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Intermediate Charcot–Marie–Tooth disease: an electrophysiological reappraisal and systematic review. J Neurol 2017; 264:1655-1677. [DOI: 10.1007/s00415-017-8474-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 03/23/2017] [Accepted: 03/24/2017] [Indexed: 01/13/2023]
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Nicolaou P, Christodoulou K. Advances in the molecular diagnosis of Charcot-Marie-Tooth disease. World J Neurol 2013; 3:42-55. [DOI: 10.5316/wjn.v3.i3.42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 07/23/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023] Open
Abstract
Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is the most common inherited neuromuscular disorder affecting at least 1 in 2500. CMT disease is pathologically and genetically heterogeneous and is characterized by a variable age of onset, slowly progressive weakness and muscle atrophy, starting in the lower limbs and subsequently affecting the upper extremities. Symptoms are usually slowly progressive, especially for the classic and late-onset phenotypes, but can be rather severe in early-onset forms. CMT is grouped into demyelinating, axonal and intermediate forms, based on electrophysiological and pathological findings. The demyelinating types are characterized by severely reduced motor nerve conduction velocities (MNCVs) and mainly by myelin abnormalities. The axonal types are characterized by normal or slightly reduced MNCVs and mainly axonal abnormalities. The intermediate types are characterized by MNCVs between 25 m/s and 45 m/s and they have features of both demyelination and axonopathy. Inheritance can be autosomal dominant, X-linked, or autosomal recessive. Mutations in more than 30 genes have been associated with the different forms of CMT, leading to major advancements in molecular diagnostics of the disease, as well as in the understanding of pathogenetic mechanisms. This editorial aims to provide an account that is practicable and efficient on the current molecular diagnostic procedures for CMT, in correlation with the clinical, pathological and electrophysiological findings. The most frequent causative mutations of CMT will also be outlined.
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Parman Y, Battaloğlu E. Recessively transmitted predominantly motor neuropathies. HANDBOOK OF CLINICAL NEUROLOGY 2013; 115:847-861. [PMID: 23931818 DOI: 10.1016/b978-0-444-52902-2.00048-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Recessively transmitted predominantly motor neuropathies are rare and show a severe phenotype. They are frequently observed in populations with a high rate of consanguineous marriages. At least 15 genes and six loci have been found to be associated with autosomal recessive CMT (AR-CMT) and X-linked CMT (AR-CMTX) and also distal hereditary motor neuronopathy (AR-dHMN). These disorders are genetically heterogeneous but the clinical phenotype is relatively homogeneous. Distal muscle weakness and atrophy predominating in the lower extremities, diminished or absent deep tendon reflexes, distal sensory loss, and pes cavus are the main clinical features of this disorder with occasional cranial nerve involvement. Although genetic diagnosis of some of subtypes of AR-CMT are now available, rapid advances in the molecular genetics and cell biology show a great complexity. Animal models for the most common subtypes of human AR-CMT disease provide clues for understanding the pathogenesis of CMT and also help to reveal possible treatment strategies of inherited neuropathies. This chapter highlights the clinical features and the recent genetic and biological findings in these disorders based on the current classification.
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Affiliation(s)
- Yeşim Parman
- Department of Neurology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
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Rinaldi C, Grunseich C, Sevrioukova I, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson M, Burnett B, Bönnemann C, Biesecker L, Ghezzi D, Zeviani M, Fischbeck K. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet 2012; 91:1095-102. [PMID: 23217327 DOI: 10.1016/j.ajhg.2012.10.008] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Revised: 08/29/2012] [Accepted: 10/09/2012] [Indexed: 01/30/2023] Open
Abstract
Cowchock syndrome (CMTX4) is a slowly progressive X-linked recessive disorder with axonal neuropathy, deafness, and cognitive impairment. The disease locus was previously mapped to an 11 cM region at chromosome X: q24-q26. Exome sequencing of an affected individual from the originally described family identified a missense change c.1478A>T (p.Glu493Val) in AIFM1, the gene encoding apoptosis-inducing factor (AIF) mitochondrion-associated 1. The change is at a highly conserved residue and cosegregated with the phenotype in the family. AIF is an FAD-dependent NADH oxidase that is imported into mitochondria. With apoptotic insults, a N-terminal transmembrane linker is cleaved off, producing a soluble fragment that is released into the cytosol and then transported into the nucleus, where it triggers caspase-independent apoptosis. Another AIFM1 mutation that predicts p.Arg201del has recently been associated with severe mitochondrial encephalomyopathy in two infants by impairing oxidative phosphorylation. The c.1478A>T (p.Glu493Val) mutation found in the family reported here alters the redox properties of the AIF protein and results in increased cell death via apoptosis, without affecting the activity of the respiratory chain complexes. Our findings expand the spectrum of AIF-related disease and provide insight into the effects of AIFM1 mutations.
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A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease. Eur J Hum Genet 2012; 21:190-4. [PMID: 22781092 DOI: 10.1038/ejhg.2012.146] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G>A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance.
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Barisic N, Claeys KG, Sirotković-Skerlev M, Löfgren A, Nelis E, De Jonghe P, Timmerman V. Charcot-Marie-Tooth disease: a clinico-genetic confrontation. Ann Hum Genet 2008; 72:416-41. [PMID: 18215208 DOI: 10.1111/j.1469-1809.2007.00412.x] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Charcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.
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Affiliation(s)
- N Barisic
- Department of Pediatrics, Zagreb University Medical School, Zagreb, Croatia.
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Ouvrier R, Geevasingha N, Ryan MM. Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood. Muscle Nerve 2007; 36:131-43. [PMID: 17410579 DOI: 10.1002/mus.20776] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing.
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Affiliation(s)
- Robert Ouvrier
- TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.
