Connexin mutations in X-linked Charcot-Marie-Tooth disease

X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry technique, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32 plays an important role in peripheral nerve.     

Charcot-Marie-Tooth disease. Clinical study in 45 patients

Charcot-Marie-Tooth (CMT) disease is the commonest inherited peripheral neuropathy. The clinical study of 45 patients with CMT is presented. They were derived from Antonio Pedro Hospital of Universidade Federal Fluminense in Niteroi, RJ, Brazil. Such patients could be divided by the motor conduction velocity in two types: a demyelinating form or type I (11 cases) and an axonal form or type II (34 cases). The disease was inherited as an autosomal dominant trait in 23 patients and as an autosomal recessive trait in 7 cases. In 15 patients the disorder was sporadic. The age of onset was in most of our cases before the 20 years. All of them had distal weakness in lower limbs. 38.2% had also distal weakness in upper limbs. 80% had distal wasting of the lower limbs and 50% had distal wasting of upper limbs. The tendon reflexes were absent in 64% in lower limbs and in 28% in upper limbs. The sensitive impairment in the distal regions of the extremities was mild in most patients. We found enlargement of peripheral nerves in 7 patients of type I. Pes cavus was present in 21 cases and scoliosis in 7. We found postural tremor of hands in 6 patients. In 9 cases there were rare features as mental retardation, trigeminal nevralgia, optic atrophy, deafness and calf enlargement. In most of our cases the clinical course was very slow progressive. A greater severity was seen in our sporadic cases.     

Total intravenous anaesthesia in Charcot-Marie-Tooth disease. Case report

A Total Intravenous Anaesthesia (TIVA) protocol in a case of hereditary motor-sensory neuropathy Charcot-Marie-Tooth disease in three consecutive orthopaedic surgical procedures is described. History, physical examination and sural nerve fascicular biopsy findings are reported. Problems related to the perioperative anaesthesiological management in peripheral neuropathies are discussed. Propofol and fentanyl without muscle relaxants, proved to be a safe technique, fast at reaching the level of surgical anaesthesia required, manageable for maintenance and rapidly reversible.     

Inherited neuropathies: Charcot-Marie-Tooth disease and related disorders

Collectively, the inherited disorders of peripheral nerves represent a common group of neurological diseases and are frequently encountered in the clinical setting. Recent advances in molecular genetics have not only provided improved diagnosis and counselling, but may ultimately lead to specific, rational therapies for the various forms of inherited neuropathy. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17p (CMT1A), chromosome 1q (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-megabase (Mb) duplication in chromosome 17p11.2-12, or may occasionally result from a point mutation in the peripheral myelin protein 22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with defects in the connexin 32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One locus for CMT2 has been assigned for chromosome 1p (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset, demyelinating polyneuropathy which may be associated with point mutations in the P0 or PMP22 genes. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal cross-over during germ-cell meiosis.     

Charcot-Marie-Tooth disease: a new paradigm for the mechanism of inherited disease

Recent work has identified the genes and mutational mechanisms that underlie several inherited diseases of the peripheral nervous system and has provided both the first genetic rationale for classification of these disorders and an insight into their biological basis. These studies have yielded some surprising findings, including the discovery that two very different mutational mechanisms (duplication and point mutation) can result in a similar clinical phenotype in Charcot-Marie-Tooth disease type 1A, and that mutations involving the same gene can give rise to different clinical phenotypes.     

Neuropathic pain in rats is associated with altered nitric oxide synthase activity in neural tissue

Peripheral nerve injury may lead to a chronic neuropathic pain state that results from an increase in excitability of central neurons. This central sensitization is mediated via an N-methyl-D-aspartic acid (NMDA) receptor and may involve the production of nitric oxide (NO). As NO is suggested to play a role in nociceptive transmission following nerve injury, we examined for altered NO synthase activity at multiple levels of peripheral and spinal neural tissue in a rat model of neuropathic pain. Peripheral neuropathy was induced in rats (N = 12) by ligation of the left L5 and L6 nerve roots. Six other rats had sham surgery. An ipsilateral decrease in paw withdrawal threshold to mechanical stimuli confirmed the presence of a neuropathic pain state. Samples of the lumbar and thoracic spinal cords, L4, L5, and L6 dorsal root ganglia (DRGs), and the sciatic nerves were obtained from the lesioned and contralateral sides at 2 and 4 weeks after neuropathic surgery (N = 6 per group). In the lumbar spinal cord, a bilateral decrease in nitric oxide synthase (NOS) activity was observed 2 and 4 weeks after neuropathic surgery. NOS activity was increased in the ipsilateral L5 and 6 DRGs 2 weeks following neuropathic surgery. An increase in NOS activity in the DRG may be an early mechanism for inducing more central changes. The bilaterally decreased NOS activity in the lumbar spinal cord may be secondary to a negative feedback mechanism resulting from increased NO production in the spinal dorsal root ganglia. Multiple alterations in expression of NOS activity that occur in both peripheral and central processing may play a role in the pain behavior resulting from peripheral nerve injury. (Preliminary results of these studies have been presented in abstract form at the annual meetings of the Society for Neuroscience, 1994, and the American Society of Anesthesiologists, 1994).     

