), including heterozygous duplications (CMT1A), deletions (HNPP), and point mutations (CMT1E). Methods: Single‐nucleotide polymorphism (SNP) arrays were used to study PMP22 mutations based on the results of multiplex ligation‐dependent probe amplification (MLPA) and polymerase chain reaction–restriction fragment length polymorphism methods in 77 Chinese Han families with CMT1. PMP22 sequencing was performed in MLPA‐negative probands. Clinical characteristics were collected for all CMT1A/HNPP probands and their family members. Results: Twenty‐one of 77 CMT1 probands (27.3%) carried duplication/deletion (dup/del) copynumber variants. No point mutations were detected. SNP array and MLPA seem to have similar sensitivity. Fifty‐seven patients from 19 CMT1A families had the classical CMT phenotype, except for 1 with concomitant CIDP. Two HNPP probands presented with acute ulnar nerve palsy or recurrent sural nerve palsy, respectively. Conclusions: The SNP array has wide coverage, high sensitivity, and high resolution and can be used as a screening tool to detect PMP22 dup/del as shown in this Chinese Han population. Muscle Nerve 52 : 69–75, 2015 相似文献
10.
Haitian Nan Ryusuke Takaki Takanori Hata Yuta Ichinose Mai Tsuchiya Kishin Koh Yoshihisa Takiyama 《Journal of the peripheral nervous system : JPNS》2019,24(1):156-160
We report the first family with a glycyl‐tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot‐Marie‐Tooth disease (DI‐CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI‐CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS. 相似文献
11.
Inverted formin 2‐related Charcot‐Marie‐Tooth disease: extension of the mutational spectrum and pathological findings in Schwann cells and axons
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Andreas Roos Joachim Weis Rudolf Korinthenberg Henry Fehrenbach Martin Häusler Stephan Züchner Christoph Mache Holger Hubmann Michaela Auer‐Grumbach Jan Senderek 《Journal of the peripheral nervous system : JPNS》2015,20(1):52-59
Mutations in the gene encoding inverted formin FH2 and WH2 domain‐containing protein (INF2), a Cdc42 effector involved in the regulation of actin dynamics, cause focal segmental glomerulosclerosis (FSGS) and intermediate Charcot‐Marie‐Tooth neuropathy combined with FSGS (FSGS–CMT). Here, we report on six patients from four families with sensorimotor polyneuropathy and FSGS. Nerve conduction velocities were moderately slowed, and amplitudes of sensory and motor potentials were decreased. One patient had internal hydrocephalus and was intellectually disabled. Molecular genetic testing revealed two known and two novel missense mutations in the second and fourth exons of the INF2 gene. Investigations of one nerve biopsy confirmed the diagnosis of intermediate‐type CMT and revealed occasional abnormal in‐ and outfoldings of myelin sheaths and expansions of the endoplasmic reticulum in axons and Schwann cells. While earlier reports suggested that mutations causing FSGS‐CMT are restricted to exons 2 and 3 of the INF2 gene, we found one CMT‐FSGS causing mutation (p.Glu184Lys) in exon 4 extending the critical region of INF2 for rapid CMT‐FSGS molecular genetic diagnosis. Study of a nerve biopsy showed abnormalities that might be related to the known role of the INF2‐binding partner CDC42 in myelination. 相似文献
12.
Gian Maria Fabrizi Stefano Tamburin Tiziana Cavallaro Ilaria Cabrini Moreno Ferrarini Federica Taioli Francesca Magrinelli Giampietro Zanette 《Clinical neurophysiology》2018,129(1):21-32
Objective
Nerve ultrasound (US) data on myelin protein zero (MPZ)-related Charcot-Marie-Tooth disease (CMT) are lacking. To offer a comprehensive perspective on MPZ-related CMTs, we combined nerve US with clinics, electrodiagnosis and histopathology.Methods
We recruited 36 patients (12 MPZ mutations), and correlated nerve US to clinical, electrodiagnostic measures, and sural nerve biopsy.Results
According to motor nerve conduction velocity (MNCV) criteria, nine patients were categorized as “demyelinating” CMT1B, 17 as “axonal” CMT2I/J, and 10 as dominant “intermediate” CMTDID. Sural nerve biopsy showed hypertrophic de-remyelinating neuropathy with numerous complex onion bulbs in one patient, de-remyelinating neuropathy with scanty/absent onion bulbs in three, axonal neuropathy in two, mixed demyelinating-axonal neuropathy in five. Electrodiagnosis significantly differed in CMT1B vs. CMT2I/J and CMTDID subgroups. CMT1B had slightly enlarged nerve cross sectional area (CSA) especially at proximal upper-limb (UL) sites. CSA was negatively correlated to UL MNCV and not increased at entrapment sites. Major sural nerve pathological patterns were uncorrelated to UL nerve US and MNCV.Conclusions
Sural nerve biopsy confirmed the wide pathological spectrum of MPZ-CMT. UL nerve US identified two major patterns corresponding to the CMT1B and CMT2I/J-CMTDID subgroups.Significance
Nerve US phenotype of MPZ-CMT diverged from those in other demyelinating peripheral neuropathies and may have diagnostic value. 相似文献13.