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Abstract
Charcot-Marie-Tooth disease (CMT) is the most common form of inherited motor and sensory neuropathy. Moreover, CMT is a genetically heterogeneous disorder of the peripheral nervous system, with many genes identified as CMT-causative. CMT has two usual classifications: type 1, the demyelinating form (CMT1); and type 2, the axonal form (CMT2). In addition, patients are classified as CMTX if they have an X-linked inheritance pattern and CMT4 if the inheritance pattern is autosomal recessive. A large amount of new information on the genetic causes of CMT has become available, and mutations causing it have been associated with more than 17 different genes and 25 chromosomal loci. Advances in our understanding of the molecular basis of CMT have revealed an enormous diversity in genetic mechanisms, despite a clinical entity that is relatively uniform in presentation. In addition, recent encouraging studies - shown in CMT1A animal models - concerning the therapeutic effects of certain chemicals have been published; these suggest potential therapies for the most common form of CMT, CMT1A. This review focuses on the inherited motor and sensory neuropathy subgroup for which there has been an explosion of new molecular genetic information over the past decade.
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Affiliation(s)
- Jung-Hwa Lee
- Department of Neurology and Ewha Medical Research Center, College of Medicine, Ewha Womans University, Seoul, Korea
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LEWIS RICHARDA, SUMNER AUSTINJ. Electrophysiologic Features of Inherited Demyelinating Neuropathies: A Reappraisal. Ann N Y Acad Sci 2006; 883:321-335. [DOI: 10.1111/j.1749-6632.1999.tb08594.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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HAHN ANGELIKAF, BOLTON CHARLESF, WHITE CHRISTOPHERM, BROWN WILLIAMF, TUUHA SASCHAE, TAN CHARLESC, AINSWORTH PETERJ. Genotype/Phenotype Correlations in X-Linked Dominant Charcot-Marie-Tooth Disease. Ann N Y Acad Sci 2006; 883:366-382. [DOI: 10.1111/j.1749-6632.1999.tb08598.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Kleopa KA, Scherer SS. Molecular genetics of X-linked Charcot-Marie-Tooth disease. Neuromolecular Med 2006; 8:107-22. [PMID: 16775370 DOI: 10.1385/nmm:8:1-2:107] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2005] [Revised: 11/10/2005] [Accepted: 11/17/2005] [Indexed: 11/11/2022]
Abstract
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.
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Affiliation(s)
- Kleopas A Kleopa
- Department of Clinical Neurosciences, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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Abstract
Since 1886, the year that Charcot and Marie and Tooth described a genetic "peroneal muscular atrophy syndrome," electrophysiological and histological studies of the peripheral nervous system have greatly aided the characterization of this syndrome, which falls among the hereditary sensory-motor neuropathies. Two principal forms of Charcot-Marie-Tooth (CMT) disease have been distinguished: CMT 1, corresponding to a demyelinating type, and CMT 2, corresponding to an axonal type. The modes of transmission of these types are variable, recessive or dominant, autosomal, or X-linked. Our discussion here is confined to the dominant forms. In recent years, advances in molecular biology have greatly modified the approach to CMT disease and related neuropathies (such as hereditary neuropathy with liability to pressure palsies). With increased knowledge of responsible gene mutations and several other loci identified by linkage studies, our understanding of the pathophysiology of these neuropathies is increasing; however, with greater understanding, the classification of these disorders is becoming more complex. In this review we present and discuss the currently characterized subtypes, with emphasis on their known histological aspects. While nerve biopsy has lost its diagnostic importance in certain forms of the disease, such as CMT 1A, CMT 1B, and X-linked CMT (CMT X), it remains important for better characterizing the lesions of CMT 2 and forms of genetic peroneal atrophy in which DNA study is unrevealing.
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Kuntzer T, Dunand M, Schorderet DF, Vallat JM, Hahn AF, Bogousslavsky J. Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a large Swiss family with Charcot-Marie-Tooth neuropathy. J Neurol Sci 2003; 207:77-86. [PMID: 12614935 DOI: 10.1016/s0022-510x(02)00394-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND The clinical manifestations of CMTX have been well described but the natural history has not yet been studied in detail. We studied phenotype variability in a family with a Pro 87 to Leu mutation of the connexin 32 (Cx32) gene. METHODS A total of 32 family members, of which 19 patients were affected, underwent clinical, electrophysiological, and genetic studies. RESULTS Onset was in the second decade. Clinical features were similar in both sexes when quantitative scores were compared, but more males had a steppage gait and skeletal deformities. All adult patients had a predominant involvement of the thenar muscles. The median values of nerve conduction velocities (NCVs) were not statistically different in men and in women. The correlation coefficients were low between motor NCVs within the same extremities, indicating nonuniform slowing between nerves, the ulnar nerve being the least affected. When disability was rated, a strong correlation was seen in male patients between severity of motor axonal loss and duration of the disease. The main pathological features were axonal loss, clusters of regenerating fibers and paranodal demyelination, the hallmark of a Schwann cell pathology. CONCLUSIONS Our data support the hypothesis that clinical disability in CMTX is caused by loss of large myelinated axons in men. Furthermore, this study shows that the nerves are not uniformly affected in terms of axonal loss. Preventing axonal degeneration and promoting axonal regeneration in the most affected nerves might be the best therapeutic approaches to ameliorate disability in CMTX.
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Affiliation(s)
- Thierry Kuntzer
- Service de Neurologie, Centre Hospitalier Universitaire Vaudois, BH 7/306, 1011, Lausanne, Switzerland.
