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A 44-year-old white woman with Charcot-Marie-Tooth disease underwent an abdominal hysterectomy. The pre-operative preparation and anaesthetic management are presented, and the specific problems discussed.
In the majority of Charcot-Marie-Tooth disease type 1A (CMT1A) patients, the peripheral myelin protein 22 (PMP-22) gene maps within 1.5 megabase duplication on chromosome 17p11.2-12. The PMP-22 gene dosage is believed to be a major determining factor in the molecular pathology of CMT1A. Median nerve conduction velocities were below 35 m/sec in 17 CMT1A patients examined. Northern blot analysis showed that the mean relative ratio of PMP-22 mRNA levels in biopsied nerves of 5 patients with CMT1A is significantly higher than that in disease controls. Immunohistochemical analysis demonstrated that Schwann cell cytoplasm including onion bulbs as well as the myelin sheath was positive for PMP-22 in some patients with CMT1A, while PMP-22 was expressed only on compact portion of the myelin sheath in non-CMT1A patients and normal subjects. A minority of CMT1A are known to carry dominant and recessive point mutations in PMP-22. Some patients with Dejerine-Sottas syndrome (DSS) also have dominant and recessive point mutations in PMP-22. Instead of being two completely distinct disease entities, DSS and CMT1A form a spectrum of inherited PMP-22 related neuropathies, including hereditary neuropathy with liability to pressure palsies which carries a deletion of the PMP-22 gene.
Electrophysiological studies remain one of the cornerstones in the diagnosis of Charcot-Marie-Tooth syndrome and related genetic neuropathies. They are helpful in defining the subtypes of this heterogeneous group of hereditary neuropathies and in differentiating them from acquired neuropathies. Major advances in defining the molecular genetics of Charcot-Marie-Tooth disease are occurring. The increasingly refined diagnosis of these disorders is highlighted. It is possible by the combination of electrophysiological studies and genetic testing. These developments are especially important for practicing neurologists as they can result immediately in more specific diagnosis of patients with inherited neuropathies.
An audiologic study of a 54-year-old patient with Charcot-Marie-Tooth disease whose initial symptom was hearing difficulty is presented. While findings from basic audiologic tests were not consistent with the degree of auditory difficulty reported by the patient, special testing did indicate a notable deficit. Although the auditory periphery was probably mildly involved, it seemed that the major auditory deficit was central.
Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a DNA duplication on chromosome 17p11.2-p12 in the majority of cases. Most of the sporadic cases are due to a de novo duplication. We have screened for this duplication in 11 Danish patients with CMT type 1, using four different techniques, and identified a de novo duplication in a sporadic case. Analysis of the fully informative pVAW409R3a alleles in this family showed the duplication to be of paternal origin.
We report data on 3 members of a family affected by a dominantly inherited disorder closely resembling Roussy-Levy syndrome (RLS). Electrophysiological findings showed a marked decrease of motor and sensory conduction velocities and EMG signs of mild neurogenic damage. Light and electron microscopy of sural nerve biopsy showed a hypertrophic neuropathy with diffuse onion-bulb formations and marked decrease of large size fibers. Teased fiber preparations evidenced reduced internodal lengths and segmental demyelination. Other data from the literature on RLS are reviewed and discussed. The hypothesis that RLS is not a disease entity but a hypertrophic-type of Charcot-Marie-Tooth disease with essential tremor (HMSN type 1) is strongly supported.
The electrophysiological studies of 45 patients with Charcot-Marie-Tooth disease (CMT) are presented. The nerve conduction of the motor median and ulnar nerves permitted us to separate our patients in two types: type I (demyelinating) with motor nerve conduction (MNC) below 38 m/s (11 cases) and type II with MNC normal or above 38 m/s (34 cases). In type I there was no correlation between reduction in MNC and clinical severity. It was not possible to classify the disease on the sural nerve sensory action potential (SAP). They were unobtainable in most cases. In many patients with CMT type II the MNC was normal. In the cases the sural SAP was absent or reduced. We concluded that the MNC study is the best useful test to classify CMT disease in type I and type II.
