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At least 811 records · Page 45Linked to original sources
PubMed1987

Genetic linkage relationships of Charcot-Marie-Tooth disease (HMSN-Ib) to chromosome 1 markers.

Hereditary motor and sensory neuropathy-Ib (HMSN-Ib) is a common autosomal dominant disorder linked to the Duffy blood group locus on human chromosome 1. The gene for antithrombin III (AT3) is also located on the long arm of chromosome 1. Using a DNA restriction fragment length polymorphism for AT3, we have investigated the genetic linkage relationship of all three markers (HMSN-Ib, Duffy, and AT3) in two affected families. Neither HMSN-Ib nor Duffy was tightly linked to AT3. The loci for both HMSN-Ib and Duffy must be close to the centromere on chromosome 1, but precise localization and gene order require study of additional markers and more families.

Adolescent↗
PubMed1993

Allelic heterogeneity in hereditary motor and sensory neuropathy type Ia (Charcot-Marie-Tooth disease type 1a).

The most frequently found mutation in autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) is a large duplication on chromosome 17p11.2 containing probes VAW409R3, VAW412R3, and EW401. We investigated a family with severe features of HMSN I, and demonstrated the absence of this duplication by a quantitative analysis of the hybridization signals of VAW409R3 and VAW412R3. Linkage analysis, however, revealed linkage with probe VAW409R3a (lod score, 3.22), which demonstrates the existence of allelic heterogeneity within the HMSN Ia locus. These findings have implications for clinical practice and for investigating the identity of the HMSN Ia gene.

Adult↗
PubMed1991

Three modality evoked potentials in Charcot-Marie-Tooth disease (HMSN-1).

Sixteen patients with dominant hereditary motor-sensory neuropathy type I (HMSN I), members of 5 families, underwent trimodality evoked potential studies. All patients had clinically normal optic nerves. History of deafness was present in 3 patients and sensory-neural hearing defect was found in 5 of 7 patients in whom audiometry was obtained. In 43.7 percent of the subjects significant prolongation of P100 of the VEP was found. Prolongation of N19 of the SEP was found in all 12 subjects examined. Significant bilateral prolongation of peak I of the ABEP was found in 37.5 percent of the subjects and in 50 percent of the ears examined: these findings indicated that in addition to peripheral nerves, the myelin of the optic and cochlear nerves is also affected in HMSN type I.

Adolescent↗
PubMed1981

Trigeminal and facial nerve involvement in Charcot-Marie-Tooth disease. An electrodiagnostic study.

The electrically and optically elicited orbicularis oculi reflex (OOR) and facial nerve latency were investigated in eight patients from three families. Each had autosomal dominant peroneal muscular atrophy. In a family with the dominantly inherited hypertrophic type markedly delayed latencies of the early reflex component of the OOR were found while the facial nerve had remained unaffected. These findings were interpreted as an indicator for supraorbital nerve involvement. In the other two investigated families of hypertrophic and neuronal type, a prolonged facial nerve latency was demonstrable. In these cases the latency of the optically evoked blink reflex was also delayed, while the latency of the early reflex component of the OOR was within normal limits or only slightly delayed. It is assumed that the different degree of cranial nerve involvement in these families is the expression of their genetically determined peculiarities.

Adolescent↗
PubMed1986

Heterogeneity of hereditary motor and sensory neuropathy type I (HMSN I): electroneurographical findings, visual evoked potentials and blood group markers in a family with Charcot-Marie-Tooth disease (CMT).

21 members of a large kinship with autosomal dominant CMT showing typical clinical findings were studied electroneurographically, with visual evoked potentials (VEP) and with blood group markers. In clinically affected members, the mean motor nerve conduction velocity (NCV) of the median nerve was found to be 17.5 m/s (SD 2.4). Contrary to previous genetic linkage studies in CMT families with comparable slow motor NCV, blood group typing in this family excluded close linkage of HMSN I to Duffy locus, which may indicate the existence of another subgroup in CMT neuropathy. Mean latencies of VEP, in both clinically affected and unaffected members, showed no pathological alterations when compared to normals. There was no correlation between NCV and P 100 latencies, but significant variation of P 100 latencies in families of twin brothers could be demonstrated. As already suggested by other authors, our findings may also indicate heterogeneity in this neuropathy.

Charcot-Marie-Tooth Disease↗
PubMed1996

Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease.