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Abrams CK, Freidin MM, Verselis VK, Bennett MV, Bargiello TA. Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res 2001; 900:9-25. [PMID: 11325342 PMCID: PMC4517190 DOI: 10.1016/s0006-8993(00)03327-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
CMTX, the X-linked form of Charcot-Marie-Tooth disease, is an inherited peripheral neuropathy arising in patients with mutations in the gene encoding the gap junction protein connexin 32 (Cx32). In this communication, we describe the expression levels and biophysical parameters of seven mutant forms of Cx32 associated with CMTX, when expressed in paired Xenopus oocytes. Paired oocytes expressing the R15Q and H94Q mutants show junctional conductances not statistically different from that determined for Cx32WT, though both show a trend toward reduced levels. The S85C and G12S mutants induce reduced levels of junctional conductance. Three other mutants (R15W, H94Y and V139M) induce no conductance above baseline when expressed in paired oocytes. Analysis of the conductance voltage relations for these mutants shows that the reduced levels of conductance are entirely (H94Y and V139M) or partly (S85C and R15W) explicable by a reduced open probability of the mutant hemichannels. The R15Q and H94Q mutations also show alterations in the conductance voltage relations that would be expected to minimally (H94Q) or moderately (R15Q) reduce the available gap junction communication pathway. The reduction in G12S induced conductance cannot be explained by alterations in hemichannel open probability and are more likely due to reduced junction formation. These results demonstrate that many CMTX mutations lead to loss of function of Cx32. For these mutations, the loss of function model is likely to explain the pathogenesis of CMTX.
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Affiliation(s)
- C K Abrams
- Albert Einstein College of Medicine, 1300, Morris Park Avenue Bronx, NY 10463, USA.
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Lewis RA, Sumner AJ, Shy ME. Electrophysiological features of inherited demyelinating neuropathies: A reappraisal in the era of molecular diagnosis. Muscle Nerve 2000; 23:1472-87. [PMID: 11003782 DOI: 10.1002/1097-4598(200010)23:10<1472::aid-mus3>3.0.co;2-#] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The observation that inherited demyelinating neuropathies have uniform conduction slowing and that acquired disorders have nonuniform or multifocal slowing was made prior to the identification of mutations in myelin-specific genes which cause many of the inherited disorders involving peripheral nerve myelin. It is now clear that the electrophysiological aspects of these disorders are more complex than previously realized. Specifically, certain mutations appear to induce nonuniform slowing of conduction which resemble the findings in acquired demyelinating neuropathies. It is clinically important to recognize the different electrodiagnostic patterns of the various inherited demyelinating neuropathies. In addition, an understanding of the relationship between mutations of specific genes and their associated neurophysiological findings is likely to facilitate understanding of the role of these myelin proteins in peripheral nerve function and of how abnormalities in myelin proteins lead to neuropathy. We therefore review the current information on the electrophysiological features of the inherited demyelinating neuropathies in hopes of clarifying their electrodiagnostic features and to shed light on the physiological consequences of the different genetic mutations.
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Affiliation(s)
- R A Lewis
- Department of Neurology, Wayne State University School of Medicine, UHC 8D, 4201 St. Antoine, Detroit, Michigan, USA.
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Abrams CK, Oh S, Ri Y, Bargiello TA. Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot-Marie-Tooth disease. BRAIN RESEARCH. BRAIN RESEARCH REVIEWS 2000; 32:203-14. [PMID: 10751671 DOI: 10.1016/s0165-0173(99)00082-x] [Citation(s) in RCA: 68] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The connexins are a family of homologous integral membrane proteins that form channels that provide a low resistance pathway for the transmission of electrical signals and the diffusion of small ions and non-electrolytes between coupled cells. Individuals carrying mutations in the gene encoding connexin 32 (Cx32), a gap junction protein expressed in the paranodal loops and Schmidt-Lantermann incisures of myelinating Schwann cells, develop a peripheral neuropathy - the X-linked form of Charcot-Marie-Tooth disease (CMTX). Over 160 different mutations in Cx32 associated with CMTX have been identified. Some mutations will lead to complete loss of function with no possibility of expression of functional channels. Some mutations in Cx32 lead to the abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus; CMTX may arise due to incorrect trafficking of Cx32 or to interference with trafficking of other proteins. On the other hand, many mutant forms of Cx32 can form functional channels. Some functional mutants have conductance voltage relationships that are disrupted to a degree which would lead to a substantial reduction in the available gap junction mediated communication pathway. Others have essentially normal steady-state g-V relations. In one of these cases (Ser26Leu), the only change introduced by the mutation is a reduction in the pore diameter from 7 A for the wild-type channel to less than 3 A for Ser26Leu. This reduction in pore diameter may restrict the passage of important signaling molecules. These findings suggest that in some, if not all cases of CMTX, loss of function of normal Cx32 is sufficient to cause CMTX.
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Affiliation(s)
- C K Abrams
- Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Ressot C, Bruzzone R. Connexin channels in Schwann cells and the development of the X-linked form of Charcot-Marie-Tooth disease. BRAIN RESEARCH. BRAIN RESEARCH REVIEWS 2000; 32:192-202. [PMID: 10751670 DOI: 10.1016/s0165-0173(99)00081-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Charcot-Marie-Tooth disease comprises a group of genetically heterogenous disorders of the peripheral nervous system. The X-linked form of Charcot-Marie-Tooth (CMTX) is associated with mutations in the gene encoding the gap junction protein connexin32 (Cx32), which is expressed in Schwann cells. Immunocytochemical evidence suggests that Cx32 is localized to the incisures of Schmidt-Lanterman and the paranodes of myelinating Schwann cells, where it appears to form reflexive gap junctions. It is currently thought that this cytoplasmic continuity provides a much shorter diffusion pathway for the transport of ions, metabolites and second messenger molecules through intracellular channels between the adaxonal and peri-nuclear regions of Schwann cells, across the myelin sheath. This review summarizes our current understanding of the role of connexins in Schwann cells and focuses on the lessons for channel function and disease pathophysiology derived from the functional analysis of Cx32 mutations. One of the most intriguing aspects emerging from this work is that several mutations retain functional competence, although the mutated channels exhibit altered gating properties. This suggests that partial and/or selective disruption of the radial communication pathway formed by Cx32 is sufficient to cause a functional deficit and lead to the development of CMTX. The next challenge will be to define, at the molecular level, the sequence of events involved in the disease process. The presence of a group of functional mutations should help understand the cellular basis of CMTX, by allowing the identification of the specific molecules that need to be exchanged through Cx32 channels, but are excluded from the mutated ones.