A selective IgA deficiency was found in five of 15 random patients with Charcot-Marie-Tooth disease. Immunologic studies of 32 members of the five families showed low IgA in 17 of the members, associated with elevated IgM in 20, without other significant immune abnormalities. The immunoglobulin pattern and the variability of symptoms in this familial peripheral neuropathy suggest that a thymic or gut-associated immune deficiency or both, may be causally related to the disease process.
A 2-year-old boy presented with early-onset Charcot-Marie-Tooth disease (CMT). His parents had not been diagnosed previously with CMT, but on careful examination they showed clinical signs of CMT and reduced nerve conduction velocities. Genetic analysis identified the boy as a heterozygote for both a peripheral myelin protein 22 (PMP22) duplication and a mutation in the lipopolysaccharide-induced-tumour-necrosis-factor-alpha-factor (LITAF) gene, whereas each parent only had one mutated CMT gene. This suggests that LITAF mutations can severely affect the CMT phenotype caused by a PMP22 duplication.
We identify the prevalence and genetic features of Charcot-Marie-Tooth disease (CMT) in Yonago and Sakaiminato, western Japan. From information in registered records and questionnaires, definite or candidate CMT patients were examined. Eleven families with 19 patients (7 female and 12 male) were identified and the prevalence was 10.8 per 100,000 in April 2000. Eleven patients in 6 families showed a Thr124Met mutation of the MPZ gene, in 2 families duplication of the PMP22 gene was suggested and no abnormalities were found in 2 families. To identify the occurrence of mildly affected CMT, the exhaustive region-matched and family study was necessary.
Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Dejerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q (CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.
Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating peripheral neuropathy. Most patients with CMT1A including sporadic cases have been found to have a 1.5 megabase tandem DNA duplication in chromosome 17 p11.2-p12 (CMT1A duplication). We reported a 7-year-old girl with sporadic CMT 1 associated with the CMT1A duplication. The diagnosis of CMT 1 was based on the symmetrical distal muscle weakness, per cavus deformity, reduced motor and sensory nerve conduction velocities, and segmental de- and remyelinatin on sural nerve biopsy. To detect the CMT 1A duplication, peripheral myelin protein 22 (PMP-22) cDNA and a polymorphic marker in this region, VAW409 R3, were employed as probes for Southern blot analysis. Sporadic cases of autosomal dominant-CMT type 1 can not be clinically differentiated from recessive-CMT1. Testing for the CMT1A duplication is an important first step even in the molecular diagnosis of sporadic CMT1.
X-linked Charcot-Marie-Tooth disease is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding connexin 32 (Cx32). Cx32 is expressed at the paranodes and Schmidt-Lantermann incisures of myelinating Schwann cells in which it is believed to form a reflexive pathway between the abaxonal and adaxonal cytoplasmic domains. Patients with the Val181Ala (V181A) mutation have a severe peripheral neuropathy. Experiments using a nude mouse xenograft system show that Schwann cells expressing only this mutant form of Cx32 are profoundly impaired in their ability to support the earliest stages of regeneration of myelinated fibers. Coupling between paired Xenopus oocytes expressing V181A is reduced compared with the coupling between oocytes expressing wild-type human Cx32 (32WT), and protein levels assayed by Western blot are substantially lower. Immunocytochemisty shows that Neuro2a cells expressing the V181A mutant have very few gap junction plaques compared with cells expressing 32WT; Cx32 protein levels are lower in these cells than in those expressing 32WT. Because failure of normal regeneration is evident before formation of myelin, loss of function of Cx32 may impact on the function of precursors of the myelinating Schwann cell before the formation of the hypothesized reflexive pathway. The Glu102Gly (E102G) mutation leads to a milder phenotype. Early regeneration is normal in grafts with Schwann cells expressing the E102G mutant. The only abnormality detected in the behavior of its channel is increased sensitivity to acidification-induced closure, a property that may lead to reduced gap junction coupling during periods of metabolic stress. This restricted functional abnormality may explain the relatively mild phenotype seen in the xenograft model and in E102G patients.