14.
Taroni F. 《Journal of the peripheral nervous system : JPNS》2001,6(1):57-57
Hereditary peripheral neuropathies are clinically and genetically heterogeneous and include the most common motor and sensory forms (HMSN) as well as the rarer pure motor and pure sensory phenotypes. As a group, Charcot-Marie-Tooth (CMT) disease and related neuropathies (Déjérine-Sottas disease [DSD], congenital hypomyelinating neuropathy [CHN] and hereditary neuropathy with liability to pressure palsies [HNPP]) represent the most common inherited peripheral nerve diseases as well as one of the most common human inherited disorders with a prevalence of ∼20–40:100,000. During the last decade, advances in molecular genetics have greatly increased our understanding of these disorders and significantly changed the clinical approach to them by providing powerful molecular tools for diagnosis. The most common form is demyelinating CMT (CMT1). Based on genetic location and the gene involved, CMT1 is further subcategorized into autosomal dominant (AD) CMT1A (PMP22, 17p11.2) and CMT1B (MPZ, 1q21.2), and X-linked dominant CMTX (Cx32, Xq13.1). Approx. 3/4 of CMT1 patients belong to the CMT1A subgroup and carry a 1.5-Mb duplication on chr. 17p11.2 encompassing the myelin protein PMP22 gene. Given the high duplication rate in sporadic cases, the diagnosis of CMT1A should be considered even in the absence of a family history. Furthermore, the reciprocal deletion of the CMT1A 1.5-Mb tract is commonly (∼80%) observed in HNPP patients. Altogether, detection of these relatively common molecular abnormalities allows diagnosis in the vast majority of CMT1 or HNPP patients. Patients who do not have the CMT1A duplication should be screened initially for Cx32 mutations which are the next most frequent cause of CMT1 accounting for ∼10% of patients. Approx. 4% of cases belong to the CMT1B subgroup, harboring mutations in the myelin protein P0 gene (MPZ). Mutations in the PMP22 gene can be found in a minority of CMT1 patients. Of the remaining cases, some have been demonstrated to carry mutations in the EGR2 gene. Interestingly, mutations in the PMP22, MPZ and EGR2 genes can also cause the more severe early-onset variants DSD and CHN. A number of loci have been linked to the rare autosomal recessive forms of CMT1. Very recently, mutations in the MTMR2 and NDRG1 genes have been associated with two distinct phenotypes, AR-CMT1 with myelin outfoldings (CMT4B) and HMSN-Lom, respectively. Approx. 20–30% of CMT patients exhibit the axonal type CMT2. For the majority of these patients, no molecular test is currently available. Although several loci have been associated with this form, only one disease gene, NF-L on chr. 8p21, has been thus far identified. However, Cx32 mutations should always be excluded in female patients diagnosed with CMT2. Finally, recent evidences have indicated that mutations in the MPZ gene can be found in ∼5% of AD-CMT2 families. 相似文献
15.
In up to 50% of chronic idiopathic axonal neuropathies, an underlying diagnosis may be identified, including hereditary neuropathy. Charcot-Marie-Tooth disease (CMT) is clinically and genetically heterogeneous. Several mutations in the myelin protein zero (MPZ) gene have been associated with different CMT phenotypes, including classical demyelinating CMT1B and the axonal form of the disease. Primary amyloidosis, a rare disease where the amyloid is formed by the N-terminal portion of a monoclonal immunoglobulin light chain, may be complicated by polyneuropathy. We report a patient who was incorrectly diagnosed with amyloid neuropathy, but was found to have axonal CMT1B only after sural nerve biopsy ruled out an acquired amyloid neuropathy. 相似文献
16.
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
17.
