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PubMed2006

Molecular genetics of X-linked Charcot-Marie-Tooth disease.

The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common molecularly designated form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive distal muscle atrophy and weakness, areflexia, and variable sensory abnormalities. Affected males have moderate-to-severe symptoms, whereas heterozygous females are usually mildly affected or even asymptomatic. Several patients also have manifestations of central nervous system involvement or hearing impairment. Electrophysiological and pathological studies of peripheral nerves show evidence of demyelinating neuropathy with prominent axonal degeneration. A large number of mutations in the GJB1 gene encoding the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X. Cx32 is expressed by Schwann cells and oligodendrocytes, as well as by other tissues, and the GJ formed by Cx32 play an important role in the homeostasis of myelinated axons. The reported CMT1X mutations are diverse and affect both the promoter region as well as the coding region of GJB1. Many Cx32 mutants fail to form functional GJ, or form GJ with abnormal biophysical properties. Furthermore, Cx32 mutants are often retained intracellularly either in the endoplasmic reticulum or Golgi in which they could potentially have additional dominant-negative effects. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. No definite phenotype-genotype correlation has yet been established for CMT1X and effective molecular based therapeutics for this disease, remain to be developed.

Amino Acid Sequence↗
PubMed2004

A novel point mutation in PMP22 gene associated with a familial case of Charcot-Marie-Tooth disease type 1A with sensorineural deafness.

Charcot-Marie-Tooth disease with deafness is a clinically distinct entity and is associated with mutations or deletions in several genes including PMP22 gene. Here, we report a large family showing characteristic phenotypes of Charcot-Marie-Tooth type 1A along with deafness in an autosomal dominant fashion. We detected a sequence variation (c.68C>G) co-segregating with the disease phenotype and leading to a T23R missense mutation in PMP22.

Adult↗
PubMed1996

Normalized Southern Hybridization to Enhance Testing for Charcot-Marie-Tooth Disease, Type 1A.

Background: Charcot-Marie-Tooth disease, type 1A (CMT,1A) is a common autosomal dominant neuromuscular disorder, which affects both motor and sensory function and is characterized usually by duplication of a region on chromosome 17 through unequal crossover. As a result, affected patients carry three copies of this region. Individuals inheriting the other deleted chromosome involved in the crossover have one copy of the region and manifest herditary neuropathy with susceptibility to pressure palsies (HNPP). One diagnostic approach to CMT,1A exploits Southern blot hybridization and the relative intensity for three polymorphic MspI restriction fragment lenth polymorphism bands within the duplicated area to judge whether patients have two or three copies of this region using a probe such as VAW409R3A. This is usually straightfoward and works well for the majority of samples that display polymorphisms. However, it is difficult to judge dosage for this region in patients who do not demonstrate polymorphic bands. Methods and Results: An assay has been developed in which a simultaneously hybridized probe (pH15), which detects a nonpolymorphic band on chromosome 22 generated by the same restriction enzyme used to digest genomic DNA, is used to normalize the signal from the CMT,1A probe after phosphorimager analysis. Normalized ratios for VAW409R3A-hybridizing Southern bands fell within discrete ranges for patients with three copies (2.72-3.69), two copies (1.60-2.40) and one copy (0.75-1.30) of this region in over 45 patient and control samples studied. Conclusions: This assay appears to provide a reliable and consistent method of analysis.

Journal Article↗
PubMed1989

Respiratory muscle weakness in Charcot-Marie-Tooth disease. A field study.

A field study on respiratory muscle function and basic pulmonary mechanics was conducted at an international convention of 200 individuals with Charcot-Marie-Tooth disease. Forty patients with respiratory symptoms were evaluated; 15 had significant respiratory muscle dysfunction and 25 were normal. The results suggest that proximal upper limb involvement in individuals with Charcot-Marie-Tooth disease is a simple but significant predictor of respiratory muscle dysfunction.

Adolescent↗
PubMed1985

Normal pyruvate oxidation in Friedreich ataxia and Charcot-Marie-Tooth disease fibroblasts.

Partial defects in activity of the pyruvate dehydrogenase complex have been described by some investigators in cell lines from Friedreich ataxia and Charcot-Marie-Tooth disease patients. Methylene blue was used to stimulate the rate of pyruvate oxidation in two different assay systems of pyruvate dehydrogenase activity in cultured human fibroblasts to determine if such partial defects, if present, could be detected in a stimulated assay system. Cell lines from normal controls, five patients with Friedreich ataxia, six related persons with Charcot-Marie-Tooth disease patients were studied. Although methylene blue (at a concentration of 25 mumol/l) significantly increased pyruvate oxidation in both assay systems and in all cell lines studied, no significant differences in pyruvate oxidation could be demonstrated between the control cells and either the Friedreich ataxia or Charcot-Marie-Tooth cell lines.

Cell Line↗
PubMed2000

A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).

