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Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.
Ann N Y Acad Sci. 1999 Sep 14; 883:366-82.AN

Abstract

We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females 7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.

Authors+Show Affiliations

Department of Clinical Neurological Sciences, London Health Sciences Centre, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10586261

Citation

Hahn, A F., et al. "Genotype/phenotype Correlations in X-linked Dominant Charcot-Marie-Tooth Disease." Annals of the New York Academy of Sciences, vol. 883, 1999, pp. 366-82.
Hahn AF, Bolton CF, White CM, et al. Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease. Ann N Y Acad Sci. 1999;883:366-82.
Hahn, A. F., Bolton, C. F., White, C. M., Brown, W. F., Tuuha, S. E., Tan, C. C., & Ainsworth, P. J. (1999). Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease. Annals of the New York Academy of Sciences, 883, 366-82.
Hahn AF, et al. Genotype/phenotype Correlations in X-linked Dominant Charcot-Marie-Tooth Disease. Ann N Y Acad Sci. 1999 Sep 14;883:366-82. PubMed PMID: 10586261.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease. AU - Hahn,A F, AU - Bolton,C F, AU - White,C M, AU - Brown,W F, AU - Tuuha,S E, AU - Tan,C C, AU - Ainsworth,P J, PY - 1999/12/10/pubmed PY - 1999/12/10/medline PY - 1999/12/10/entrez SP - 366 EP - 82 JF - Annals of the New York Academy of Sciences JO - Ann. N. Y. Acad. Sci. VL - 883 N2 - We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females 7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/10586261/Genotype/phenotype_correlations_in_X_linked_dominant_Charcot_Marie_Tooth_disease_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=1999&volume=883&spage=366 DB - PRIME DP - Unbound Medicine ER -