Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Charcot-Marie-Tooth type X disease (CMTX) is the second most frequent inherited neuropathy, after CMT1A type associated with 17p11.2-p12 duplication. CMTX is inherited as X dominant trait and is caused by point mutations in Cx32 gene. In the study the first Polish group of 11 patients with CMTX from 4 families is presented. The following four mutations were found in Cx32 gene: Gly110Asp, Val 152 Asp, Arg 183 His and Glu 208 Gly. CMTX is characterized by X dominant trait of inheritance, a mild clinical course in affected females and slowly progressive atrophy and weakness of distal limb muscles. Both electrophysiological and sural nerve biopsy studies show axonal changes with secondary demyelination.
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PMID:[Charcot-Marie Tooth type X (CMTX) disease: clinical and genetic characteristics of eleven patients]. 1271 86

Sensory loss and weakness in Charcot-Marie-Tooth (CMT) neuropathy is due to axonal loss. However, the pattern and degree of axonal loss cannot be accurately determined from routine electrodiagnostic or strength testing due to collateral reinnervation. We sought to quantify axonal loss in two upper extremity muscles in CMT1A and CMT2 subjects using the electrophysiologic endpoint measure of motor unit number estimation (MUNE). Hypothenar and biceps-brachialis muscle groups were studied in 9 CMT1A, 9 CMT2, and 10 control subjects. The spike-triggered averaging (STA) technique was used to collect surface motor unit potentials for MUNE calculations, and a needle electrode was used to collect corresponding intramuscular data. Maximal voluntary hypothenar and handgrip strength was measured quantitatively, while biceps-brachialis strength was measured qualitatively. Compared to normal subjects, CMT1A and CMT2 subjects had significantly lower MUNE values in hypothenar muscles. Biceps-brachialis MUNE values were reduced in CMT2 but not in CMT1A subjects. In support of proximal axonal loss in CMT2 subjects, surface motor unit and intramuscular potential amplitudes were higher in biceps-brachialis muscles compared to controls. Correlations between quantitative strength and MUNE were significant for hypothenar but not for grip muscle groups. Axonal loss is demonstrated in distal muscles in CMT1A and CMT2 supporting a length-dependent axonopathy. Despite clinical findings of normal or near-normal strength and small reductions in compound muscle action potential (CMAP) amplitude, MUNE values were significantly lower in CMT2 subjects in proximal muscles, consistent with more diffuse denervation. These data indicate that subclinical axonal loss is present that cannot be appreciated using clinical examination or routine electrodiagnostic techniques.
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PMID:Assessment of axonal loss in Charcot-Marie-Tooth neuropathies. 1476 67

A nationwide study of CMT and FAP has been performed. In FAP TTR Met30 families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms, consistent with pathological findings. In contrast, families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction. Demyelinating versus axonal phenotypes are major issues in CMT. CMT1A duplication caused mainly demyelinating phenotype, while axonal features were variably present. In CMT1B, two distinctive phenotypic subgroups were present: one showed exclusively axonal features; and another was exclusively demyelinating. CMTX showed intermediate slowing of MCV, predominantly axonal features, and relatively mild demyelinating pathology. Differing from CMT1B, these axonal and demyelinating features were concomitantly present in individual patients in variable extent. Median nerve MCVs were well maintained independently of age, disease duration, and severity of clinical and pathologic abnormalities. Amplitude of CMAPs was correlated significantly with distal muscle strength, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. CMT patients with demyelinating and/or axonal features, together with FAP patients with axonal feature and scattered distribution, are supposed to increase according to the development of genetic diagnosis for hereditary neuropathy that verifies late-onset, de novo and asymptomatic patients.
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PMID:[Clinical phenotype of Charcot-Marie-Tooth disease (CMT) and familial amyloid polyneuropathy (FAP)]. 1515 60