In seven unrelated patients with a demyelinating motor and sensory neuropathy, we found mutations in exons 2 and 3 of the P0 gene. Morphologic examination of sural nerve biopsy specimens showed a demyelinating process with onion bulb formation in all cases. In four patients, ultrastructural examination demonstrated uncompacted myelin in 23 to 68% of the myelinated fibers, which is in agreement with the widely accepted function of P0 as a homophilic adhesion molecule. Three patients showed normal compact myelin, but morphology was dominated by the abundant occurrence of focally folded myelin. The two divergent pathologic phenotypes exemplify that some mutations act differently on P0 protein formation or function than others, which is probably determined by site and nature of the mutation in the P0 gene.

Adolescent↗
PubMed1989

Somatosensory evoked potentials in Charcot-Marie-Tooth disease.

SEPs by median nerve stimulation have been performed in 18 adult patients (12 males and 6 females) affected by CMTD (type I, 13 patients; type II, 5 patients). All patients underwent MCV studies (median, ulnar, peroneal nerve), SCV studies (median and sural nerve), VEP, BAEP. N9 and N13 peaks were not detectable in 7/13 and 5/13 cases (HMSN type I) while cortical N19 were always recorded. Latency values of all responses were moderately or markedly delayed in all cases with HMSN type I, but proved normal or slightly delayed in HMSN type II cases. The prolonged latencies were mainly related to slowing of peripheral conduction. N9-N13 inter-peak was abnormally prolonged in 2 cases and N13-N19 in 2 other cases; both were prolonged in another case. In another 3 cases an abnormal BAEP was recorded. The few patients with abnormal CCT and BAEP probably belong to a borderline form between HMSN and hereditary ataxias.

Adult↗
PubMed1990

[The nosological situation of hereditary motor and sensory neuropathies (HMSN, Charcot-Marie-Tooth disease, neural muscular atrophy)].

Hereditary motor and sensory neuropathies (HMSN) comprise a heterogeneous group of disorders. Since phenotypic manifestations are similar in most families, classification is based on differences in the mode of inheritance, onset and progression of the disease, nerve conduction velocity and nerve biopsy findings. Autosomal dominant, autosomal recessive, X-dominant and X-recessive forms, substantial intrafamilial differences, intermediate forms and the combination of neuropathies with spinocerebellar degeneration within one and the same sibship have been described. On the basis of selected own cases it is demonstrated that there is a broad spectrum of functional and structural abnormalities depending on the progression of the disease and on the site of nerve studied (proximal or distal part). Both the neuronal and hypertrophic variants begin with axonal degeneration of the dying back type followed by segmental demyelination and variable degrees of hypertrophic Schwann cell proliferation. Constantly, posterior columns of the spinal cord reveal fiber loss. Since the molecular basis of the different forms remains to be clarified it seems to be of greater interest to underline common features than to separate seemingly different nosological entities. It is suggested that the latter are partly the result of a selection of cases with a variable severity. Evidently, the syndrome of myatrophic ataxia comprises apart from "pure" HMSN with unsignificant degenerations of posterior columns and "pure" Friedreich's ataxia with mild peripheral nerve fiber loss intermediate forms.

Adult↗
PubMed1997

[Heterogeneity in breakpoint location of duplication in Japanese Charcot-Marie-Tooth disease type 1A].

The crossover breakpoints for CMT1A are located in the CMT1A-REP repeat flanking a 1.5 Mb region of chromosome 17p11.2-12. We analysed the relationship between the breakpoint locations and clinical phenotypes in 21 Japanese patients with CMT1A duplication. The CMT1A-REP region was divided in 5 regions, A, B, C, D and E, based on restriction site differences between the proximal and distal CMT1A-REP repeats (Kiyosawa et al., HMG, 1995). The breakpoint location within the CMT1A-REP was heterogeneous, the frequency distribution of which was hightest in the B/C region and similar to that in Caucasian patients. The clinical phenotypes, such as foot deformity, muscular weakness and atrophy, sensory impairment and electrophysiologic finding, were extensively variable among the CMT1A patients with PMP22 gene duplication. The location of breakpoints was not related to the clinical phenotypes, suggesting that there is a factor other than the location of the crossover breakpoint, which influences phenotypic manifestation of CMT1A.

Adult↗
PubMed1998

Charcot-Marie-Tooth disease and Noonan syndrome with giant proximal nerve hypertrophy.

