Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation.

OBJECTIVE: In X-linked Charcot-Marie-Tooth disease (CMTX), electrophysiological and histopathological studies have suggested either a demyelinating or an axonal polyneuropathy. We report a CMTX family with a striking heterogeneity of nerve conductions between and within nerves. METHODS: Two men and one woman have been studied by conduction velocities, sural nerve biopsy with morphometry (one man) and DNA analysis. RESULTS: In both men motor conduction velocities were slowed in the demyelinating range, conduction velocity differences among nerves in the same subject varied from 13 to 24 m/s, and distal median compound muscle action potential (CMAP) amplitudes were 3-5 times reduced compared to ulnar CMAPs. Abnormal area reduction or excessive temporal dispersion of proximal CMAP was present in at least two nerves in all patients. Sural nerve biopsy showed reduction of large myelinated fibres, cluster formations, occasional onion bulbs. Teased fibres study revealed short internodes for fibre diameter, enlarged Ranvier nodes but no evidence of segmental demyelination and remyelination. DNA analysis showed an Arg(15)Gln mutation in connexin32 gene in all patients. CONCLUSIONS: In this family conduction slowing and segmental conduction abnormalities, in absence of morphological evidence of de-remyelination, may be related to short internodes, widened Ranvier nodes and the specific effect of the mutation. The occurrence in some CMTX patients of a non uniform involvement between and within nerves, as in acquired demyelinating neuropathies, should be kept in mind to avoid misdiagnoses.     

X连锁Charcot-Marie-Tooth病1型六个家系的病理和基因突变特点

目的 报道6个X连锁Charcot-Marie-Tooth病1型(CMTX1)家系的神经病理和基因型改变特点.方法 6个CMTX1家系的先证者均为男性,发病年龄11 ～24岁,出现下肢远端为主的肌无力、腱反射减低和轻度感觉减退.先证者1伴随发作性白质脑病,先证者5伴随小脑性共济失调.12名家系成员也出现周围神经损害症状,另7名存在高弓足或腱反射减低.对6例先证者行腓肠神经活体组织检查,并对6例先证者、8名受累家庭成员和10名无症状家系成员及50名健康女性进行缝隙连接蛋白32( Cx32)基因测序.结果 6例先证者有髓神经纤维出现轻-中度减少伴轴索再生变性,5例出现薄髓鞘神经纤维,其中3例伴洋葱球样结构,2例伴炎细胞浸润.6个家系的Cx32基因存在5种新突变和1种同义突变,即L20T、I127F、D178G、A197V错义突变,403_404T insT插入突变和L10L沉默突变,10名无症状家系成员中有4名女性为携带者,6名男性和健康对照均没有这些基因突变.结论 该组CMTX1患者的周围神经病理改变以慢性轴索损害为主,Cx32基因较多新突变的出现提示我国CMTX1患者具有个体突变特点.     

Clinical characterization and genetic analysis of Korean patients with X‐linked Charcot‐Marie‐Tooth disease type 1

Mutations in the gap junction protein beta 1 gene (GJB1) cause X‐linked Charcot‐Marie‐Tooth disease type 1 (CMTX1). CMTX1 is representative of the intermediate type of CMT, having both demyelinating and axonal neuropathic features. We analyzed the clinical and genetic characterization of 128 patients with CMTX1 from 63 unrelated families. Genetic analysis revealed a total of 43 mutations including 6 novel mutations. Ten mutations were found from two or more unrelated families. p.V95M was most frequently observed. The frequency of CMTX1 was 9.6% of total Korean CMT family and was 14.8% when calculated within genetically identified cases. Among 67 male and 61 female patients, 22 females were asymptomatic. A high‐arched foot, ataxia, and tremor were observed in 87%, 41%, and 35% of the patients, respectively. In the male patients, functional disability scale, CMT neuropathy score, and compound muscle action potential of the median/ulnar nerves were more severely affected than in the female patients. This study provides a comprehensive summary of the clinical features and spectrum of GJB1 gene mutations in Korean CMTX1 patients.     

Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q)

OBJECTIVE: To report a family with X-linked Charcot-Marie-Tooth disease (CMTX) with proven connexin 32 (Cx32) mutation associated with deafness. METHODS: Twelve members of a CMTX family were examined clinically. Electromyography and sensory and motor conduction studies were performed in three men, two women, and a 7-year-old boy. Audiometric testing was carried out in the three men, one woman, and an 8-year-old girl. Molecular genetic analysis was performed in six men and five women. RESULTS: The three men and the 7-year-old boy had the usual sensorimotor deficit and pronounced reduction of motor nerve conduction velocity. A 15-year-old boy was asymptomatic and had only areflexia. The women had impairment of vibratory sensation and slight slowing of nerve conduction velocities. Sensorineural deafness was observed in the three men and in an 8-year-old girl without any motor or sensory deficit. Molecular genetic analysis revealed a new missense mutation located in codon 142 of the Cx32 gene leading to the substitution of an arginine by a glutamine. CONCLUSION: CMTX due to Cx32 mutations often shows interfamilial and intrafamilial phenotypic variation, which is also the hallmark of this family. The sensorineural deafness observed in this family suggests that Cx32 could play an important role in the auditory pathway.     

Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease

X-linked Charcot-Marie-Tooth disease (CMTX) is the second most common form of Charcot-Marie-Tooth disease. Variable histopathological and nerve conduction velocity (NCV) results have suggested either a primary demyelinating or axonal polyneuropathy. We identified five individuals across three generations in a family with CMTX associated with a mutation in the gene coding for connexin 32. All individuals were studied by clinical neurological examination, DNA analysis, and nerve conduction studies. The proband (1174/KD) also underwent a sural nerve biopsy. As expected, all the affected males were more clinically affected than the females. All affected males and obligate female carriers exhibited some electrophysiological characteristics of demyelination. However, striking heterogeneity of nerve conduction velocities was seen. This family shows that CMTX is a heterogeneous and distinctly nonuniform demyelinating polyneuropathy, the severity of which varies with sex and age. Such electrophysiological variability is unique among hereditary neuropathies.     

腓骨肌萎缩症X型伴有可逆性中枢神统系统受累

目的探讨的腓骨肌萎缩症X型的临床特点和引起中枢神经系统受累可能的发病机制。方法报道1例国内未报道过的CMTX可引起中枢神经系统受累Cx32基因突变,分析该例患者的临床、电生理及病理改变特点。结果该患者为基因检查确诊Arg424Trp(R142W)突变的CMTX。临床存在可逆性眼震,电生理提示感觉运动神经受累均受累,轴索髓鞘均损害。肌肉活检提示慢性神经源性病理改变。周围神经活检示周围神经髓鞘损害为主。BAEP提示可逆性中枢性损害。结论 R142W突变的CMTX可以在应激条件下出现可逆性中枢神经系统损害。     

X连锁腓骨肌萎缩症Cx32基因的突变、临床和电生理特点

目的 分析X连锁腓骨肌萎缩症（CMTX）患者Cx32基凶的突变及其临床表现和电生理特点、方法应用多聚酶链反应一单链构象多态性分析结合DNA直接测序的方法,对24例无周围髓鞘蛋白（PMP）22基因大片段重复突变,家系中无男传男的腓骨肌萎缩症（CMT）先证者进行Cx32基因的突变分析;对先证者及其家系内患者进行临床和电生理检查。结果 在6个X连锁遗传家系和1例散发患者中发现了7个不同的Cx32基因突变,其中4个家系临床分型为CMTI型,2个家系为CMT中间型,散发病例为CMT1型检测到有Cx32基因突变的家系成员共38例,其巾男性20例,全部为CMTX患者;女性18例,其中6例为CMTX患者,12例为无临床症状的携带者;26例患者均为周围神经轻、中度受累。结论 CMTX的遗传方式可为X连锁显性、X连锁隐性遗传,也可为散发。根据临床和电生理特点分为CMTI型或CMT中间型,多为周围神经轻、中度受累,男性患者的症状通常较女性重。在没有检测到PMP22基因大片段重复突变和无男传男的CMT家系中应首先进行Cx32基因突变分析。     