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Affiliation(s)
- C Ressot
- Unité de Neurovirologie et Régénération du Système Nerveux, Institut Pasteur, 25, rue du Dr. Roux, F-75724, Paris, France
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Tabaraud F, Lagrange E, Sindou P, Vandenberghe A, Levy N, Vallat JM. Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings. Muscle Nerve 1999; 22:1442-7. [PMID: 10487913 DOI: 10.1002/(sici)1097-4598(199910)22:10<1442::aid-mus16>3.0.co;2-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
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.
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Affiliation(s)
- F Tabaraud
- Department of Neurology, University Hospital, 87042 Limoges, France
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Abstract
Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B) 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 in rare patients may 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 or MPZ) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine-Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile-onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene or the P0 gene and shares considerable clinical and pathological features with CMT1. 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 results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q and 11q. Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder causing painful, recurrent brachial plexopathies and maps to chromosome 17q25.
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Affiliation(s)
- M P Keller
- Department of Pediatrics, University of Washington School of Medicine, Seattle, USA
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20
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Valentijn LJ, Baas F. Genetic basis of peripheral neuropathies. PROGRESS IN BRAIN RESEARCH 1999; 117:249-64. [PMID: 9932413 DOI: 10.1016/s0079-6123(08)64020-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Affiliation(s)
- L J Valentijn
- Department of Neurology, K2-214 Academic Medical Center, Amsterdam, The Netherlands
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21
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Bell C, Haites N. The peripheral neuropathies and their molecular genetics. ADVANCES IN GENETICS 1998; 36:1-44. [PMID: 9348652 DOI: 10.1016/s0065-2660(08)60306-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- C Bell
- Department of Medicine and Therapeutics, University of Aberdeen Medical School, Scotland
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Sander S, Nicholson GA, Ouvrier RA, McLeod JG, Pollard JD. Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1). Muscle Nerve 1998; 21:217-25. [PMID: 9466597 DOI: 10.1002/(sici)1097-4598(199802)21:2<217::aid-mus9>3.0.co;2-e] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5-10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6+/-5.5 m/s) than in CMT1A patients (18.2+/-6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed.
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Affiliation(s)
- S Sander
- Institute of Clinical Neurosciences, University of Sydney, NSW, Australia
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24
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Thomas PK, King RH, Small JR, Robertson AM. The pathology of charcot-marie-tooth disease and related disorders. Neuropathol Appl Neurobiol 1996; 22:269-84. [PMID: 8875461 DOI: 10.1111/j.1365-2990.1996.tb01105.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Approximately a quarter of a century ago, the disorders originally designated as Charcot-Marie-Tooth disease and Dejerine-Sottas disease were shown by combined clinical, electrophysiological and nerve biopsy studies to be genetically complex. In pathological terms they could be broadly classified into demyelinating neuropathies and axonopathies. Advances in the molecular genetics of these disorders, particularly for those with a demyelinating basis, have recently produced substantial new insights. The identification of mutations in genes for myelin proteins has provided the opportunity for investigating the precise mechanisms of these neuropathies, including the use of spontaneous and genetically engineered animal models.
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Affiliation(s)
- P K Thomas
- Department of Clinical Neurosciences, Royal Free Hospital School of Medicine, London, UK
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25
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Ionasescu V, Ionasescu R, Searby C. Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy. AMERICAN JOURNAL OF MEDICAL GENETICS 1996; 63:486-91. [PMID: 8737658 DOI: 10.1002/(sici)1096-8628(19960614)63:3<486::aid-ajmg14>3.0.co;2-i] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size.
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Affiliation(s)
- V Ionasescu
- Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City 52242, USA
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26
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Abstract
Although the prevalence of the hereditary motor and sensory neuropathies in childhood is not clearly established and the age of presentation may overlap the arbitrary boundary between pediatric and adult neurology, the recent explosion of genetic information regarding these conditions has completely altered our understanding and classification of these diseases. The current status of our understanding of the molecular basis of the hereditary neuropathies which might present in childhood is reviewed. The impact of this information on our concepts of the mechanisms operative in the production of the clinical signs and symptoms in these diseases is discussed.
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Affiliation(s)
- R A Ouvrier
- Department of Neurology, New Children's Hospital, Westmead, NSW Australia
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27
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Ouvrier R. Correlation between the histopathologic, genotypic, and phenotypic features of hereditary peripheral neuropathies in childhood. J Child Neurol 1996; 11:133-46. [PMID: 8881991 DOI: 10.1177/088307389601100214] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In recent years, there have been remarkable advances in the understanding of the molecular genetic basis of the hereditary polyneuropathies. Linkage of the genes for Charcot-Marie-Tooth disease to chromosomes 1 and then 17 was followed by the discovery that the commonest form of Charcot-Marie-Tooth disease (CMT1A) was due to a duplication of DNA at 17p11.2-12. This duplication was shown to contain the gene for peripheral myelin protein PMP22. The finding that mutations of the myelin protein PMP22 gene were present in some Charcot-Marie-Tooth disease cases lacking the duplication confirmed the myelin protein PMP22 gene as the site of the defect in Charcot-Marie-Tooth disease. Similarly, defects of the myelin protein P0 gene on chromosome 1 have been demonstrated in a rarer form of Charcot-Marie-Tooth disease (CMT1B). A deletion of DNA at 17p11.2-12 results in the disorder hereditary neuropathy with liability to pressure palsies. Other mutations of the myelin protein PMP22 and myelin protein P0 genes have been associated with the clinical syndrome known as Dejerine-Sottas disease. An X-linked form of Charcot-Marie-Tooth disease (CMTX) has been characterized and shown to be due to mutations of the gap junction protein, connexin 32. Transgenic murine models with inactivated myelin protein PMP22 and myelin protein P0 genes have shown pathologic changes strinkingly similar to those seen in human patients with disturbances of those genes. In this paper, the clinical and histopathologic characteristics of these conditions are discussed in relation to the genotypic basis. It will be argued that there is still an important place for the clinician and nerve pathologist in a medical world immersed in the wonders of molecular genetics.