INTRODUCTION: Charcot-Marie-Tooth disease (CMTD) or hereditary motor and sensory neuropathy shows great genetic heterogeneity. The type 1 (CMT-1) or demyelinating form and the type 2 (CMT-2) or neuronal form are two clinically and genetically distinct forms. DEVELOPMENT: Apart from the above mentioned motor and sensory forms, there is another type of neuropathy in which the clinical and neurophysiological involvement is exclusively motor and is known as distal spinal atrophy or hereditary distal motor neuropathy (HDMN), which is a syndrome to be included among the CMTD. The CMT-1 is the most prevalent form and the best understood from the genetic point of view. At least four genes have been reported to be involved: the gene for 22 kDa peripheral myelin protein (PMP-22), situated on the 17p11.2 chromosome (locus CMT-1A); the gene for myelin 0 protein situated on chromosome 1q23 (locus CMT-1B); the gene for conexine 32 (Cx32), found on chromosome Xq13 (locus CMT-X) and the gene EGR2 found on chromosome 10q21.1-q22.1. The genes PMP-22 and PO are related to autosomal dominant forms, the gene Cx32 is transmitted linked to chromosome X and transmission of gene EGR2 has been shown in both autosomal dominant and autosomal recessive forms. In the demyelinating forms with autosomal recessive inheritance, positive linkage has been found on four different loci: 8q21.1 (CMT-4A), 11q23 (CMT-4B), 5q23-33 (CMT-4C) and 8q24 in a form related to deafness (CMT-Lom). Two loci have been identified for the autosomal dominant forms of the HDMN. A large family initially and predominantly of the upper limbs is mapped on chromosome 7p (HDMN-V) and another with the classical phenotype mapped on chromosome 12q24. In the familial neuropathy with liability to pressure palsies in most families, deletion of the locus CMT-1A was found, and in rare cases mutation precisely of the PMP-22 gene. In familial amyotrophic neuralgia, genetic molecular analysis has shown linkage with markers on the chromosome 17q24-25.
Operative charts were reviewed in 86 patients with Charcot-Marie-Tooth disease, a condition characterized by chronic muscular denervation. A total of 161 surgical procedures was performed. Major complications were few, and only one operative death occurred, unrelated to anaesthesia. Succinylcholine and malignant hyperthermia triggering agents were used in 41 (48%) and 77 (90%) patients, respectively, without untoward effects. Contrary to previous reports, this survey supports the safe use of succinylcholine and MH triggering agents in this disease.
Gm and Km immunoglobulin allotypes were studied in 46 Caucasian patients with Charcot-Marie-Tooth disease (CMT). No significant association of Gm and Km phenotypes with CMT was found. Family studies revealed that Gm haplotypes and CMT were not inherited together, thus arguing against the involvement of immunoglobulin allotypes in CMT.
In the cases of Charcot-Marie-Tooth disease associated with essential tremor so far reported, motor conduction velocity studies strongly suggested that demyelination was a prominent feature of the neuropathy. For the first time two sibs are reported in whom the electrophysiological changes favour axonal degeneration as the main trait of their peripheral neuropathy.
PURPOSE: We report a case of a parturient with peroneal muscular atrophy-Charcot-Marie-Tooth disease type 1 (CMT)-who received epidural analgesia for labour. The effects of pregnancy and labour on the course of CMT are reviewed, together with the current literature on the provision of epidural and general anaesthesia in this disease. CLINICAL FEATURES: A 26-yr-old primipara with CMT was provided with epidural analgesia for labour. She experienced good pain control and suffered no untoward neurological sequelae. CONCLUSION: Epidural analgesia, after thorough discussion with the patient, may be offered to parturients with CMT.