Chromosomal imbalance of the peripheral myelin protein-22 gene (PMP22) is known to be the most frequent genetic abnormality in Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy
with liability to pressure palsy (HNPP). We applied a new quantitative PCR method, the direct-double-differential PCR (dddPCR),
to the gene dosage determination of PMP22. The method allows the quantification of the PMP22 gene copy number independently from DNA fragmentation, even in highly degraded DNA from up to 12-year-old sural nerve biopsy
samples. Chromosomal imbalance of the PMP22 gene, which had been detected by examination of four microsatellites located directly adjacent to the PMP22 gene, between the CMT1A-repetition (CMT1A-REP) elements was reliably confirmed by the dddPCR. Using this method we unexpectedly
identified two cases with PMP22 imbalance, although morphologically the neuropathies were of a neuronal or axonal type and not of a demyelinating type as
usual. One sural nerve biopsy was from a 58-year-old male diabetes mellitus patient with a disproportionately severe polyneuropathy
showing a heterozygous duplication of PMP22. The second biopsy exhibiting a heterozygous deletion of PMP22 was from a 58-year-old female patient with a more axonal than demyelinating type of neuropathy without typical tomaculous
changes seemingly altered by exogenous, possibly traumatic factors other than diabetes mellitus. Thus, the dddPCR provides
a fast and reliable diagnostic tool for the screening and identification of CMT1A and HNPP cases, which is fast and may be
essential even when nerve biopsies show morphologically atypical changes.
Received: 10 April 2000 / Accepted: 7 June 2000 相似文献
18.
Phenotype variability and histopathological findings in patients with a novel DNM2 mutation
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Mutations of Dynamin 2 (DNM2) are responsible for several forms of neuromuscular disorder such as centronuclear myopathy, Charcot–Marie–Tooth disease (CMT) dominant intermediate type B, CMT 2M, and lethal congenital contracture syndrome 5. We describe a young man manifesting as length‐dependent sensorimotor neuropathy with hypertrophic cardiomyopathy, but his mother only had very mild symptoms of peripheral neuropathy. The electrophysiological data meet the criteria of intermediate CMT. The main pathological findings of sural nerve biopsy reveal a severe loss of large myelinating fibers and some clusters of regenerative fibers in fascicles, which are consistent with an axonal neuropathy. However, myopathological changes show a chronic myopathy‐like pattern characterized by great variations of fiber size, increased connective tissue, rimmed vacuoles and predominance of type 2 fibers. A novel DNM2 mutation (p.G359D) in the middle domain is identified, which is highly evolutionarily conserved. DNM2‐related CMT disease is phenotypically heterogeneous in age at onset, clinical features and electrophysiological changes. The histopathological findings indicate the coexistence of typical axonal neuropathy and chronic myopathy in DNM2‐related neuromuscular diseases. 相似文献
19.
目的研究腓骨肌萎缩症(CMT)临床特征、基因测定、病理及神经电生理检查在其诊断和分型中的价值。方法收集50例CMT患者临床资料,对其进行肌电图检查及腓肠神经活检,并采用PCR技术直接测序进行基因突变分析。结果 40例CMT患者双下肢运动及感觉传导速度减慢(双胫、腓总神经为15~28 m/s,腓肠神经为12~30 m/s),10例双下肢未引出反应电位;50例正中神经运动及感觉传导速度亦减慢分别为19~48 m/s和20~52 m/s。CMT患者神经传导速度减慢的程度和临床表现的严重程度并不平行。腓肠神经活检符合慢性脱髓鞘部分伴轴索改变性周围神经病。PMP22、Cx32、MPZ、MFN2、GDAP1致病基因的突变分析发现14例患者存在PMP22基因的大片段重复突变(28%),13例患者存在Cx32基因的点突变(26%),4例患者存在MPZ基因的点突变(8%),3例患者存在MFN2基因的点突变(6%),未发现GDAP1基因的突变,16例患者未检测出上述基因突变。结论电生理、病理、基因测定在CMT的诊断及分型中有重要价值。 相似文献
20.
Leal A Berghoff C Berghoff M Del Valle G Contreras C Montoya O Hernández E Barrantes R Schlötzer-Schrehardt U Neundörfer B Reis A Rautenstrauss B Heuss D 《Neurogenetics》2003,4(4):191-197
Charcot-Marie-Tooth disease type 1B (CMT 1B) is caused by mutations in the gene coding for peripheral myelin protein zero (MPZ, P0) that plays a fundamental role in adhesion and compaction of peripheral myelin. Here we report a Costa Rican family with a hereditary peripheral neuropathy due to a novel Tyr145Ser MPZ mutation. Four family members were heterozygously affected; two siblings of two heterozygous carriers were homozygous for this mutation. On neurological examination the heterozygous parents and their homozygous children both showed distal sensory deficits. The mother and the siblings displayed impaired deep tendon reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with an earlier age of onset, distal motor weakness, and pupillary abnormalities. Electrophysiological studies revealed both signs of demyelination and axonal nerve degeneration. The sural nerve biopsy of one sibling showed thinly myelinated nerve fibers, onion bulb formation, and clusters of regenerating fibers. On electron microscopy axonal degeneration and decompaction of inner myelin layers were found. This Costa Rican family shows phenotypic variability depending on the homozygous or heterozygous state of the Tyr145Ser mutation carriers.A. Leal and C. Berghoff contributed equally to this work. 相似文献