Age associated axonal features in HNPP with 17p11.2 deletion in Japan

OBJECTIVE: To clarify age related changes in the clinicopathological features of hereditary neuropathy with liability to pressure palsy (HNPP) in Japanese patients with deletion of 17p11.2, particularly concerning axonal abnormalities. METHODS: Forty eight proband patients from 48 HNPP families were assessed as to clinical, electrophysiological, and histopathological features, including age associated changes beyond those in controls. RESULTS: Motor conduction studies showed age associated deterioration of compound muscle action potentials in nerves vulnerable to repetitive compression (median, ulnar, and peroneal nerves), but not in others such as the tibial nerve. Sensory conduction studies revealed more profound reduction of action potentials than motor studies with little age related change. Large myelinated fibre loss was seen in the sural nerve irrespective of age at examination. CONCLUSIONS: Irreversible axonal damage may occur at entrapment sites in motor nerves in HNPP patients, progressing with aging. Sensory nerves may show more profound axonal abnormality, but without age association. The electrophysiological features of HNPP are presumed to be a mixture of abnormalities occurring from early in life and acquired features caused by repetitive insults at entrapment sites. Unlike Charcot-Marie-Tooth disease type 1A, age associated axonal damage may not occur unless the nerves are subjected to compression.     

Machado-Joseph disease in a family of Spanish origin

The clinical observations in five patients, of a family of catalan origin (NE of Spain), affected with Machado-Joseph disease are reported. The pedigree showed the presence of 22 members affected (15 men, 7 women) over six generations. The symptoms and signs were variable among the patients and also variable in a same patient during the course of the disease. However, the main neurological alterations were ataxia, akinesia, distal amyotrophy, progressive external ophthalmoplegia, facial and lingual fasciculations and bulging eyes. The neuropathological examination performed in one patient disclosed degeneration of the posterior and spinocerebellar tracts in the spinal cord, marked nerve cell loss in Clarke's column and anterior horns and axonal degeneration of the peripheral nerves, in addition to nerve cell loss in the nuclei of the III, IV and VII cranial nerves and neuronal depletion in the substantia nigra. No other structures, including the striate complex and dentate nucleus, were significantly affected.     

Charcot-Marie Tooth type X (CMTX) disease: clinical and genetic characteristics of eleven patients

Charcot-Marie-Tooth type X disease (CMTX) is the second most frequent inherited neuropathy, after CMT1A type associated with 17p11.2-p12 duplication. CMTX is inherited as X dominant trait and is caused by point mutations in Cx32 gene. In the study the first Polish group of 11 patients with CMTX from 4 families is presented. The following four mutations were found in Cx32 gene: Gly110Asp, Val 152 Asp, Arg 183 His and Glu 208 Gly. CMTX is characterized by X dominant trait of inheritance, a mild clinical course in affected females and slowly progressive atrophy and weakness of distal limb muscles. Both electrophysiological and sural nerve biopsy studies show axonal changes with secondary demyelination.     

Charcot-Marie-Tooth disease: Histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and Connexin32 mutations (CMTX1)

The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5–10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6 ± 5.5 m/s) than in CMT1A patients (18.2 ± 6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 217–225, 1998     

腓骨肌萎缩症X1型1个家系的临床、电生理和Connexin32基因突变分析

目的观察腓骨肌萎缩症(CMT)X1型的临床、电生理特点和Connexin32(Cx32)基因突变情况.方法对1个无基因重复的临床可疑的CMTX1家系中的3例患者进行详尽的临床和神经电生理检查,并应用变性高效液相色谱结合混和样品池法和DNA序列测定对包括先证者在内的3名成员的Cx32基因进行突变检测.结果 该家系中的病人发生了Gly12Ser,50名正常人中未发现上述改变,提示该突变为致病性突变.家系中男性病人临床症状重于女性;电生理特点为脱髓鞘改变;同一病人的不同神经间存在异质性.结论 Gly12Ser突变可能导致原发性脱髓鞘性神经病,不伴有特殊的临床表现.     

Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease

X-linked Charcot-Marie-Tooth disease (CMTX) is a clinically heterogeneous hereditary motor and sensory neuropathy with X-linked transmission. Common clinical manifestations of CMTX, as in other forms of Charcot-Marie-Tooth disease (CMT), are distal muscle wasting and weakness, hyporeflexia, distal sensory disturbance, and foot deformities. Motor nerve conduction velocity is reduced. In male patients it is often less than 38 m/s in the median nerve (a value often used to distinguish between "demyelinating" and "axonal" forms of CMT), but in female patients conduction velocity may be faster than this or normal. Mutations in the connexin32 (gap junction protein beta 1 (GJB1)) gene are responsible for the majority of CMTX cases. This report describes six British CMTX families with six novel mutations (four missense, one nonsense, and one frame shift) of the GJB1 gene. Affected members in these six families had typical signs of CMT but in some affected members of three families there was additional central nervous system involvement or deafness in the absence of any other explanation other than CMT.     

Early axonal loss predicts long-term disability in chronic inflammatory demyelinating polyneuropathy

ObjectiveTo investigate early pre-treatment nerve fiber loss as a predictor of long-term clinical outcome in chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsIn 14 patients, motor and sensory conduction studies of the median, fibular, and sural nerves were performed at pre-treatment and follow-up 11–28 years later. Z-scores of amplitudes were combined as biomarkers of axonal loss and Z-scores of conduction properties as demyelination scores. The axonal loss was further examined by electromyography (EMG) and motor unit number estimation. Axonal and demyelination scores were compared to clinical outcomes in the Inflammatory Rasch-built Overall Disability Scale, the Neuropathy Impairment Score, and dynamometry.ResultsAt follow-up 12 patients walked independently, one needed support and one could not walk. The initial and follow-up axonal and demyelination scores were markedly abnormal. The initial axonal loss but not demyelination was strongly associated with both the follow-up axonal loss and the clinical measures. Moreover, delay of treatment initiation negatively influenced the axonal scores and clinical outcomes.ConclusionIn this hypothesis generating limited study, we found that axonal loss at early CIDP was highly predictive for long-term nerve fiber loss and disability.SignificanceThe study indicates that prompt initiation of treatment to prevent nerve fiber loss is necessary for outcome in CIDP.     

腓骨肌萎缩症伴神经性耳聋一家系临床和分子遗传学分析

目的探讨一个X连锁腓骨肌萎缩症(CMTX)伴常染色体隐性遗传的神经性耳聋家系的临床特点并研究其分子遗传学病因。方法对9名家系成员进行详细的临床检查，先证者进行了神经肌电图、听觉诱发电位和神经活检，3名耳聋患者进行电测听检查。运用聚合酶链反应一单链构象多态性分析技术(PCR-SSCP)结合直接测序法进行间隙连接蛋白32(eonnexin32)的突变分析，直接测序法进行间隙连接蛋白26(connexin26)的突变分析。结果家系中3名腓骨肌萎缩症患者为X连锁显性遗传，3名神经性耳聋患者为常染色体隐性遗传，其中1名患者同时出现腓骨肌萎缩症和神经性耳聋的临床症状。CMTX由connexin32错义突变C223T(Arg75Trp)引起。耳聋症状与connexin32点突变无共分离现象，对connexin26直接测序亦未发现突变，耳聋的致病基因有待进一步探讨。结论该家系腓骨肌萎缩症和耳聋分别由不同基因突变引起，这种在一个家系中同时出现两种不同遗传方式，不同致病基因的遗传病罕有报道。     

X-LINKED DOMINANT CHARCOT-MARIE-TOOTH NEUROPATHY: ANALYSIS OF A PEDIGREE WITH A NOVEL MUTATION OF CONNEXIN 32

Objective: To report a family with X-linked Charcot-Marie-Tooth neuropathy (CMTX) with a novel mutation of connexin 32 (Cx32).
Background: Cx32, a gap-junction protein, is expressed in various neural and non-neural tissues. In the peripheral nervous system (PNS), Cx32 is expressed by the Schwann cell and it is believed to form reflexive gap-junctions at the Schmidt-Lantermann incisures and paranodes; in the central nervous system, Cx32 is expressed by neurons and oligodendrocytes. Mutations of Cx32 causes an apparently tissue-specific disorder of PNS: CMTX.
Methods: We examined, clinically and electrophysiologically, 2 brothers with CMT and their asymptomatic mother. We performed a sural nerve biopsy in the 29-year-old proband and analysed the Cx32 gene (GJB1) by direct nucleotide sequencing.
Results: We detected a novel GTA→GAA of GJB1 that is predicted to cause a Val23Glu substitution in the first transmembrane domain of Cx32. NCV studies disclosed features of a demyelinating neuropathy in the severely-affected hemizygous brother, and slowing of the sensory conduction velocity in the sural nerve in the mother who showed pes cavus and areflexia. In all three examined patients, BAEPs showed both delayed wave 1 and prolonged interpeak-latency-time (IPL I-V); central motor conduction time by MEPs was normal. The nerve biopsy in the proband was consistent with a primary axonal degeneration.
Conclusions: Cx32 mutations may lead also to a dysfunction of the CNS. Electrophysiological abnormalities of the CNS pathways may orientate the diagnosis of CMT towards Cx32.     

X-linked Charcot-Marie-Tooth disease: phenotypic expression of a novel mutation Ile127Ser in the GJB1 (connexin 32) gene

We report a family with X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Three affected family members are described, who underwent detailed clinical, electrophysiological, molecular genetic, and histopathological studies. A novel isoleucine at position 127 with serine (Ile127Ser) mutation in the gap junction protein beta 1 (GJB1) gene was detected. The electrophysiological findings were consistent with a primary demyelinating neuropathy with secondary axonal loss and support this model of disease progression. All patients having the CMT phenotype and intermediate conduction velocities who are negative for CMT1A duplication/hereditary neuropathy with liability to pressure palsies (HNPP) deletion, and whose family shows a dominant trait without male-to-male transmission, should be screened for CMTX1.     

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred.

Members of a Roma (Gypsy) family with hereditary motor and sensory peripheral neuropathy (HMSN) and concomitant auditory and vestibular cranial neuropathies were identified in Kocevje, Slovenia. The illness begins in childhood with a severe and progressive motor disability and the deafness is delayed until the second decade. There are no symptoms of vestibular dysfunction. The family structure is consistent with an autosomal recessive pattern of inheritance and the genetic locus for the disorder is linked to the same region of chromosome 8q24 as other Roma families with HMSN and deafness from Lom, Bulgaria (HMSN-Lom). The present study shows that the deafness is caused by a neuropathy of the auditory nerve with preserved measures of cochlear outer hair cell function (otoacoustic emissions and cochlear microphonics) but absent neural components of auditory brainstem potentials. The hearing loss affects speech comprehension out of proportion to the pure tone loss. Vestibular testing showed absence of caloric responses. Physiological and neuropathological studies of peripheral nerves were compatible with the nerve disorder contemporaneously affecting Schwann cells and axons resulting in both slowed nerve conduction and axonal loss. Genetic linkage studies suggest a refinement of the 8q24 critical region containing the HMSN-Lom locus that affects peripheral motor and sensory nerves as well as the cranial auditory and vestibular nerves.