Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease

被引:71
作者
Hahn, AF
Bolton, CF
White, CM
Brown, WF
Tuuha, SE
Tan, CC
Ainsworth, PJ
机构
[1] London Hlth Sci Ctr, Dept Clin Neurol Sci, London, ON N6A 5A5, Canada
[2] Univ Western Ontario, London, ON N6A 5A5, Canada
[3] Univ Calgary, Calgary, AB T2N 1N4, Canada
[4] