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PubMed2004

Charcot-Marie-Tooth disease type 1A: a clinical, electrophysiological, pathological, and genetic study.

Various clinical manifestations, electrophysiological findings, and sural nerve biopsies are reported in a Taiwanese family with type 1A Charcot-Marie-Tooth disease (CMT-1A). In addition, molecular genetic studies for duplication of the peripheral myelin protein 22 (PMP22) gene were also performed. There were 3 patients (2 men and 1 woman) with ages at onset ranging from 37 to 44 years. The onset of symptoms was insidious, and the neurological manifestations included distal muscle weakness and wasting, mild sensory loss, and hyporeflexia or areflexia. The severity of clinical manifestations varied from mild to severe, although with very prominent demyelinating polyneuropathy in electrophysiological studies. The sural nerve biopsy study revealed demyelination and an onion-bulb appearance. The molecular genetic studies confirmed duplication of the PMP22 gene in chromosome 17p11.2-12. We conclude that the clinical presentations, electrophysiological studies, and pathological studies as well as the molecular genetic analysis remain important in the clinical diagnosis of CMT-1A.

Adult↗

PubMed2000

Clinico-electrophysiological correlation of extensor digitorum brevis muscle atrophy in children with charcot-marie-tooth disease 1A duplication.

The purpose of the study is to describe the electrophysiologic abnormalities accounting for the appearance and progression of extensor digitorum brevis (EDB) muscle atrophy in Charcot-Marie-Tooth-disease type 1A (CMT-1A) children. Twelve children with CMT-1A duplication were serially evaluated. Initial ages of clinico-electrophysiological exams ranged from 1 month to 4 years (mean: 2 years) and final ages from 6 to 23 years (mean: 13). All subjects had two or more electrophysiological studies of the peroneal nerve. EDB atrophy was observed in two out of 12 (17%) patients by the age of 5, in eight out of ten (80%) examined between 5 and 9 years, and in all eight (100%) patients who had reached the second decade at the end. Nerve conduction maturation was systematically abnormal, but by age of 5 the mean values of nerve conduction parameters of peroneal nerve did not significantly differ from those in older patients. Compound muscle action potential (CMAP) amplitudes of EDB were reduced in 42% of cases initially and 100% upon last exam. Furthermore, a constant finding throughout the study was progressive attenuation of CMAPs, these becoming unobtainable in four cases. EDB muscle atrophy in CMT-1A children is an age-dependent sign which is accounted for by gradual reduction of the distal peroneal nerve CMAP amplitudes.

Action Potentials↗

PubMed1998

Autosomal dominant Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies: detection of the recombination in Slovene patients and exclusion of the potentially recessive Thr118Met PMP22 point mutation.

Charcot-Marie-Tooth disease type 1 (CMT1) and hereditary neuropathy with liability to pressure palsies (HNPP) are the most frequent autosomal dominantly inherited disorders of the peripheral nervous system. The recessive inheritance is observed only exceptionally. Unequal crossing-over of misaligned flanking CMT1A-REP elements on chromosome 17p11.2 is the most frequent cause of the CMT1A duplication and of the reciprocal deletion in HNPP patients. Recently a recombination was noted. In our study 71 Slovene CMT1 patients from 36 families, 12 HNPP patients from 6 families and their 31 healthy relatives were analysed for the presence of these recombination mutations. In 29 of 36 unrelated CMT1 (81%) and in all 6 unrelated HNPP patients the duplication or the deletion, on chromosome 17p11.2-12 was detected. In 26 out of 29 duplication patients (CMT1A) (90%) a 3.2 kb EcoRI/SacI duplication junction fragment was observed. The analogous 7.8 kb EcoRI/EcoRI deletion junction fragment was found in 4 out of 6 unrelated HNPP deletion patients (67%). Overall we found a recombination mutation inside the in 86% of unrelated Slovene CMT1A and HNPP patients. One hundred and thirty-six DNA samples of the CMT1 and HNPP patients and of the healthy controls were negative for the potentially recessive Thr118Met PMP22 amino acid substitution. Dominantly inherited CMT1A duplications and HNPP deletions on chromosome 17p11.2 are thus, as in most other European countries, the most common mutations in Slovene CMT1 and HNPP patients. No signs of polymorphism or of potentially recessive mutation were found at the specific Thr118Met PMP22 site.

Charcot-Marie-Tooth Disease↗

PubMed2006

Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study.