Adult↗
PubMed2002

Two amino-acid substitutions in the myelin protein zero gene of a case of Charcot-Marie-Tooth disease associated with light-near dissociation.

Charcot-Marie-Tooth disease caused by mutations of the myelin protein zero gene demonstrates considerable phenotypical variability. We describe a 45-year-old female with a peripheral neuropathy with demyelinating and axonal features, pes cavus and pupillary light-near dissociation. She was heterozygous for two mutations in the myelin protein zero gene (His81Tyr and Val113Phe), both present on the same allele. Our patient shows a less severe phenotype than previously described patients with a His81Arg mutation. Multiple mutations in the myelin protein zero gene, as well as Charcot-Marie-Tooth with pupillary abnormalities have previously been described in rare instances. However, concurrent occurrence of both phenomena is a novel finding.

Adult↗
PubMed2004

Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3.

Charcot-Marie-Tooth disease (CMT) comprises a heterogeneous group of hereditary motor and sensory peripheral neuropathies. The autosomal recessive axonal form of CMT (ARCMT2) is rare. Eight patients of a large consanguineous family of Spanish ancestry in Costa Rica were diagnosed with ARCMT2B; previous genetic studies of this family revealed linkage to chromosome 19q13.3. The clinical and electrophysiological features of these patients are reported. All patients presented with a symmetric motor and sensory neuropathy, which was more pronounced in the lower limbs. Further, distal muscle wasting and impaired deep tendon reflexes were found. Age at onset was between 26 and 42 years, and the disease duration ranged from 2 to 19 years. Electrophysiological studies revealed a primary axonal degenerative process. The clinical characteristics of this family differed in several aspects from previously reported families with ARCMT2.

Action Potentials↗
PubMed2004

Differential diagnosis of Charcot-Marie-Tooth disease and related neuropathies.

The diagnosis of Charcot-Marie-Tooth disease (CMT) and related neuropathies (e. g. Déjèrine-Sottas disease; hereditary neuropathy with liability to pressure palsies) appears to be easy. However, the incredible advances in molecular genetics have greatly complicated the classification of these disorders, and the proper diagnosis of the CMT subtype may be important for correct genetic counselling and prognosis. Moreover, these diseases may be confused with potentially treatable acquired and inherited neuropathies, such as dysimmune neuropathies, familial amyloid polyneuropathy, and Refsum's disease. A number of clinical, laboratory, electrophysiological, morphological and neuroradiological features that may help in the diagnostic process are reviewed in the present paper. DNA investigations are fundamental but need to be properly addressed. Currently, great interest is focused on the role of the immune system in hereditary neuropathies, and surprising findings are coming from research on animal models.

Charcot-Marie-Tooth Disease↗
PubMed1978

Hereditary angioneurotic edema and Charcot-Marie-Tooth disease in the same family.

In one family two genetic diseases were transmitted as autosomal dominant traits; hereditary angioneurotic edema was inherited from the paternal side and Charcot-Marie Tooth disease from the maternal side of the family. The conditions occurred separately in 8 and 11 members respectively and together (an exceedingly rare occurrence) in 3. Of six siblings, two girls and four boys, all had Charcot-Marie-Tooth disease, and three, the two girls and one of the boys, also had hereditary angioneurotic edema.

Adolescent↗
PubMed1979

Charcot-Marie-Tooth disease associated with 'essential tremor' and normal and/or slightly diminished motor conduction velocity. Report of 7 cases.

We present a study of 7 cases of Charcot-Marie-Tooth disease, associated with a dyskinesia clinically identical with essential tremor, in which motor conduction velocity in the upper limbs was normal or slightly diminished. An analysis of age of onset, sex distribution and clinical signs from cases in the literature is compared with the present series. A family with Charcot-Marie-Tooth disease in which affected members have widely different motor conduction velocity values is reported. Stress is laid upon the fact that categorization of this disease on electrophysiological studies in the upper limbs may present considerable difficulties.

Adult↗
PubMed2004

Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E.

The axonal type 2 Charcot-Marie-Tooth disease (CMT2) is phenotypically poorly characterized. Here the authors report a family with a Pro22Ser mutation in the neurofilament-light gene (NF-L; CMT2E) manifesting electrophysiologically as the demyelinating type 1 CMT (CMT1) and pathologically as an axonopathy with giant axons and accumulation of disorganized NF. NF-L should be investigated in CMT2 as well as in CMT1 not associated with the usual genes PMP22, Cx32, and P0.

Adult↗
PubMed1999

Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings.

