Charcot‐Marie‐Tooth type X: unusual phenotype of a novel CX32 mutation

Background: X‐linked Charcot‐Marie‐Tooth disease (CMTX), caused by mutations in the gene encoding connexin32, is the second most common form of inherited demyelinating neuropathy, next to CMT 1A, and accounts for 10–20% of all hereditary demyelinating neuropathies. Aims of the study: To describe clinical and electrophysiological data of an Italian family carrying a novel mutation in the Cx32 gene. Patients and methods: Clinical, electrophysiological, and genetic findings of three patients carrying the Ser128Leu mutation in the intracellular domain of the Cx32 gene were reported. Brain MRI studies were also performed. Results: In our family the disease was characterized by a moderate‐to‐severe polyneuropathy affecting similarly males as well females. In the proband the phenotype was quite unusual in terms of late‐onset, rapidity of evolution and severity. Abnormal brain MRI in association with CNS symptoms were also observed. Both sons had also clinical evidence of CNS involvement. Conclusions: The Ser128Leu mutation in the Cx‐32 gene is a novel substitution, which has not been reported so far. This novel mutation could be added to the group of Cx‐32 mutations with CNS phenotypes. The identification of new CMTX causing mutations is a crucial step for carrier detection and pre‐symptomatic diagnosis.     

Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease

X-linked Charcot-Marie-Tooth disease (CMTX) is a hereditary demyelinating neuropathy caused by mutations in the connexin 32 (Cx32) gene. Cx32 is widely expressed in brain and peripheral nerve, yet clinical manifestations of CMTX mainly arise from peripheral neuropathy. We have evaluated two male patients with CMTX who on separate occasions developed transient ataxia, dysarthria, and weakness within 3 days of returning from ski trips at altitudes above 8,000 feet. Magnetic resonance imaging studies in both patients showed nonenhancing, confluent, and symmetrical white matter abnormalities that were more pronounced posteriorly and that resolved over several months. Magnetic transfer images in one patient demonstrated increased magnetization transfer ratios distinct from that seen in demyelination or edema. Both patients returned to their normal baseline within 2 to 3 weeks. These cases suggest that CMTX patients are at risk for developing an acute, transient, neurological syndrome when they travel to places at high altitudes and return to sea level. Cx32 mutations may cause central nervous system dysfunction by reducing the number of functioning gap junctions between oligodendrocytes and astrocytes, making both cells more susceptible to abnormalities of intercellular exchange of ions and small molecules in situations of metabolic stress.     

X‐linked Charcot‐Marie‐Tooth type 1: stroke‐like presentation of a novel GJB1 mutation

X‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap‐Junction Beta‐1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation‐carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29‐year‐old man with CMTX1 who, at 16 years, showed short‐lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2‐day period, with concurrent white matter hyperintensity on MRI. These “stroke‐like” episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.     

Corticospinal tract MRI hyperintensity in X-linked Charcot-Marie-Tooth Disease.

In X-linked hereditary demyelinating neuropathies (CMTX), caused by mutations in Connexin 32, mild subclinical CNS involvement is not unusual. We present a young male patient suffering from genetically proven CMTX who presented with permanent bilateral corticospinal tract hyperintensities in cranial MRI -- a finding previously described to be characteristic for amyotrophic lateral sclerosis. MRI seems to be able to visualize corticospinal tract abnormalities, even if subclinical, in CMTX.     

Central motor and sensory pathway involvement in an X-linked Charcot-Marie-Tooth family

The aim of the present study was to investigate the subclinical involvement of the central nervous system (CNS) in an X-linked Charcot-Marie-Toth (CMTX) family. MATERIAL AND METHODS: Seven subjects, all members of one family with a C.462T > G connexin 32 (Cx32) mutation were investigated by Blink reflex, Somatosensory evoked potentials (SEP) and Transcranial magnetic stimulation (TMS). There were five clinically symptomatic for CMT neuropathy (four male and one female) and two asymptomatic (female) subjects. RESULTS: Subclinical CNS involvement was observed in all, symptomatic and asymptomatic subjects. CONCLUSION: This is the largest CMTX neuropathy family investigated for CNS involvement. Electrophysiological involvement of the CNS in every examined member of this family was observed, raising the question of a more systematic involvement of the CNS in CMTX disease.     

