Acute deterioration of Charcot-Marie-Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy.
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BACKGROUND: Severe up to life-threatening neuropathy has been observed in patients with hereditary neuropathies receiving vincristine. CASE REPORT: A 52-year-old female painter suffering from high-grade non-Hodgkin's lymphoma (stage IVB) was treated with a total of 4 mg of vincristine during two courses of CHOP chemotherapy (cyclophosphamide, vincristine, adriamycin, prednisone). At onset of treatment no neurological problems were reported. There was good lymphoma response to chemotherapy. At the same time, however, the patient gradually developed dysphagia, dysarthria, muscular weakness of both lower and upper extremities, areflexia, paraesthesia of the fingertips and bilateral sensory impairment of feet and lower legs. These symptoms continually worsened over a period of seven weeks until she was unable to walk or to perform her work. Electrophysiological studies showed peripheral axonal and demyelinative sensorimotor neuropathy in correlation to histological findings. Molecular analysis revealed 17p11.2 duplication typical for Charcot-Marie-Tooth disease IA. While continuing chemotherapy without the use of vincristine the patient's neurologic symptoms slowly recovered within six months. CONCLUSION: Prior to administration of vincristine family and patient history as well as physical examination should be performed carefully to look for underlying hereditary neuropathy. For those patients with a clinical history or symptoms suggestive for CMT nerve conduction velocity studies and on an individual base even molecular genetic analysis are necessary to prevent serious neurologic complications. worsened significantly resulting in dependency on a wheelchair and inability to perform her work as a painter. Finally she consulted a neurologist and was admitted to hospital for further diagnostic studies and continuation of treatment for her lymphoma in March 1998 with a provisional diagnosis of severe vincristine-induced neuropathy. Medical history at time of admission included hyperthyroidism, that was currently treated with propylthiouracil, a MALT lymphoma 1983, that was treated surgically only, and a meningoencephalitis in 1968. No further medication was taken. In addition she had a history of Lyme disease since 1993 with positive IgM-titer until December 1997, when antibiotic therapy with doxycycline and ceftriaxone was administered successfully. Family history obtained on admission revealed that her mother had non-specific neuropathic symptoms as well as a poorly defined foot deformities of the mother's father. The patient's brother does not show any neurologic impairment and is in good physical health. (+info)
Neurophysiology and molecular genetics of Charcot-Marie-Tooth type 1 neuropathy in Croatian children: follow-up study.
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AIM: Longitudinal assessment of clinical and neurophysiological abnormalities in childhood and adolescence and incidence analysis of tandem Charcot-Marie-Tooth disease type 1A gene duplication in Croatian children with Charcot-Marie-Tooth type 1 neuropathy. METHODS: Eight Croatian children with Charcot-Marie-Tooth type 1 neuropathy, aged 4-19 years, were studied clinically, neurophysiologically, and neuropathologically during 1-11 years of follow-up. All children were examined at least once, and in 4 children the measurements were repeated. Molecular genetic analysis was performed in all patients and their family members in order to determine the presence of the Charcot-Marie-Tooth disease type 1A duplication on chromosome 17p11.2-p12, using restriction fragment length polymorphic and short tandem repeat markers. RESULTS: Clubfoot was the most frequently observed clinical feature in children under 10 years of age, whereas muscle hypotrophy, scoliosis, and contractures developed in the second decade of life. All patients showed decreased motor nerve conduction velocity (7-30 m/s) and prolonged distal motor latencies on the first and follow-up examinations. Compound muscle action potential amplitude reduction (0.1-1.25 mV) was recorded in the first and second decade of life. In 6 out of 8 children, molecular genetic studies demonstrated the presence of the 1.5 megabase tandem Charcot-Marie-Tooth disease type 1A duplication in 17p11.2-p12, mostly of paternal origin. CONCLUSION: Pronounced neurographic abnormalities and mild clinical features characterize Charcot-Marie-Tooth type 1 neuropathy in the first decade. There were no significant differences in neurographic abnormalities in the first or second decade of life between Croatian children with and without Charcot-Marie-Tooth type 1A duplication. (+info)
Exposure at the cell surface is required for gas3/PMP22 To regulate both cell death and cell spreading: implication for the Charcot-Marie-Tooth type 1A and Dejerine-Sottas diseases.