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Affiliation(s)
- R Ouvrier
- Department of Neurology, University of Sydney, Australia
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28
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29
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Speer MC, Kingston HM, Boustany RM, Gaskell PC, Robinson LC, Lennon F, Wolpert CM, Yamaoka LH, Kahler SG, Hogan EL. Confirmation of locus heterogeneity in the pure form of familial spastic paraplegia. AMERICAN JOURNAL OF MEDICAL GENETICS 1995; 60:307-311. [PMID: 7485266 DOI: 10.1002/ajmg.1320600409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Familial spastic paraplegia (FSP), characterized by progressive spasticity of the lower extremities, is in its "pure" form generally of autosomal dominant inheritance pattern. Hazan et al. [Nat Genet 5:163-167, 1993] reported tight linkage of a large FSP family to the highly polymorphic microsatellite marker D14S269 with z (theta) = 8.49 at theta = 0.00 They further demonstrated evidence for locus heterogeneity when they showed that 2 FSP families were unlinked to this region. We have subsequently studied 4 FSP families (3 American, one British) and excluded the disease locus in these families for approximately 30 cM on either side of D14S269, thereby confirming evidence for locus heterogeneity within the spastic paraplegia diagnostic classification.
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Affiliation(s)
- M C Speer
- Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA
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30
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Ionasescu V, Searby C, Ionasescu R, Meschino W. New point mutations and deletions of the connexin 32 gene in X-linked Charcot-Marie-Tooth neuropathy. Neuromuscul Disord 1995; 5:297-9. [PMID: 7580242 DOI: 10.1016/0960-8966(94)00077-m] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The purpose of this study was the identification of new mutations of the connexin 32 (CX32) gene in CMTX families. We report six new mutations of the CX32 gene including two medium sized (29 and 18 bp) deletions. The clinical phenotype is consistent with CMT peripheral neuropathy in all patients. Four families show both male and female patients, with more severe symptoms in males. The disease is asymptomatic in females in two families. The clinical deficit in CMTX families Nos 1, 2 and 4 with missense mutations of the CX32 gene was mild or moderate. Severe weakness of the feet and hands was present in CMTX family No. 5 with a G insertion and family No. 6 with a 29 bp deletion in the carboxyl terminal region of the CX32 gene. Most likely the severe clinical impact in those families was related to frame shift and premature termination of the protein.
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Affiliation(s)
- V Ionasescu
- Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City 52242, USA
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31
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Ionasescu VV. Charcot-Marie-Tooth neuropathies: from clinical description to molecular genetics. Muscle Nerve 1995; 18:267-75. [PMID: 7870103 DOI: 10.1002/mus.880180302] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Ninety-five families with Charcot-Marie-Tooth (CMT) neuropathies were studied clinically, electrophysiologically (MNCVs and EMGs), and by molecular genetics. Fifty-four families (56.8%) were type 1A mapped at 17p11.2-p12 and DNA duplication was present in 50 (92.6% of CMT1A families). One family with type 1B (1.1%) mapped at 1q22-q23 showed a point mutation of the myelin P0 gene. Eighteen families (18.9%) were type CMT2 based on electrophysiological studies. Molecular genetics was not yet conclusive. Twenty CMT families were with X-linked dominant inheritance (CMTX1) (21.1%) mapped at Xq13.1 and connexin 32 (CX32) point mutations were present in 15 families (75%) (five nonsense mutations, eight missense mutations, two deletions). Two CMT families (2.1%) with X-linked recessive inheritance showed no point mutations of CX32 and their mapping was different from CMTX1, respectively at Xp22.2 for CMTX2 and at Xq26 for CMTX3.
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Affiliation(s)
- V V Ionasescu
- Department of Pediatrics, University of Iowa Hospitals, Iowa City 52242
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32
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Guzzetta V, Santoro L, Gasparo-Rippa P, Ragno M, Vita G, Caruso G, Andria G. Charcot-Marie-Tooth disease: molecular characterization of patients from central and southern Italy. Clin Genet 1995; 47:27-32. [PMID: 7774040 DOI: 10.1111/j.1399-0004.1995.tb03917.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The syndrome of peroneal muscular atrophy, or Charcot-Marie-Tooth (CMT), disease represents the most common inherited peripheral neuropathy, with a prevalence of about 1 per 2500. The disease is usually transmitted in an autosomal dominant fashion, although it can display all the mendelian patterns of inheritance. The chromosome 17-linked form (CMT1a) appears to be the most common form of the disease in all the ethnic groups studied so far, Italians included, and is due to a tandem duplication in 17p11.2. In order to study the distribution of CMT types and to establish a genotype-phenotype correlation in patients from Central and Southern Italy, we collected 19 CMT pedigrees diagnosed in the years 1992-1993. Simple tandem repeats (STR) polymorphism analysis with the marker RM11-GT and Southern blotting with the probes pVAW409R3 and pVAW412 were performed, demonstrating a high prevalence (about 60%) of 17p duplication in the families studied. No clinical or electrophysiological differences were noted between CMT1 patients with or without 17p duplication, respectively. Two families affected by CMT2 showed no evidence of rearrangement at the D17S122 locus. These data are consistent with the hypothesis of a different molecular basis for CMT2.