OBJECTIVE: To describe a large pedigree with Charcot-Marie-Tooth disease type 1A (CMT1A) duplication in which severe pelvic and thigh musculature weakness occurred in two patients, detected by analysing the leg muscle atrophy pattern on magnetic resonance imaging (MRI). METHODS: The pedigree comprised 18 patients, aged between 15 and 85 (median 46) years, who were serially evaluated for up to three decades. All 18 patients and 13 non-affected at-risk people underwent electrophysiological examination. An MRI study of lower limb musculature was carried out in four patients. Three patients underwent sural-nerve biopsy. Genetic testing was carried out in 17 patients and in all 13 at-risk normal people. RESULTS: Fourteen patients were asymptomatic or slightly disabled. The two oldest patients, aged 84 and 80, showed a moderate phenotype. Two other patients, aged 70 and 53, showed late-onset and gradually progressive peroneal paresis extending up to the thigh and pelvic musculature, resulting in waddling gait. MRI scans of all three patients with a mild phenotype showed subtle and subclinical fatty infiltration of calf anterolateral muscle compartments, with thigh muscle involvement in one patient, and extensive atrophy of intrinsic foot muscles. In the youngest patient with proximal leg weakness, the MRI scan showed massive fatty atrophy of all the calf muscles, posteromedial thigh muscle compartments, and internal and external hip rotator muscles. Sural-nerve biopsy specimens showed hypertrophic neuropathy with no superimposed inflammation. Good correlation was seen between electrophysiological and genetic testing. CONCLUSIONS: Late in the clinical course, a small proportion of patients with CMT1A develop severe proximal leg weakness, and long-term follow-up is essential for its detection. MRI scans may show subclinical involvement of the thigh musculature.

Adolescent↗

PubMed2001

Clinical and molecular studies in a family with probable X-linked dominant Charcot-Marie-Tooth disease involving the central nervous system.

OBJECTIVE: To investigate the clinical and molecular characteristics of an apparently X-linked dominant form of Charcot-Marie-Tooth (CMT) disease in a family with central nervous system involvement and additional features. BACKGROUND: Charcot-Marie-Tooth disease may be inherited as an autosomal dominant, autosomal recessive, or X-linked trait. In the X-linked dominant form of CMT, females demonstrate milder clinical and electrophysiological features compared with their male relatives. METHODS: Clinical and related examinations were performed in 4 affected individuals from a family with a novel form of CMT affecting males more severely than females. DNA analysis of the connexin 32 (Cx32) gene and proteolipid protein (PLP) gene was performed. We genotyped 3 members of the family to determine which regions of the X chromosome were inherited discordantly in the affected and unaffected brothers. RESULTS: Clinical studies revealed significant spasticity, hyperreflexia, and delayed central conduction, in addition to peripheral neuropathy. Nerve conduction velocities were slower in the affected males than in the affected females. Direct DNA sequencing of the Cx32 coding region and neural-specific promoter were normal. A PLP null mutation was excluded. Levels of very long chain fatty acids were normal. Genotyping studies of the X chromosome supported X-linked inheritance of the neuropathy. CONCLUSIONS: This family differs from others with hereditary motor and sensory neuropathic diseases by the presence of upper motor neuron signs and additional features. The clinical features and inheritance pattern are consistent with X-linked dominant inheritance or autosomal dominant inheritance.

Adult↗

PubMed1994

Peripheral myelin protein-22 expression in Charcot-Marie-Tooth disease type 1a sural nerve biopsies.

Peripheral myelin protein-22 (PMP22) is expressed in myelinating Schwann cells and shows significant homology to murine growth arrest-specific gene gas3. Charcot-Marie-Tooth disease type 1a (CMT1a) is a common hereditary demyelinating neuropathy. Recently it was demonstrated that the gene for PMP22 is duplicated in CMT1a patients. A gene dosage mechanism has been postulated to cause CMT1a. According to this hypothesis, the increase in copy number of PMP22 gene would lead to an elevated expression of PMP22 and thereby cause the demyelinating phenotype of CMT1a. In the present communication we analyzed PMP22 mRNA and protein expression in sural nerve biopsies from CMT1a patients and normal controls. We show that PMP22 mRNA expression in CMT1a is not uniform. We found both elevated as well as normal PMP22 mRNA levels in patients. Interestingly, the highest PMP22 mRNA level was found in the least affected patient. In contrast to the mRNA levels, PMP22 was clearly reduced in all CMT1a patients as shown by immunohistochemistry. Thus the CMT1a phenotype may not be strictly correlated with increased PMP22 mRNA and protein expression. Possible roles of PMP22 in the pathogenesis of CMT1a are discussed.