X-linked Charcot-Marie-Tooth disease (CMT-X) is caused by mutations of connexin-32 (Cx-32), which encodes a gap-junction protein. Whether the neuropathy is primarily demyelinative or axonal remains to be established. We report findings of prominent demyelination in a 71-year-old woman with late-onset disease. Electrophysiological studies revealed a nonuniform slowing of motor conduction velocities and dispersion of compound action potentials indicative of a demyelinating process which was confirmed by nerve biopsy. Such electrophysiological features are unusual in hereditary neuropathies and are more commonly found with acquired chronic demyelinating neuropathies. A systematic search confirmed the molecular genomic diagnosis of CMT-X, illustrating the value of such tests in sporadic cases. Severity of clinical symptoms and signs may vary with age and sex of the patient. The pathology of CMT-X in other reported cases has been variably interpreted as axonal, demyelinating, or showing both features. Our observations emphasize the demyelinative nature.

Action Potentials↗
PubMed1989

Long-term results of triple arthrodesis in Charcot-Marie-Tooth disease.

We evaluated sixteen patients who had Charcot-Marie-Tooth disease and had had a total of thirty triple arthrodeses. The average age at the time of operation was fifteen years, and the average length of follow-up was twenty-one years. Of the thirty feet, the result in two (7 per cent) was rated excellent; in five (17 per cent), good; in nine (30 per cent), fair; and in fourteen (47 per cent), poor. Each of the fourteen feet that had a poor result had severe impairment of function and needed an orthosis. Six limbs had an arthrodesis of the ankle for degenerative joint disease. Progressive muscle imbalance resulted in recurrent cavovarus deformity in seven feet that initially had had satisfactory alignment. Degenerative changes of the ankle and joints of the mid-part of the foot were noted radiographically in twenty-three feet. The large number of unsatisfactory long-term results in these patients who had had a triple arthrodesis for deformity of the foot secondary to progressive peripheral neuropathy differs from those in earlier reports on patients who had poliomyelitis, who retained normal sensation and had a permanent, stable muscle imbalance. We believe that triple arthrodesis should be considered only as a salvage procedure in patients who have progressive peripheral neuropathy and should be limited to those who have severe, rigid deformity.

Adolescent↗
PubMed2006

NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement.

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive demyelinating polyneuropathy, associated with deafness exclusively found in Gypsies and resulting from a homozygous R148X mutation in the N-myc downstream-regulated gene 1 (NDRG1). We report the detailed phenotypic study of a family without Gypsy ancestry, who presented with severe demyelinating polyneuropathy, deafness, subcortical white matter abnormalities on brain magnetic resonance imaging studies, and the R148X mutation in NDRG1. For the first time, central nervous system white matter lesions are demonstrated in CMT4D. This report extends the clinical knowledge of CMT4D and indicates that the role of the R148X mutation in NDRG1 in the central nervous system should be further studied.

Adolescent↗
PubMedDate not supplied

Hip abnormalities in children with Charcot-Marie-Tooth disease.

Hip dysplasia was recently observed in association with Charcot-Marie-Tooth disease (CMT). We retrospectively reviewed available radiographs of 74 of 100 children with clinically and electrodiagnostically proven CMT and noted six cases of hip dysplasia. Minor hip abnormalities, most commonly increased neck shaft angles, were noted in 21 other patients. Type I usually causes more weakness and had more hip dysplasia than type II. A female predominance was noted but may have resulted from sampling of more immature radiographs in males. Most dysplasia was asymptomatic and was detected only on screening radiographs.

Adolescent↗
PubMed1994

Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease.

The X-linked form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in the gene encoding connexin32, a member of the family of proteins forming intercellular channels. We have compared the functional properties of three mutant connexin32 genes with those of the wild-type gene by testing their ability to form intercellular channels in the paired oocyte expression system. Whereas wild-type connexin32 induced the development of large junctional conductance between paired oocytes, no functional channels were detected between pairs expressing CMTX mutants. Furthermore, CMTX mutants selectively acted as dominant inhibitors of intercellular communication by interfering with the channel-forming ability of connexin26 but not with that of connexin40. These results demonstrate a functional loss in the product of a candidate gene for a demyelinating form of CMT.

Animals↗
PubMed1999

Atypical phenotype of charcot-marie-tooth disease type 1A.

Two sisters with a Charcot-Marie-Tooth disease type 1A (CMT1A) duplication, who had an unusual CMT1A clinical phenotype, are described. The 63-year-old proband presented with dysesthesia on the inner side of the right leg. Neurological examination revealed a localized sensory disturbance in the lower extremities and mild weakness in the feet and left hand. Her 61-year-old sister had experienced several episodes of acute paralysis, and neurological examination showed moderate, sensory-dominant polyneuropathy. A reduction of myelinated fibers with many onion-bulb formations were observed in the sural nerve of the proband, and electrophysiological studies showed reduced motor nerve conduction velocities in both sisters. To diagnose CMT1A, we developed a CMT1A duplication test based on detection of CMT1A-specific junction fragments using the long polymerase chain reaction (PCR) method. A 3.3-kb CMT1A-specific junction fragment was detected in both patients, and their neuropathy may therefore have been associated with CMT1A duplication.

Charcot-Marie-Tooth Disease↗