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Affiliation(s)
- V Guzzetta
- Department of Pediatrics, Federico II University, Naples, Italy
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33
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Le Guern E, Ravise N, Gugenheim M, Vignal A, Penet C, Bouche P, Weissenbach J, Agid Y, Brice A. Linkage analyses between dominant X-linked Charcot-Marie-Tooth disease, and 15 Xq11-Xq21 microsatellites in a new large family: three new markers are closely linked to the gene. Neuromuscul Disord 1994; 4:463-9. [PMID: 7881290 DOI: 10.1016/0960-8966(94)90085-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
X-linked dominant inheritance was suspected in a large family with Charcot-Marie-Tooth disease since no male to male transmission was observed, and since the sensory and motor neuropathy was more severe in males than in females. To test linkage to the dominant X-linked Charcot-Marie-Tooth disease (DCMTX) locus in Xq13, genotypes of 19 affected and 19 unaffected individuals from this family were determined for 4 microsatellite markers. Close linkage to mfd66 (DXS453) was found by bipoint analysis (Zmax = 4.8 at theta = 0.00). Multipoint analysis mapped the gene between the androgen receptor and DXYS1. In addition, linkage analysis performed with 11 microsatellite markers, derived from a high density map spanning 16 cM on Xq11-Xq21 revealed 3 new tightly linked loci: afm287zg1 (DXS1216), afm261zh5 and afm207zg5 (DXS995). Multipoint analysis localized the DCMTX gene to a 7.5 cM interval between afm123xd4 (DXS988) and afm116xg1 (DXS986). Combined analysis with these new microsatellites provides a powerful tool for carrier detection because of their high informativity and the small genetic distance (< 10 cM) between the markers flanking the gene.
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Affiliation(s)
- E Le Guern
- INSERM U289, Hôpital de la Salpêtrière, Paris, France
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34
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Müller U, Graeber MB, Haberhausen G, Köhler A. Molecular basis and diagnosis of neurogenetic disorders. J Neurol Sci 1994; 124:119-40. [PMID: 7964863 DOI: 10.1016/0022-510x(94)90318-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Over the past few years, molecular neurogenetics has developed into one of the most promising and active research fields. The new discipline applies modern molecular genetic techniques to the investigation of classical neurological disorders. In the following article, a definition of neurogenetic disease is introduced, the molecular basis of four groups of neurogenetic disorders is described and recent diagnostic developments are presented. The first group of diseases is caused by trinucleotide expansions. "Expanding" trinucleotide repeats were not known to occur in any species until about three years ago. Today, disorders such as Huntington's disease, spinocerebellar ataxia type 1, fragile X mental retardation, spinobulbar muscular atrophy and myotonic dystrophy are all known to be caused by the expansion of trinucleotides. The second group is characterized by chromosomal deletions or uniparental disomies. Lissencephaly and the Miller-Dieker syndrome, Prader-Willi and Angelman syndromes and Duchenne and Becker muscular dystrophies belong to this category. The third group includes those neurogenetic disorders that are mainly caused by point mutations such as the X-linked leukodystrophies, including Pelizaeus-Merzbacher disease and adrenoleukodystrophy, Charcot-Marie-Tooth syndrome type 1, familial forms of amyotrophic lateral sclerosis, several types of craniosynostoses and some CNS tumor syndromes. Finally, Alzheimer's and Parkinson's disease are discussed as representatives of group four, i.e. genetically heterogeneous neurological disorders.
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Affiliation(s)
- U Müller
- Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany
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35
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Patel PI, Lupski JR. Charcot-Marie-Tooth disease: a new paradigm for the mechanism of inherited disease. Trends Genet 1994; 10:128-33. [PMID: 7518101 DOI: 10.1016/0168-9525(94)90214-3] [Citation(s) in RCA: 127] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
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.
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Affiliation(s)
- P I Patel
- Department of Neurology, Baylor College of Medicine, Houston, TX 77030
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36
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Cochrane S, Bergoffen J, Fairweather ND, Müller E, Mostacciuolo ML, Monaco AP, Fischbeck KH, Haites NE. X linked Charcot-Marie-Tooth disease (CMTX1): a study of 15 families with 12 highly informative polymorphisms. J Med Genet 1994; 31:193-6. [PMID: 7912286 PMCID: PMC1049740 DOI: 10.1136/jmg.31.3.193] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
X linked dominant Charcot-Marie-Tooth disease (CMTX1) has previously been localised to Xq13-21. Fifteen families were studied using 12 highly informative polymorphisms in the pericentric region of the X chromosome. Phase known recombinations in these families localise the X linked dominant CMT gene to the region distal to DXS106 (Xq11.2-12) and proximal to DXS559 (Xq13.1). These markers flank approximately 2 to 3 Mb of DNA to which GJB1 and CCG1 have already been mapped. A recent report of mutations in the GJB1 gene in subjects with CMTX1 makes this a strong candidate gene.
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Affiliation(s)
- S Cochrane
- Department of Molecular and Cell Biology, University of Aberdeen Medical School, Foresterhill, UK
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37
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Abstract
We report 3 patients from 2 families with myotonic dystrophy who do not show an abnormal expansion of CTG trinucleotide repeats within the myotonic dystrophy gene. Characteristic features of myotonic dystrophy in these patients were frontal balding, cataracts, cardiac conduction abnormalities, and testicular atrophy with myotonia and muscle weakness. Results of muscle histopathology were consistent with myotonic dystrophy. Genetic analysis of leukocyte and muscle DNA showed a normal number of CTG repeats. The demonstration of normal CTG repeat number for the myotonic dystrophy gene does not exclude the diagnosis of myotonic dystrophy.
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Affiliation(s)
- C A Thornton
- Neuromuscular Disease Center, University of Rochester School of Medicine and Dentistry, NY 14620
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38
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Thomas FP, Lebo RV, Rosoklija G, Ding XS, Lovelace RE, Latov N, Hays AP. Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome. Acta Neuropathol 1994; 87:91-7. [PMID: 7511317 DOI: 10.1007/bf00386259] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We performed morphological and immunohistochemical studies on sural nerve biopsies from two members of a Charcot-Marie-Tooth type 1B family, in which a mutation of the P0 gene on chromosome 1 had been found. Biopsies showed a tomaculous neuropathy with loss of myelinated fibers and frequent small onion bulbs. Immunofluorescence with antibodies to P0 showed this protein to be present in tomaculous and non-tomaculous areas of the myelin sheath. The severity of the myelin abnormalities suggests that in this family Charcot-Marie-Tooth disease may result from a generalized disturbance of Schwann cells as a result of an abnormal P0 protein.