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Gas3/PMP22 is a tetraspan membrane protein highly expressed in myelinating Schwann cells. Point mutations in the gas3/PMP22 gene account for the dominant inherited peripheral neuropathies Charcot-Marie-Tooth type 1A disease (CMT1A) and Dejerine-Sottas syndrome (DSS). Gas3/PMP22 can regulate apoptosis and cell spreading in cultured cells. Gas3/PMP22 point mutations, which are responsible for these diseases, are defective in this respect. In this report, we demonstrate that Gas3/PMP22-WT is exposed at the cell surface, while its point-mutated derivatives are intracellularly retained, colocalizing mainly with the endoplasmic reticulum (ER). The putative retrieval motif present in the carboxyl terminus of Gas3/PMP22 is not sufficient for the intracellular sequestration of its point-mutated forms. On the contrary, the introduction of a retrieval signal at the carboxyl terminus of Gas3/PMP22-WT leads to its intracellular accumulation, which is accompanied by a failure to trigger cell death as well as by changes in cell spreading. In addition, by substituting the Asn at position 41 required for N-glycosylation, we provide evidence that N-glycosylation is required for the full effect on cell spreading, but it is not necessary for triggering cell death. In conclusion, we suggest that the DSS and the CMT1A neuropathies derived from point mutations of Gas3/PMP22 might arise, at the molecular level, from a reduced exposure of Gas3/PMP22 at the cell surface, which is required to exert its biological functions. (+info)
Rapid real-time fluorescent PCR gene dosage test for the diagnosis of DNA duplications and deletions.
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BACKGROUND: Current methods to determine gene dosage are time-consuming and labor-intensive. We describe a new and rapid method to assess gene copy number for identification of DNA duplications or deletions occurring in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively. METHODS: We studied 16 patients with HNPP, 4 with CMT1A, and 49 control subjects. We used real-time PCR on the LightCycler system with use of a single capillary tube and no post-PCR handling. A polymorphic fragment of the PMP22 gene was amplified to determine gene dosage for heterozygous samples. The presence of two alleles was used to indicate that no deletion was present in HNPP samples. The ratio obtained between the areas under each allele melting curve of heterozygous CMT1A samples was used to determine whether the sequence was duplicated or normal. Homozygous samples required a competitive gene dosage test, where the ratio between the areas under the melting curves of the target DNA of samples and of the competitor molecule was used to determine whether the target sequence was duplicated, deleted, or normal. Samples from HNPP, CMT1A, and controls were analyzed. RESULTS: Area ratios were approximately 0.6, 1.0, and 2.0 for HNPP, control, and CMT1A samples, respectively. The results agreed with those obtained by Southern blotting and microsatellite analysis in the same samples. CONCLUSIONS: Direct and competitive real-time fluorescent PCR can differentiate one, two, or three copies of the target DNA. The method described is sensitive and accurate for detection of CMT1A duplications and HNPP deletions and is faster and easier than current methods. (+info)
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).
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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. (+info)
Epitope-tagged P(0) glycoprotein causes Charcot-Marie-Tooth-like neuropathy in transgenic mice.
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In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P(0)) glycoprotein. Point mutations in this region of P(0) cause human hereditary demyelinating neuropathies such as Charcot-Marie-Tooth. We describe transgenic mice expressing a full-length P(0) modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth, with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P(0)myc retained partial adhesive function, and suggested that the transgene inhibits P(0)-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P(0) ECD mutants and the normal interactions of P(0) in the myelin sheath. (+info)
MR imaging of the cauda equina in hereditary motor sensory neuropathies: correlations with sural nerve biopsy.
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BACKGROUND AND PURPOSE: Although spinal root abnormalities are known to occur, spinal MR examination is seldom performed in hereditary motor and sensory neuropathies (HMSN). The following work was undertaken to assess the MR imaging spectrum of lumbosacral spinal nerve root abnormalities and determine whether intradural nerve root involvement could be related to any biopsy feature. METHODS: Ten consecutive patients (eight male, two female; age range, 28-65 yrs) with Charcot-Marie-Tooth (CMT) (type I = 5, type II = 2) and Dejerine-Sottas disease (DSD) (n = 3) underwent a contrast-enhanced lumbosacral MR examination. Sural nerve biopsy was performed in all patients. Atypical clinical features were present in two patients. The MR scans of each patient were reviewed for possible causes of myeloradiculopathy, spinal nerve root and ganglia dimensions, signal change, and abnormal enhancement. RESULTS: In the seven patients with CMT, abnormal MR findings were intradural nerve root hypertrophy (n = 2), signal abnormalities (n = 2), and enhancement (n = 3). Two of three patients with DSD had the abnormal MR finding of intradural nerve root enhancement. In both patients with atypical clinical features, MR imaging showed nerve root hypertrophy and enhancement. Both findings were related to an increased number of onion bulbs at sural nerve biopsy. Inflammatory infiltrates were not observed in any patients. CONCLUSION: In patients with HMSN enhancement of intradural spinal nerve roots, whether or not associated with marked thickening, may be found on lumbosacral MR examinations. Spinal nerve root thickening may be responsible for atypical symptoms, and its visibility on MR images represents a useful adjunct to diagnosis. Lumbosacral spinal nerve root abnormalities were related to an extremely high number of onion bulbs (indicating active demyelination) at sural nerve biopsy. Nerve root enhancement does not seem to be related to inflammatory infiltrates. (+info)
A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.
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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). (+info)