X‐linked hereditary motor sensory neuropathy (type 1) presenting with a stroke‐like episode

X‐linked hereditary motor sensory neuropathy type 1 (CMTX 1) is caused by mutation in the GJB1 gene that codes for the connexin 32 protein. Central nervous system involvement with or without white matter changes on magnetic resonance imaging (MRI) has rarely been reported in this condition. We report the case of a 7‐year‐old, previously well male who presented with a stroke‐like episode that manifested as left hemiparesis and dysphasia. An initial brain MRI showed white matter signal changes affecting the corpus callosum and periventricular areas with a posterior predominance. Our patient made a complete clinical recovery in 36 hours. Clinical examination at this stage showed no evidence of a peripheral neuropathy. A repeat brain MRI 6 weeks later showed almost complete resolution of the changes seen initially. Subsequent investigations showed a Val177Ala mutation in the GJB1 gene. This mutation has so far not been described in the Caucasian population and has been only described once before. Electrophysiological studies showed a mixed demyelinating and axonal sensorimotor neuropathy in keeping with CMTX 1. Five months after the initial presentation our patient developed clinical evidence of a peripheral neuropathy in the form of absent ankle reflexes, weak dorsiflexors, and evertors of both feet.     

Episodic neurological dysfunction in hereditary peripheral neuropathy

Episodic transient neurological symptoms are an important set of problems presenting to a neurologist in his routine practice. Occasionally, detailed clinical history including past and family history supplemented with focused examination can bring out a rare cause for such symptoms. We describe in this report in a young male presenting with episodic focal neurological dysfunction, with family history of similar episodes in mother and brother. Examination showed features of pes cavus and peripheral neuropathy for which patient was asymptomatic. Mother and brother were established cases of hereditary neuropathy. Imaging on multiple occasions showed reversible white matter abnormalities. Clinical suspicion of X-linked Charcot-Marie-Tooth disease type 1 (CMT1X) was confirmed with detection of mutation in Gap Junction B1 (GJB1) gene, which codes for connexin 32 protein (c.425G>A; p.R142Q hemizygous mutation). Though this mutation has been already reported in CMTX patients, it has not been associated with transient neurological dysfunctions. This is probably the first reported case of CMTX patient with transient neurological dysfunction from India, whose family members had similar episodes.     

X-linked motor and sensory neuropathy with pyramidal signs and cerebral white matter lesions

We report two brothers with hereditary motor and sensory neuropathies and pyramidal signs. Electrophysiological evaluation revealed polyneuropathy and involvement of the central motor, somatosensory, and auditory pathways. Brain magnetic resonance imaging studies showed diffuse white matter lesions, and sural nerve biopsy identified a reduction in the large myelinated nerve fibers. The patients' mother and sister exhibited similar, but milder neurologic findings suggesting that the genetic defect may be X-linked; however, a point mutation in the connexin 32 gene was negative.     

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.     

Central nervous system involvement in hereditary neuropathy with liability to pressure palsies: description of a large family with this association

OBJECTIVE: To describe a large family with hereditary neuropathy with liability to pressure palsies associated with central nervous system demyelination. DESIGN: We examined the 18 members of a pedigree. Genetic analysis was performed on 15 subjects, standard nerve conduction studies on 10 subjects, and brain magnetic resonance imaging studies on 8 subjects. RESULTS: Hereditary neuropathy with liability to pressure palsies was confirmed in 9 patients of the pedigree. Brain magnetic resonance imaging findings showed multiple areas of demyelination in 6 of 6 affected members and were normal in 2 of 2 healthy relatives. Magnetic resonance imaging abnormalities were predominantly located in the subcortical frontal white matter. All patients had acute and recurrent nerve palsies, while clinical features of central nervous system involvement were not a characteristic of this pedigree. CONCLUSIONS: We demonstrate that this association, previously reported in sporadic cases, is not coincidental. Therefore, patients with hereditary neuropathy with liability to pressure palsies can present central nervous system white matter lesions, and the role of the PMP22 (peripheral myelin protein 22) gene deletion in the central nervous system should be further studied.     

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.     

White matter alteration in a patient with Graves' disease

A case of Graves' disease with white matter abnormalities is presented here. The diagnosis as Graves' disease was made when the patient was 5 years old, and a subtotal thyroidectomy was performed when she was 10. Her neurological symptoms began at age 19 with paresthesia of her legs and lower body. Cranial magnetic resonance imaging was normal; thoracic magnetic resonance imaging revealed demyelinating lesions. Intravenous pulse steroid therapy improved her symptoms. Ten months later she described dizziness, lower body paresthesia, and ataxia. Both her cranial and thoracic magnetic resonance imagings revealed demyelinating lesions. After pulse steroid therapy, glatiramer acetate therapy was initiated with diagnosis of an autoimmune multiphasic demyelinating syndrome. Five months later, she presented with right-sided mild optic neuritis followed by rapid spontaneous remission. Antithyroglobulin antibody levels remained normal; antithyroid peroxidase antibody level was high. This presents a rare case of Graves' disease associated with multiphasic demyelinating autoimmune syndrome.     

A novel Cx32 mutation causes X-linked Charcot-Marie-Tooth disease with brainstem involvement and brain magnetic resonance spectroscopy abnormalities

Abstract The objective of this study was to study genetic and phenotypic features of a family with X-linked Charcot-Marie-Tooth consisting of a healthy father, affected mother, two affected sons and one healthy one. A detailed electrophysiological and neuroimaging study, along with sequencing of the Cx32 gene, was performed in all family members. A novel Cx32 123 G>C mutation, determining an aminoacid variation (Glu41Asp), was found in the mother and the affected sons. An alteration in brainstem evoked potentials was found in the mother and one affected son. The affected son, who underwent magnetic resonance imaging, showed symmetrical hyperintensities in paratrigonal white matter, not found in his heterozygous mother, while both subjects exhibited alterations in brain metabolite ratios derived from localised proton-magnetic resonance spectroscopy. These data extend previous findings about central nervous system involvement in Cx32 mutated subjects and further support a functional role of the protein expression in oligodendrocytes.     

Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene

BACKGROUND: X linked dominant Charcot-Marie-Tooth disease (CMT1X) is an inherited motor and sensory neuropathy that mainly affects the peripheral nervous system. CMT1X is associated with mutations in the gap junction protein connexin 32 (Cx32). Cx32 is expressed in Schwann cells and oligodendrocytes in the peripheral (PNS) and in the (CNS) respectively. METHODS: A CMT1X family with a Cx32 mutation was examined clinically and electrophysiologically to determine whether PNS, or CNS, or both pathways were affected. RESULTS: In a CMT1X family a novel mutation (Asn205Ser) was found in the fourth transmembrane domain of Cx32. The patients showed typical clinical and electrophysiological abnormalities in the PNS, but in addition visual, acoustic, and motor pathways of the CNS were affected subclinically. This was indicated by pathological changes in visually evoked potentials (VEPs), brainstem auditory evoked potentials (BAEPs), and central motor evoked potentials (CMEPs). CONCLUSIONS: These findings underscore the necessity of a careful analysis of CNS pathways in patients with CMT and Cx32 mutations. Abnormal electrophysiological findings in CNS pathway examinations should raise the suspicion of CMTX and a search for gene mutations towards Cx32 should be considered.     

A novel hereditary small vessel disease of the brain

OBJECTIVE: Only few hereditary ischemic small vessel diseases of the brain (SVDB) have been reported so far. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent of them. Herein, we report a family affected by a SVDB distinct from CADASIL. METHODS: After the occurrence of a small deep infarct associated with white matter lesions both in a 46-year-old man and in his 52-year-old sister, clinical and neuroimaging investigations were conducted in 13 of their relatives originating from Portugal. Other investigations included (1) skin biopsy immunostaining with a Notch3 monoclonal antibody, (2) sequencing of the 23 exons encoding the epidermal growth factor-like domains of the NOTCH3 gene, and (3) a NOTCH3 locus haplotype analysis. RESULTS: Diffuse white matter hyperintensities were observed on T2-weighted magnetic resonance imaging (MRI) in six individuals. In contrast with MRI results in the father and paternal uncle of the proband who were hypertensive, white matter lesions were extensive in the mother who had no vascular risk factor. MRI data in four asymptomatic family members together with the results in the two initial cases were suggestive of an underlying hereditary small vessel disease of the brain. Skin biopsy and NOTCH3 gene mutation screening were negative. Haplotype analysis excluded the NOTCH3 locus. INTERPRETATION: These data strongly suggest that this family is affected by a novel hereditary small vessel disease of the brain and that the mutated gene is distinct from NOTCH3.     

Chronic inflammatory demyelinating polyradiculoneuropathy associated with central nervous system involvement--as compared to multiple sclerosis

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with central nervous system (CNS) demyelinating lesions has recently been reported to mimic multiple sclerosis (MS). In this paper, a series of patients with CIDP were examined to see if they had CNS involvement. CIDP patients with CNS lesions were then compared to patients with MS with peripheral nervous system (PNS) involvement for similarities. CNS and PNS involvement were detected by clinical symptoms, neurological findings, neuro-otological and neuro-ophthalmological tests, electrophysiological examinations such as electroencephalography, evoked potentials, blink reflex, conventional peripheral nerve conduction studies and electromyography, as well as computed tomography and magnetic resonance imaging (MRI). There were 7 of 17 CIDP patients with CNS involvement, but only 2 of 59 MS patients with PNS lesions were found. The rate of CIDP with CNS involvement (41.2%) was higher than that of MS with PNS lesions (3.4%). The CNS signs and symptoms of 7 CIDP patients were not so constant as their PNS symptoms, and consisted of 1 case with optic neuritis, 4 cases with cerebellar atxia and/or nystagmus, and 3 cases with spinal symptoms. These signs and symptoms are all well known in MS. Prolonged latencies on evoked potentials and high signal white matter lesions on T2 weighted MRI, indicating demyelinating CNS lesions were also similar to those found in MS. The CNS involvement in those patients with CIDP was therefore similar in character to those found in MS, but was far less severe than the PNS finding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peripheral neuropathy as initial sign of mitochondrial disorder

Charcot‐Marie‐Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into demyelinating (type 1) and axonal (type 2) neuropathies. The form of Charcot‐Marie‐Tooth neuropathy that maps to Xq13 may present mild electrophysiological changes (NCV > 40 M/s), mixed neuropathy (NCV: Intermediate (30–40 M/s), or demyelinating neuropathy (NCV: Slow (<37 M/s). On molecular grounds, CMTX is caused by mutations in GJB1 gene, coding for Connexin 32 protein. A 42‐year‐old man, with no other affected family members, was clinically evaluated for CMT. Three years ago he noticed thumb abductor atrophy and then leg muscle atrophy. He presented with hand and leg muscle atrophy, bilateral pes cavus, areflexia, and apallesthesia. The median and ulnar motor NVC were 35–38 m/s, and the median sensory NVC was 35 m/s. Both motor and sensory nerve action potentials were markedly reduced. After exclusion of CMT1A and 1B, analysis for CMTX was performed. The mutation screening of GJB1 gene showed a 9bp insertion upstream the 194ATG codon (Met194) with preservation of the downstream sequence. The three new amino acids (Thr‐Val‐Phe) inserted are localized between the end of the second extracellular domain and the beginning of the fourth transmembrane domain. This is the first 9bp insertion found in GJB1 gene; a genotype‐phenotype correlation may be deduced.     

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.