Myelographic evidence for nerve root enlargement in a case of Charcot-Marie-Tooth disease

The myelographic findings of enlarged nerve roots in a patient with Charcot-Marie-Tooth disease is found to be identical to those of Hypertrophic Interstitial Neuritis and Neurofibromatosis. The hypertrophy of the roots may represent a single response to different noxious stimuli. Clinical and laboratory differentiation are given for the diseases.     

Pregnancy after preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A

Charcot-Marie-Tooth (CMT) disease type 1A is an autosomal dominant peripheral neuropathy characterized by slow progressive distal muscle wasting and weakness, and decreased nerve conduction velocities. Most CMT1A cases (>98%) are caused by a duplication of a 1.5 Mb region on the short arm of chromosome 17 containing the PMP22 gene. A couple with a previous history of CMT followed by termination of pregnancy was referred to our centre for preimplantation genetic diagnosis (PGD). The husband carries the CMT1A duplication which can be detected by polymerase chain reaction (PCR) analysis using polymorphic (CA)n markers localized within the duplication. PCR amplification of genomic DNA of the parents-to-be with one of the two primers labelled with fluorescein, followed by automated laser fluorescence (ALF) gel electrophoresis of the amplified fragments allows the distinction between both genotypes. Embryos obtained after intracytoplasmic sperm injection (ICSI) were evaluated for the presence of the normal allele of the father. PCR with single Epstein-Barr virus-transformed lymphoblasts and blastomeres resulted in 91.4 and 93.5% amplification efficiency respectively, whereas none of the blank controls gave a positive signal. Allele drop-out (ADO) was observed in eight out of 32 lymphoblasts (25%) or in five out of 21 blastomeres (23.8%). However, within this set-up ADO will never lead to transfer of an affected embryo. A first ICSI-PGD cycle did not result in embryo transfer for the patient. A second cycle involved 10 mature oocytes of which eight were fertilized, resulting in five embryos for biopsy. Two unaffected embryos were available for transfer and resulted in a singleton pregnancy. The genotype of the fetus has been confirmed healthy by chorionic villus sampling.     

Neuropathic pruritus

Colonization of the urinary tract by Candida species occurs particularly in diabetic or immunocompromised patients. We report the cases of two patients presenting with pneumaturia and urinary tract infection who were initially thought to have colovesical fistulae. In both patients a diagnosis of emphysematous pyelonephritis or cystitis due to candidal infection was subsequently made. These cases serve as a reminder of this rare presentation of a not uncommon urinary tract infection.     

Pressure palsy as the initial presentation in a case of late-onset Charcot-Marie-Tooth disease type 1A

OBJECTIVE: To find out the duration of postoperative pneumoperitoneum and the factors that are responsible for its persistence. DESIGN: Prospective open (non-random) study. SETTING: County hospital, Denmark. SUBJECTS: 32 patients over 18 years of age undergoing abdominal operations during a 6 month period. INTERVENTIONS: Abdominal radiographs with the patient in the left lateral position were taken at fixed time intervals until no free air could be seen. MAIN OUTCOME MEASURES: The amount of free air and the time postoperatively by which it had disappeared. RESULTS: In 20 [corrected] patients the air had disappeared within 48 hours and only one patient (3%) had free air for more than five days postoperatively. High body mass index and a small initial amount of free air were associated with the shortest period of postoperative pneumoperitoneum. CONCLUSION: Postoperative pneumoperitoneum disappeared within two days in most patients. Heavier patients and patients with small volumes of free air initially had the shortest duration of pneumoperitoneum. There were large variations among patients in the volumes of free air.     

Molecular basis of Charcot-Marie-Tooth neuropathy

Charcot-Marie-Tooth neuropathy (CMT) is the most common inherited peripheral neuropathy. CMT is classified into type types on the basis of pathological and electrophysiological findings: type 1(CMT1), characterized by decreased nerve conduction velocities and by "onion bulb" formation: type 2(CMT2), in which nerve conduction velocities are normal and "onion bulb" formations are rarely seen. CMT1 loci map to chromosome 17 (CMT1A), chromosome 1(CMT1B), another unknown autosome (CMT1C) and the X chromosome (CMTX). Recent work has identified the gene products corresponding to CMT1A, CMT1B and CMTX as peripheral myelin protein-22(PMP22), Po and connexin 32, respectively. Dejerine-Sottas disease has been identified as being caused by the mutation of PMP-22 or Po gene.     

Neuropathic arthropathy of the shoulder

We retrospectively reviewed the records of six men (seven shoulders) with neuropathic arthropathy of the shoulder who were referred to our shoulder service during a twenty-eight-year period (from 1969 through 1997). The etiology of the neuropathic condition was syringomyelia in five patients (six shoulders) and chronic alcoholism in one patient. Five patients (six shoulders) were initially misdiagnosed, and seven operative procedures that were unrelated to the etiology of the neuropathic condition were performed in four of these patients. Radiographs revealed destruction of the shoulder joint and marked resorption of the humeral head in all patients. Magnetic resonance images revealed a syrinx of the central cord in all of the patients except for the one who had chronic alcoholism.     

Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families

Charcot-Marie-Tooth disease can be inherited either autosomal dominantly or recessively or linked to the X chromosome. X-linked dominant Charcot-Marie-Tooth disease (CMTX) is a sensorimotor peripheral neuropathy in which males have usually more severe clinical symptoms and decreased nerve conduction velocities than do females. CMTX is usually associated with mutations in exon 2 of the connexin 32 (Cx32) gene. DNA from 35 unrelated CMT patients, without the 17p11.2 duplication, but with median nerve conduction between 30 and 40 m/s, were tested for the presence of Cx32 mutations. The entire coding sequence of the Cx32 gene was explored using a rapid nonradioactive technique to detect single-strand conformation polymorphisms (SSCP) on large PCR fragments. Thirteen abnormal SSCP profiles were detected and characterized by sequencing. In addition, systematic sequencing of the entire Cx32 coding region in the remaining index cases revealed another mutation that was not detected by SSCP. A total of 14 mutations were found, five of which were not previously reported. These results demonstrate the high frequency (40%) of mutations in the coding region of the Cx32 gene in CMT patients with intermediate MNCV, without 17p11.2 duplications. Most of these mutations (93%) can be detected by SSCP.     

Charcot-Marie-Tooth disease--muscle biopsy findings in relation to neurophysiology

Nine patients with Charcot-Marie-Tooth disease with reduced motor nerve conduction velocity (MNCV), i.e. type 1 (CMT1), demyelinating form, and nine patients with Charcot-Marie-Tooth disease with normal or near-normal MNCV, i.e. type 2 (CMT2), axonal form, were subjected to percutaneous muscle biopsy from the anterior tibial muscle in order to characterize histopathological abnormalities and evaluate differences between the two groups. Data from the biopsies were compared with those from 18 age- and sex-matched healthy controls. Muscle biopsies from the CMT1 patients exhibited angular atrophic fibres that were scattered or in small groups, findings commonly described as neuropathic. Muscle biopsies from the CMT2 patients exhibited atrophic fibres that were rounded or elongated in groups and hypertrophic fibres with central nuclei and fibre splitting. There were also increased amounts of connective tissue, 'whorled fibres', degeneration and signs of regeneration, findings commonly regarded as myopathic. In conclusion, muscle biopsies from patients with CMT1 and CMT2 showed markedly different histopathological abnormalities. Possible underlying mechanisms are discussed.     

A new point mutation affecting the fourth transmembrane domain of PMP22 results in severe de novo Charcot-Marie-Tooth disease

OBJECTIVE: Fiji is a Pacific nation with roughly equal numbers of indigenous Fijians and Indians. Previous studies, using police and medical records, have suggested significant racial, regional, age and gender differences in suicidal behaviour. The objective of the present study is to use a unique data set (autopsy reports) in the evaluation of earlier reports and to identify groups at greater risk. METHOD: Hanging and poisoning autopsy reports from two distinct regions were examined. RESULTS: The rate of autopsy (per 100000 population per year) among Indians (19.5) is significantly greater (p < 0.0001) than among Fijians (1.53). In the north, among the Indians, there are more autopsies in females (21.2) than males (16.8), and hanging constitutes 85% of total suicides, while in the Central and Eastern Divisions hanging constitutes only 58% of the total. These are regional influences. Among Fijians, the rates of hanging autopsy are significantly greater (p < 0.001) in males (1.98) than females (0.40); however, among Indians there is no significant difference. This is a racial difference. Hanging remains the preferred option for all groups. The mean age at autopsy is 31.7. There is no significant difference between the mean ages of the races, the sexes or the regions. There is no significant difference between the mean age of poisoning (31.5) and hanging (31.8). CONCLUSION: There is a significant racial difference in rates of suicide but the influences of region, age and method are relatively slight.     

Scheuermann's kyphoscoliosis associated with Charcot-Marie-Tooth syndrome

Much confusion and disagreement exists regarding the classification and characteristics of inherited disorders manifesting neurogenic muscular atrophy. Many authors consider Charcot-Marie-Tooth syndrome (CMTS) and Roussy Levy syndrome (RLS) forme fruste or variants of Friedreich's ataxia (FA). Familial kyphoscoliosis has often been described in FA and RLS but not with CMTS. The purpose of this paper is to present detailed clinical and laboratory findings in a family with three cases of Scheuermann's kyphoscoliosis and CMTS in three generations. In all cases Scheuermann's kyphoscoliosis was associated with pes cavus, markedly diminished vibratory and position sensation in the lower extremities, absent deep tendon reflexes and muscular atrophy, predominantly of the distal muscles. Fine rhythmic tremor of outstretched hands and positive Romberg sign were present in one case only. Serum creating phosphokinase was elevated in two cases. Motor nerve conduction studies revealed impaired function in the median, ulnar, tibial and peroneal nerves. Sensory nerve conduction wal also impaired in median and ulnar nerves. There was evidence of left ventricular hypertrophy in one case only. The nosology and relationship between CMTS, RLS and FA are discussed.