Biopsy↗

PubMed1988

Charcot-Marie-Tooth disease and cardiac arrhythmias.

A child with several episodes of supraventricular tachycardia was treated in our department from birth to the age of seven years. At this age a diagnosis of Charcot-Marie Tooth disease was made on the basis of the results of clinical and neurophysiological examinations, blood analysis and a neuromuscular biopsy. The association between sensorimotor neuropathies and cardiac involvement is controversial, especially at pediatric ages. We describe a case presenting this association.

Charcot-Marie-Tooth Disease↗

PubMed2000

An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val).

OBJECTIVES AND METHODS: Seven families were studied with an axonal form of Charcot-Marie-Tooth disease (CMT) associated with mutations in the peripheral myelin protein zero (MPZ) gene-Thr124Met or Asp75Val. RESULTS: Patients with these mutations commonly showed relatively late onset sensorimotor neuropathy predominantly involving the lower limbs. Sensory impairment typically was marked, and distal muscle atrophy and weakness were also present in the legs. Adie's pupil and deafness were often present, and serum creatine kinase concentrations were often raised irrespective of which MPZ mutation was present. Relatively well preserved motor and sensory nerve conduction velocities contrasted with reduced or absent compound muscle action potentials and sensory nerve action potentials. Axonal change with marked axonal sprouting was seen in sural nerve specimens. CONCLUSION: The similar associated clinical findings suggest that patients with axonal CMT with an MPZ gene mutation share distinctive clinical features.

Adult↗

PubMed1998

Rapid detection of a recombinant hotspot associated with Charcot-Marie-Tooth disease type IA duplication by a PCR-based DNA test.

A 1.5-Mb duplication on chromosome 17p11.2-p12 (CMT1A duplication) caused by a misalignment of the CMT1A repeat sequences (CMT1A-REPs) is associated with Charcot-Marie-Tooth disease type 1A (CMT1A). A hotspot of crossover breakpoints located in a 3.2-kb region of the CMT1A-REPs accounts for three-quarters of the rearrangements in CMT1A patients. We developed a PCR-based diagnostic method to detect a recombination hotspot associated with the CMT1A duplication. Thirty-one CMT1A Chinese patients from different families and 50 healthy people over 65 years of age were studied. Twenty-seven of the 31 cases demonstrated the 3.2-kb hotspot crossover, of which there were two subgroups. The type 1 crossover breakpoint was located at the distal CMT1A-REP around the PmeI site, and accounted for 24 of the 27 cases with a 3.2-kb hotspot crossover in CMT1A duplication patients. The type 2 crossover breakpoint was located at the distal CMT1A-REP around the base 3625 region, accounting for 3 of the 27 cases. The results correlated very well with the results of Southern transfer analysis. This study has a potentially important role in the diagnosis of CMT1A disease.

Charcot-Marie-Tooth Disease↗

PubMed1983

Peripheral and central sensory nerve conduction in Charcot-Marie-Tooth disease and comparison with Friedreich's ataxia.

Somatosensory evoked potentials were recorded in response to stimulation of the median nerve at the wrist and the elbow in 14 cases of Charcot-Marie-Tooth disease (CMTD). Cervical and cortical latencies were used to derive conduction times and velocities over peripheral and central segments of the pathway. Sensory conduction velocities between the wrist and the elbow were distributed bimodally (12-27 m/s and 36-70 m/s), but did not correspond with the bimodality of motor conduction velocity values in 4 cases. Three patients had severely slowed sensory conduction in one arm but only moderate slowing in the other. In the majority of cases sensory conduction was considerably faster from the elbow to the spinal cord than from the wrist to the elbow. This was most apparent in 2 young patients, suggesting that demyelination secondary to axonal degeneration may gradually progress from distal to proximal segments. Compared with a group of Friedreich's ataxia (FA) patients, almost all CMTD cases could be distinguished by a greater degree of peripheral conduction slowing (not significant in FA). In FA there was a much higher incidence of impaired conduction over central segments of the somatosensory pathway, although evidence of this was also seen in 5 CMTD cases. Three of the latter had presented with atypical symptoms suggestive of CNS involvement, and also had delayed visual evoked potentials.