We report a family with Noonan syndrome (NS), giant proximal nerve hypertrophy, and hereditary motor sensory neuropathy type 1A (HMSN1A). Five members of a family were found to have clinical features of NS. In all cases, NS was associated with giant hypertrophy of proximal nerves and two individuals also exhibited café-au-lait spots. In one case, an 8-to-10-cm diameter pelvic mass was shown to be a grossly hypertrophied nerve, with histologic features of demyelination and remyelination. In addition, four of five family members affected with NS were found to have HMSN1A clinically and by demonstration of constitutional HMSN1A duplication on DNA testing. Linkage analysis for NS ruled out the involvement of the neurofibromatosis type 1 gene and the known NS locus in chromosome 12, supporting the existence of an additional NS locus.

Adolescent↗
PubMed2006

Clinical and molecular analysis of X-linked Charcot-Marie-Tooth disease type 1 in Spanish population.

From 1995 to 2004, 979 families with hereditary peripheral neuropathy were referred to the Genetic Diagnosis Center. Using single-strand conformation analysis (SSCA), the connexin 32 gene was analysed in all the patients from 498 families with sporadic or dominant inheritance with no male-to-male transmission and absence of the 17p2 duplication or deletion. Affected males had pes cavus, distal leg weakness, muscular distal atrophy, areflexia and distal sensory loss. The 106 families in which SSCA revealed abnormal migration electrophoresis were directly sequenced. We found 34 families (59 patients) with mutations in connexin 32 gene. In electrophysiological studies, 58.8% families presented slow and 14.7% intermediate nerve conduction velocities. Molecular findings revealed that codon 164 (29.4 +/- 15.3%) and the second extracellular (EC2) domain (44.1 +/- 16.6%) were the most frequently affected codon and domain of the connexin 32. Six novel mutations, Leu39fs, Glu47Gly, His153fs, Cys179Tyr, Cys201Phe and Ser211fs, were found in our study.

Amino Acid Sequence↗
PubMed1999

Overview of Charcot-Marie-Tooth disease type 1A.

Type 1A CMT disease is most commonly due to a segmental duplication on chromosome 17p11.2, leading to the presence of an extra copy of the gene for peripheral myelin protein 22 (PMP22). Inheritance is autosomal dominant in pattern. Analysis of nerve biopsies suggests that the disorder is caused by increased gene dosage. Occasionally CMTIA results from point mutations in the PMP22 gene. Onset of symptoms in cases with a duplication is usually in the first decade of life; slowing of nerve conduction velocity is evident from the age of 2 years. Active demyelination is restricted to childhood. It leads to hypertrophic "onion bulb" changes and is accompanied and followed by progressive axonal loss. The commonest clinical phenotype is the CMT syndrome with distal muscle wasting and weakness, tendon areflexia, usually mild sensory loss, and foot deformity. Other phenotypes include the Roussy-Lévy syndrome, in which postural tremor and ataxia are associated, and cases with severe distal sensory loss and acrodystrophic changes.

Charcot-Marie-Tooth Disease↗
PubMed1983

[Anatomo-clinical study of a neuronal form of Charcot-Marie-Tooth disease].

A 79 years-old man suffered gait disturbance for more than ten years. During the last year the gait worsened. Twenty days after having developed a right hemiparesis, he died from cardiorespiratory failure. Neurological signs were characterized by cogwheel rigidity, distal paresis and amyotrophy of the legs. E.M.G. demonstrated a denervation; ulnar conduction velocity was 38 m/s. The sural nerve biopsy showed a loss of myelinated fibres and no onion-bulb-like formations. A sister (72 years) and two nephews (51 and 39 years) also suffer gait disturbance. The E.M.G.'s demonstrate denervation of the legs. The amplitudes of the motor and sensory nerves are reduced and conduction velocities range between 39 and 59 m/s. Pathologic examination of the propositus showed recent left frontal subcortical infarction, partial neuronal depopulation of the substantia nigra and Lewy inclusions. Microscopic examination of the spinal cord showed integrity of the posterior columns, anterior and posterior spinal roots, cauda equina, and of a thoracic posterior root ganglion. The anterior horns showed a mild gliosis and a slight neuronal depopulation with a few pale or atrophic neurons and very rare neuronophagias. This is believed to be the first autopsy report of a dominant sensory motor neuropathy of the neuronal type. The relative integrity of the spinal cord suggests that the peripheral motor and sensory neurons are affected to the greatest degree at their distal extremity.

Aged↗
PubMed2003

Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease?

A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.

Action Potentials↗
PubMed2005

Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA.