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Affiliation(s)
- F P Thomas
- Department of Pathology (Division of Neuropathology), College of Physicians & Surgeons, Columbia University, New York, NY
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39
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Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ, Paul DL, Chen K, Lensch MW, Chance PF, Fischbeck KH. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 1993; 262:2039-42. [PMID: 8266101 DOI: 10.1126/science.8266101] [Citation(s) in RCA: 733] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
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.
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Affiliation(s)
- J Bergoffen
- Department of Neurology, University of Pennsylvania Medical School, Children's Hospital of Philadelphia 19104
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40
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Lebo RV, Martelli L, Su Y, Li L, Lynch E, Mansfield E, Pua KH, Watson DF, Chueh J, Hurko O. Prenatal diagnosis of Charcot-Marie-Tooth disease type 1A by multicolor in situ hybridization. AMERICAN JOURNAL OF MEDICAL GENETICS 1993; 47:441-50. [PMID: 8135298 DOI: 10.1002/ajmg.1320470334] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Genetic heterogeneity within the most common genetic neuropathy, Charcot-Marie-Tooth disease (CMT) results in about 70% slow nerve conduction CMT1 and 30% normal nerve conduction CMT2. Autosomal dominant CMT1A on chromosome 17p11.2 represents about 70% of CMT1 cases and about 50% of all CMT cases. Three different size CMT1A duplications with variable flanking breakpoints were characterized by multicolor in situ hybridization and confirmed by pulsed field gel electrophoresis and quantitative polymerase chain reaction (PCR) amplification. These different size duplications result in the same CMT1A phenotype confirming that trisomy of a normal gene region results in CMT1A. The smallest duplication does not include the 409 locus used previously to screen for CMT1A duplications. Direct analysis of interphase nuclei from fetuses and at-risk patients by multicolor in situ hybridization to a commonly duplicated CMT1A probe is informative more often than polymorphic PCR analysis, faster than pulsed field gel electrophoresis (PFGE), and faster, more informative, and more reliable than restriction enzyme analysis. CMT1B restriction enzyme analysis of CMT pedigrees without CMT1A is expected to diagnose another 8% of at-risk CMT1 patients (total: 78%).
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Affiliation(s)
- R V Lebo
- Department of Obstetrics, Gynecology, University of California, San Francisco 94143-0720
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41
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Hayasaka K, Himoro M, Sato W, Takada G, Uyemura K, Shimizu N, Bird TD, Conneally PM, Chance PF. Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nat Genet 1993; 5:31-4. [PMID: 7693129 DOI: 10.1038/ng0993-31] [Citation(s) in RCA: 245] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
P0, a major structural protein of peripheral myelin, is a homophilic adhesion molecule and maps to chromosome 1q22-q23, in the region of the locus for Charcot-Marie-Tooth neuropathy type 1B (CMT1B). We have investigated P0 as a candidate gene in two pedigrees with CMT1B and found point mutations which are completely linked with the disease (Z = 5.5, theta = 0). The mutations, glutamate substitution for lysine 96 or aspartate 90, are located in the extracellular domain, which plays a significant role in myelin membrane adhesion. Individuals with CMT1B are heterozygous for the normal allele and the mutant allele. Our results indicate that P0 is a gene responsible for CMT1B.
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Affiliation(s)
- K Hayasaka
- Department of Pediatrics, Akita University School of Medicine, Japan
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Abstract
The neuronal forms of hereditary motor and sensory neuropathy (HMSN) are genetically heterogeneous with observed autosomal dominant, autosomal recessive and X-linked dominant inheritance. All three forms are characterized by degeneration of select populations of motor and sensory neurons with accompanying atrophy and degeneration of their axons. Large calibre myelinated fibres are predominantly affected and fibre degeneration and fibre loss progresses from distally to proximally. Attempts of regeneration are noted in all except the severe childhood form. The clinical picture is that of peroneal and distal leg muscle wasting and weakness, distal sensory loss and areflexia. Hand muscles may be severely affected in the autosomal recessive and X-linked dominant forms. Motor and sensory nerve conduction velocities are only moderately slowed and evoked maximum compound motor and sensory amplitudes are reduced according to the degree of fibre loss. The gene locus remains unknown in both the autosomal dominant and autosomal recessive types. For the X-linked dominant HMSN, the gene locus has been mapped closely by linkage analysis to DNA loci in the pericentromeric region of the X-chromosome.
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Affiliation(s)
- A F Hahn
- Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada
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Chance PF, Alderson MK, Leppig KA, Lensch MW, Matsunami N, Smith B, Swanson PD, Odelberg SJ, Disteche CM, Bird TD. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 1993; 72:143-51. [PMID: 8422677 DOI: 10.1016/0092-8674(93)90058-x] [Citation(s) in RCA: 521] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that causes episodes of focal demyelinating neuropathy following minor trauma to peripheral nerves. We assign the HNPP locus to chromosome 17p11.2 and demonstrate the presence of a large interstitial deletion associated with this disorder in three unrelated pedigrees. De novo deletion is documented in one pedigree. The deleted region appears uniform in all pedigrees and includes the gene for peripheral myelin protein 22 (PMP-22), suggesting that underexpression of PMP-22 may cause HNPP. The deletion in HNPP spans approximately 1.5 Mb and includes all markers that are known to map within the Charcot-Marie-Tooth neuropathy type 1A (CMT1A) duplication. Furthermore, the breakpoints in HNPP and CMT1A map to the same intervals in 17p11.2, suggesting that these genetic disorders may be the result of reciprocal products of unequal crossover.