Adolescent↗

PubMed1991

X-linked Charcot-Marie-Tooth disease. A linkage study in a large family by using 12 probes of the pericentromeric region.

Linkage analysis was performed on 41 subjects belonging to a large family with a recurrence of X-linked Charcot-Marie-Tooth disease (CMTX), by using 12 restriction fragment length polymorphism markers mapping in p11-q13. The results are in agreement with previous linkage data. Three new markers that are potentially useful for genetic analysis of CMTX families are described. A more precise estimate of the localization of the disease locus was attempted by multipoint linkage analysis.

Blotting, Southern↗

PubMed1995

X-linked dominant Charcot-Marie-Tooth disease and other potential gap-junction diseases of the nervous system.

Gap junctions play important roles in the exchange of information and metabolites in the nervous system. These roles are highlighted by peripheral neuropathy (X-linked dominant Charcot-Marie-Tooth disease) that is associated with mutations in a gap-junction protein (connexin32), resulting in loss of function, and by somatic dysfunctions where changes in expression, organization or function of gap junctions are associated with neuronal hyper- or hypoexcitability. In this review, the causes and consequences of this gap-junction-related peripheral neuropathy and other pathological conditions of the nervous system, where dysfunctions of junctional communication are considered to play a casual role, are considered.

Charcot-Marie-Tooth Disease↗

PubMed1990

A family with tomaculous neuropathy mimicking Charcot-Marie-Tooth disease.

The appearance of Guillain-Barré syndrome in a 9-year-old girl led to the detection of a hereditary neuropathy in her family. This neuropathy showed clinical and electrophysiological characteristics of Charcot-Marie-Tooth disease. Only nerve biopsy performed in a sister of the proband allowed diagnosis of tomaculous neuropathy which presented unusual clinical, electrophysiological and bioptic aspects.

Biopsy↗

PubMed2006

Crystallization and preliminary X-ray analysis of a native human tRNA synthetase whose allelic variants are associated with Charcot-Marie-Tooth disease.

Glycyl-tRNA synthetase (GlyRS) is one of a group of enzymes that catalyze the synthesis of aminoacyl-tRNAs for translation. Mutations of human and mouse GlyRSs are causally associated with Charcot-Marie-Tooth disease, the most common genetic disorder of the peripheral nervous system. As the first step towards a structure-function analysis of this disease, native human GlyRS was expressed, purified and crystallized. The crystal belonged to space group P4(3)2(1)2 or its enantiomorphic space group P4(1)2(1)2, with unit-cell parameters a = b = 91.74, c = 247.18 A, and diffracted X-rays to 3.0 A resolution. The asymmetric unit contained one GlyRS molecule and had a solvent content of 69%.

Alleles↗

PubMed1995

[Abnormality of PMP-22 gene in Japanese patients with Charcot-Marie-Tooth disease--comparison between Southern blot and polymerase chain reaction analysis in the detection of PMP-22 gene duplication].

We investigated the duplication of the PMP-22 gene in 23 Japanese patients with Charcot-Marie-Tooth disease (CMT) by Southern blot and PCR analysis. To detect duplication of the PMP-22 gene region, PMP-22 cDNA and a polymorphic marker, VAW409R3, located in the region flanking the PMP-22 gene, were used as probes for Southern blot analysis. A marker, 6G1, also located in the PMP-22 flanking region, was amplified using the quantitative PCR method. The signal intensity of the 2.8-kb and 2.7-kb bands of MspI digests probed with VAW409R3 was different in patients with duplication. The ratio of these two bands, measured by densitometry, ranged from 1.75 to 2.13 in the patients with duplication and from 1.01 to 1.15 in those without duplication and in normal controls. The signal ratio of PMP-22 to the reference marker SF85 of BamHI digests ranged from 1.15 to 1.33 in the patients with duplication and from 0.96 to 1.04 in those without duplication, when compared with normal controls assigned a value of 1.0. The ranges of the intensity in these two groups were narrow, but did not overlap. The signal ratio of the PCR products of 6G1 to reference marker D1S80 on quantitative PCR analysis was also measured. The ratio ranged between 1.67 and 2.23 with duplication and between 1.29 and 1.74 without duplication according to the results of Southern blot analysis. However, some patients exhibited overlapping signal intensity in the duplication and non-duplication ranges. Thus, these three methods each has its own advantages and disadvantages in regard to detecting duplication.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed2005

Charcot-Marie-Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles.