We investigated early peripheral nervous system impairment in PMP22-transgenic rats ("CMT rat"), an established animal model for Charcot-Marie-Tooth disease 1A, at postnatal day 30 (P30), when the clinical phenotype is not yet apparent. Hemizygous CMT1A rats and wildtype littermates were studied by means of behavioral examination, electrophysiology, molecular biology, and light microscopy analysis. Behavioral studies only showed, a mild, but significant, decrease in toe spread 1-5, suggesting a weakness of distal foot muscles in CMT1A rats compared with normal littermates. Nerve conduction studies disclosed a severe slowing in motor conduction velocity, a temporal dispersion and a dramatic decrease of amplitude of motor waves in P30 transgenic animals. Coherently with a demyelinating process, affected nerves showed a significant thinning of myelin. Interestingly, axonal diameter and area were unchanged, but expression of non-phosphorylated neurofilaments was increased in CMT1A rats compared with normal controls. Our results confirm the fidelity of this animal model to human disease. Similarly, in young CMT1A patients, the MCV is significantly reduced and the muscle weakness is confined to distal segments, whereas morphological and morphometrical signs of axonal atrophy are absent. However, the presence of a molecular and functional damage of the axons suggests that this may be the correct moment to start neuroprotective therapies.
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PMID:Early abnormalities in sciatic nerve function and structure in a rat model of Charcot-Marie-Tooth type 1A disease. 1547 94

Hereditary neuropathy with liability to pressure palsy (HNPP) is characterised by recurrent mononeuropathies following minor trauma. We describe a case of fulminant HNPP beginning on the first day of military physical training. Protracted weakness, muscle atrophy, hand contractures, and multifocal sensory loss developed during a further three weeks of basic training. Nerve conduction changes were typical of HNPP, but without segmental slowing. Electromyographically, there was prominent acute denervation in muscles of the hands and right shoulder. Sural nerve biopsy demonstrated tomaculae and remyelination. Genetic testing revealed PMP-22 gene deletion. This case report demonstrates that HNPP can present with rapidly progressive peripheral nerve dysfunction and electrophysiological evidence of focal axonal loss.
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PMID:Hereditary neuropathy with liability to pressure palsy: fulminant development with axonal loss during military training. 1548 3

The most frequent type of Charcot-Marie-Tooth (CMT) neuropathy is that associated with the 17p11.2-p12 chromosome duplication, whose characteristics have been well described in European and North American populations. In this study, we analyzed a Brazilian population exhibiting the mutation, found in 57 patients from 42 families (79%) of a cohort of 53 families with demyelinating CMT. Almost 20% of the duplicated cases were sporadic. In 77% of the duplicated families the mutation event occurred in the hot spot area of the CMT1A-Rep region. Forty-five percent of patients were females, 84% were Caucasians and 13% of African descent. Distal limb weakness was the most frequent abnormality, appearing in 84% of patients, although uncommon manifestations such as severe proximal weakness, floppy baby syndrome, diaphragmatic weakness and severe scoliosis were also observed. One patient was wheelchair-bound, and three suffered severe hand weakness. Sensory abnormalities were detected in 84% of the cases, but 80% were unaware of this impairment. Twelve patients complained of positive sensory manifestations such as pain and paresthesias. Progression was reported by 40%. Motor conduction velocities in the upper limbs were always less than 35 m/s, and less than 30.4 m/s in the peroneal nerve. The findings of this study expand the clinical spectrum of the disease.
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PMID:17p duplicated Charcot-Marie-Tooth 1A: characteristics of a new population. 1576 65