How demyelination and remyelination affect the function of myelinated axons is a fundamental aspect of demyelinating diseases. We examined this issue in Trembler-J mice, a genetically authentic model of a dominantly inherited demyelinating neuropathy of humans. The K+ channels Kv1.1 and Kv1.2 channels were often improperly located in the paranodal axon membrane, typically associated with improperly formed paranodes, and in unmyelinated segments between internodes. As in wild-type nerves, Trembler-J nodes contained Nav1.6, ankyrin-G, betaIV-spectrin, and KCNQ2, but, unlike wild-type nerves, they also contained Kv3.1b and Nav1.8. In unmyelinated segments bordered by myelin sheaths, these proteins were clustered in heminodes and did not appear to be diffusely localized in the unmyelinated segments themselves. Nodes and heminodes were contacted by Schwann cells processes that did not have the ultrastructural or molecular characteristics of mature microvilli. Despite the presence of Nav1.8, a tetrodotoxin-resistant sodium channel, sciatic nerve conduction was at least as sensitive to tetrodotoxin in Trembler-J nerves as in wild-type nerves. Thus, the profound reorganization of axonal ion channels and the aberrant expression of novel ion channels likely contribute to the altered conduction in Trembler-J nerves.

Amino Acid Substitution↗
PubMed1997

Central motor pathway evaluation using magnetic coil stimulation in hereditary motor and sensory neuropathy type I (HMSN type I, Charcot-Marie-Tooth disease).

Central Motor Conduction Time (CMCT) was investigated in 18 patients (5 m, 13 f; age range: 11-69 yrs) with clinical and electrophysiological features of HMSN type I, using Magnetic Coil (MC) stimulation. No one exhibited clinically pyramidal signs. Brain stimulation Motor Evoked Potentials (MEPs), recorded monolaterally from the left abductor digiti minimi (ADM) and tibialis anterior (TA) muscles, were evoked in all patients from upper extremities and absent in 11.1% from lower limbs. Total Motor Conduction Time (TMCT), as well as Peripheral Motor Conduction Time estimated by either magnetic nerve root stimulation (mag-PMCT) or F-wave latency values (F-PMCT), were markedly delayed in all patients. Central Motor Conduction Time was calculated by subtracting both the latency of mag-PMCT (mag-CMCT) and F-PMCT (F-CMCT) from that one obtained by cortical stimulation. F-CMCT was abnormal in 22.2% in upper extremities and in 27.8% patients from lower extremities, whereas mag-CMCT in 22.2% from ADM muscles and in 33.3% from TA muscles. Furthermore, CMCT to both methods was not possible to evaluate in 5.6% from upper and lower extremities and following magnetic root stimulation in 11.1% from lower limbs. These findings prove lower motor neuron involvement, in agreement with electroneurographic data, and suggest a possible central motor pathways impairment, even in patients without any clinical evidence, but they cannot explain which is the underlying pathophysiological mechanism, a true upper motor neuron involvement or an abnormal spinal motor neuron excitability.

Adolescent↗
PubMed1994

[A familial Charcot-Marie-Tooth disease type 1B (CMTD1B) manifesting a new mutation of myelin P0 gene].

A 15-year-old girl (case 1) was admitted to our hospital because of progressive muscle weakness of the lower limbs and numbness of the upper limbs. She noted these symptoms beginning at 13 years of age. Neurological examination revealed that deep tendon reflexes were absent and hypesthesia of touch and pain sensation were distributed in a glove-and-stocking pattern. Muscle weakness and atrophy were predominantly present in the distal portions of the extremities. There were obvious pes cavus and champagne-bottle shape deformities. The motor conduction velocity of the median nerve was markedly delayed and sensory potentials were not evoked in any nerves examined. Lumbar MRI showed thickening of the nerve radices. Cranial MRI showed thickening of the acoustic nerves, as well. Histological studies of a biopsied sural nerve revealed a marked decrease in the number of myelinated and unmyelinated fibers and remarkable onion bulb formation. The patient's clinical manifestations and histological findings were more severe than that seen in the usual case of CMT1A. Her mother (case 2, 39 years old) had similar neurological and electrophysiological findings. DNA duplication encoding peripheral myelin protein 22, was not detected in either case 1 or 2. Sequencing of DNA from these patients revealed the presence of a mutant allele containing an A- to G-substitution of nucleotide 245, which replaced tyrosine with cysteine in the extracellular Ig-domain of the P0 protein.

Adolescent↗
PubMed1999

Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.

We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females 7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.

Charcot-Marie-Tooth Disease↗