MRI is an ideal method for identifying areas of muscle atrophy and fatty infiltration. Studies comparing clinical and MRI features of foot and leg muscle atrophy in Charcot-Marie-Tooth disease type 1A (CMT-1A) duplication are lacking. The aim of this study is to describe clinical and MRI patterns of lower limb amyotrophy in CMT-1A. A total of 10 secondary CMT-1A patients and 1 proband patient with de novo mutation were prospectively evaluated. Ages of patients ranged from 8 to 61 years (median, 24). Disease severity in terms of ability to walk and run was established using a nine-point functional disability scale (FDS). We administered the CMT neuropathy score (CMTNS), based on patient's symptoms, neurological examination and neurophysiological testing. Muscle strength of flexo-extensor ankle and toe muscles was assessed manually with the standard Medical Research Council scale. In all 11 patients, leg MRI study included T1- and T2-weighted spin-echo sequences in coronal and axial planes, and a T1-weighted spin-echo sequence with chemical sift fat suppression before and after paramagnetic contrast agent injection. In seven patients both feet were simultaneously studied in coronal and axial planes. Six patients had pes cavus, an FDS score of 0 (normal), mild CMTNS and normal muscle power of foot flexo-extensors. In these six patients, MRI showed muscle fatty infiltration of intrinsic foot muscles mainly involving the lumbricals, all four leg muscle compartments being preserved. The remaining five patients had FDS scores from 1 (cramps or fatigability) to 3 (walking difficulty), mild to moderate CMTNS and variable weakness of peroneal musculature. In these five patients MRI showed, besides intrinsic foot muscle involvement, variable and distally accentuated fatty infiltration of the lateral, anterior and superficial posterior leg muscle compartments and, to a lesser degree, of the deep posterior compartment. In four patients muscle oedema and post-contrast enhancement was noted. MRI demonstrated fatty infiltration of clinically normal muscles. We conclude that clinical-MRI patterns of lower limb muscle atrophy vary with evolution of semiology. Selective involvement of intrinsic foot muscles is the characteristic pattern of CMT-1A cases with minimal disease signs. Afterwards this pattern usually combines variable involvement of leg muscles. Our findings help to clarity the pathogenesis of pes cavus in the disease.

Action Potentials↗

PubMed1984

[3 cases of scapulo-peroneal neurogenic amyotrophy (Dawidenkow's syndrome). Nosological situation in relation to Charcot-Marie-Tooth disease].

Three cases of neuropathic scapulo-peroneal syndrome are reported. One case was of the hypertrophic type, two were of the neuronal type. The nosological situation of the Dawidenkow syndrome is discussed. Cases of scapulo-peroneal amyotrophy with peripheral neuropathy should be regarded as a topographical variety of Charcot-Marie-Tooth disease.

Adolescent↗

PubMed1990

Genetic mapping of autosomal dominant Charcot-Marie-Tooth disease in a large French-Acadian kindred: identification of new linked markers on chromosome 17.

We have performed linkage analysis in a large French-Acadian kindred segregating one form of autosomal dominant Charcot-Marie-Tooth disease (CMTD) (type IA) using 17 polymorphic DNA markers spanning human chromosome 17 and demonstrate linkage to several markers in the pericentromeric region, including DNA probes pA10-41, EW301, S12-30, pTH17.19, c11-2B, and p11-2c11.5. Linkage of markers pA10-41 and EW301 to CMTD type IA has been reported elsewhere. Four new markers, 1516, 1517, 1541, and LL101, which map to chromosome 17 have been identified. The marker 1516 appears to be closely linked to the CMTD locus on chromosome 17 as demonstrated by a maximum lod score of 3.42 at theta (recombination fraction) = 0. This marker has been mapped to 17p11.2 using a somatic cell hybrid constructed from a patient with Smith-Magenis syndrome [46,XY, del(17)(p11.2p11.2)]. A lod score of 6.16 has been obtained by multipoint linkage analysis with 1516 and two markers from 17q11.2, pTH17.19, and c11-2B. The markers 1517 and 1541 have been mapped to 17p12-17q11.2 and demonstrate maximum lod scores of 2.35 and 0.63 at recombination values of .1 and .2, respectively. The marker LL101 has been mapped to 17p13.105-17p13.100 and demonstrates a maximum lod score of 1.56 at a recombination value of .1. Our study confirms the localization of CMTD type IA to the pericentromeric region of chromosome 17.

Animals↗