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Affiliation(s)
- P F Chance
- Department of Pediatrics, University of Utah Medical Center, Salt Lake City 84132
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Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve 1992; 15:368-73. [PMID: 1557086 DOI: 10.1002/mus.880150317] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We describe three families with X-linked recessive Charcot-Marie-Tooth (CMT) neuropathies. The disease phenotype in family 1 was characterized by infantile onset, weakness of lower legs, areflexia, pes cavus, and mental retardation (2 of 5 patients). The disease phenotype in families 2 and 3 was characterized by late onset, distal weakness, and normal intelligence. Hereditary spastic paraparesis was also present in the CMT patients of family 2. Thirty X-linked DNA markers were used for linkage studies. A maximum lod score of +3.48 was obtained by multipoint linkage analysis for the DXS16 locus mapped at Xp22.2 in family 1. In families 2 and 3, there was suggestion of linkage of Xq26 markers; the peak multipoint lod score for these 2 CMT families was 1.81, at DXS144. These results were suggestive of heterogeneity. The joint analysis including both regions (Xp22.2 and Xq26) provided evidence against homogeneity (chi 2 = 9.12, P less than 0.005).
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Affiliation(s)
- V V Ionasescu
- Department of Pediatrics, University of Iowa Hospitals, Iowa City 52242
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Lebo RV, Chance PF, Dyck PJ, Redila-Flores MT, Lynch ED, Golbus MS, Bird TD, King MC, Anderson LA, Hall J. Chromosome 1 Charcot-Marie-Tooth disease (CMT1B) locus in the Fc gamma receptor gene region. Hum Genet 1991; 88:1-12. [PMID: 1683643 DOI: 10.1007/bf00204921] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy) loci have been reported to be on at least three chromosomes: 1 (CMT1B, HMSN1B), 17 (CMT1A), and X (CMTX). In this study multipoint linkage analysis of two Duffy-linked families given a combined LOD score of 8.65 to establish that the Duffy-linked CMT1B gene exists in the 18 centimorgan region between the antithrombin III gene and the Duffy/sodium-potassium ATPase loci. The simultaneous segregation of polymorphisms near the CMT1A locus on chromosome 17 excludes linkage to this chromosome region in both families. Polymorphic sites that flank the CMT1B gene have been subchromosomally localized to the proximal chromosome-1 long arm (1q21.2----1q25) by spot blot analysis of sorted chromosomes, polymorphic deletion analysis, in situ hybridization, and multipoint linkage analysis.
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Affiliation(s)
- R V Lebo
- Department of Obstetrics, Gynecology, University of California, San Francisco 94143-0720
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Brunner HG, Smeets B, Smeets D, Nelen M, Cremers CW, Ropers HH. Molecular genetics of X-linked hearing impairment. Ann N Y Acad Sci 1991; 630:176-90. [PMID: 1683204 DOI: 10.1111/j.1749-6632.1991.tb19586.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- H G Brunner
- Department of Human Genetics, University Hospital, Nijmegen, The Netherlands
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47
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Mostacciuolo ML, Müller E, Fardin P, Micaglio GF, Bardoni B, Guioli S, Camerino G, Danieli GA. X-linked Charcot-Marie-Tooth disease. A linkage study in a large family by using 12 probes of the pericentromeric region. Hum Genet 1991; 87:23-7. [PMID: 1674715 DOI: 10.1007/bf01213086] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Linkage analysis was performed on 41 subjects belonging to a large family with a recurrence of X-linked Charcot-Marie-Tooth disease (CMTX), by using 12 restriction fragment length polymorphism markers mapping in p11-q13. The results are in agreement with previous linkage data. Three new markers that are potentially useful for genetic analysis of CMTX families are described. A more precise estimate of the localization of the disease locus was attempted by multipoint linkage analysis.
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48
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Vance JM, Barker D, Yamaoka LH, Stajich JM, Loprest L, Hung WY, Fischbeck K, Roses AD, Pericak-Vance MA. Localization of Charcot-Marie-Tooth disease type 1a (CMT1A) to chromosome 17p11.2. Genomics 1991; 9:623-8. [PMID: 1674726 DOI: 10.1016/0888-7543(91)90355-i] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Charcot-Marie-Tooth (CMT) disease type 1a has been previously localized to chromosome 17 using the markers D17S58 and D17S71. In that report we were unable to provide unequivocal localization of the CMT1A gene on either the proximal p or the q arm. Therefore, data from one additional CMT1A family and typing of other probes spanning the pericentromeric region of chromosome 17 (D17S73, D17S58, D17S122, D17S125, D17S124) were analyzed. Multipoint analysis demonstrates convincing evidence (log likelihood difference greater than 5) that the CMT1A gene lies within 17p11.2 and most likely between the flanking markers D17S122 and D17S124.
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Affiliation(s)
- J M Vance
- Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
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49
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Affiliation(s)
- J M Vance
- Department of Medicine, Duke University Medical Center, Durham, NC 27710
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50
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Sghirlanzoni A, Pareyson D, Scaioli V, Marazzi R, Pacini L. Hereditary motor and sensory neuropathy type I and type II. ITALIAN JOURNAL OF NEUROLOGICAL SCIENCES 1990; 11:471-9. [PMID: 2272782 DOI: 10.1007/bf02336567] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In an attempt to clearly identify the different HMSN subgroups, we prospectively evaluated 128 subjects (46 index cases, 39 affected and 43 unaffected relatives) on clinical, genetic and electrophysiological grounds. The diagnosis of HMNS I or II was made in 77 patients. Differential diagnosis between type I and II patients was impossible on clinical grounds alone, but nerve conduction study showed a clear-cut subdivision into two populations. MCV behavior was consistent within families. Inheritance, autosomal dominant in almost all cases, was probably recessive in three HMSN I subjects and pedigree analysis pointed to X-linked transmission in one HMSN I family. We found no evidence for linkage to Duffy locus. We think that similar HMSN phenotypes can be determined by different gene defects. Ulnar nerve F-conduction velocity did not significantly differ from distal MCV in HMSN I: the evidence of a diffuse slowing of nerve conduction supports the hypothesis of a primary myelin defect.
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Affiliation(s)
- A Sghirlanzoni
- III Divisione di Neurologia Istituto Nazionale Neurologico C. Besta, Milano
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