Charcot-Marie-Tooth (CMT) disease is a common hereditary neuropathy that causes progressive distally pronounced muscle weakness and can lead to life-long disability in patients. In most cases, the disorder has been associated with a partial duplication of human chromosome 17 (CMT1A), causing 1.5-fold overexpression of the peripheral myelin protein 22 kDa (PMP22). Increased PMP22 gene dosage results in demyelination, secondary axonal loss, and neurogenic muscle atrophy. Experimental therapeutic approaches based on the role of progesterone and ascorbic acid in myelin formation recently have reached preclinical proof-of-principle trials in rodents. It was shown that progesterone receptor antagonists can reduce PMP22 overexpression and clinical severity in a CMT1A rat model. Furthermore, ascorbic acid treatment reduced premature death and demyelination in a CMT1A mouse model. Thus, basic research has opened up new vistas for the understanding and treatment of hereditary neuropathies.
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PMID:Myelin disorders: Causes and perspectives of Charcot-Marie-Tooth neuropathy. 1663 77

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of disorders sharing the same clinical phenotype, characterized by distal limb muscle wasting and weakness, usually with skeletal deformities, distal sensory loss, and abnormalities of deep tendon reflexes. Mutations of genes involved in different functions eventually lead to a length-dependent axonal degeneration, which is the likely basis of the distal predominance of the CMT phenotype. Nerve conduction studies are important for classification, diagnosis, and understanding of pathophysiology. The subdivision into demyelinating CMT1 and axonal CMT2 types was a milestone and is still valid for the majority of patients. However, exceptions to this partition are increasing. Intermediate conduction velocities are often found in males with X-linked CMT (CMTX), and different intermediate CMT types have been identified. Moreover, for some genes, different mutations may result either in demyelinating CMT with slow conduction, or in axonal CMT. Nerve conduction slowing is uniform and diffuse in the most common CMT1A associated with the 17p12 duplication, whereas it is often asymmetric and nonhomogeneous in CMTX, sometimes rendering difficult the differential diagnosis with acquired inflammatory neuropathies. The demyelinating recessive forms, termed CMT4, usually have early onset and run a more severe course than the dominant types. Pure motor CMT types are now classified as distal hereditary motor neuronopathy. The diagnostic approach to the identification of the CMT subtype is complex and cannot be based on the clinical phenotype alone, as different forms are often clinically indistinguishable. However, there are features that may be of help in addressing molecular investigation in a single patient. Late onset, prominent or peculiar sensory manifestations, autonomic nervous system dysfunction, cranial nerve involvement, upper limb predominance, subclinical central nervous system abnormalities, severe scoliosis, early-onset glaucoma, neutropenia are findings helpful for diagnosis.
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PMID:Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. 1677 64

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.
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PMID:Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy. 1677 74

To evaluate the clinical and electrophysiological similarities and differences between two large groups of patients with Charcot-Marie-Tooth disease, i.e. CMT1A and CMT2, we performed a post hoc comparison of clinical and electrophysiological data. Most CMT1A and CMT2 patients had the classical CMT phenotype. Age of onset was significantly later in CMT2. Total areflexia was present in approximately half of the CMT1A patients whereas it was rare in CMT2. Foot deformities and weakness of knee extensor and foot dorsal flexor muscles were more frequent in CMT1A. Median nerve motor nerve conduction velocities (MNCV) were always less than 38 m/s in CMT1A patients, whereas this was also the case in 16% of the CMT2 patients. Sensory nerve conduction velocities showed less overlap. In both CMT1A and CMT2 CMAP and SNAP amplitudes were often reduced or not obtainable in the legs. In CMT1A, SNAP amplitude was more reduced and SNAP duration more prolonged than in CMT2. We conclude that there are no robust clinical signs or symptoms that differentiate between CMT1A and CMT2 patients. Electrodiagnostical studies show a length-dependent motor and sensory axonal dysfunction in both CMT-types. Additional SNAP and SNCV evaluation may be helpful in focusing molecular genetic analysis in the occasional case of CMT2 showing slow motor nerve conduction velocities overlapping with CMT1A values. The reduction of CMAP and SNAP amplitudes in CMT1A is probably a combined effect of demyelination and axonal dysfunction.
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PMID:Comparison of CMT1A and CMT2: similarities and differences. 1694 Oct 80


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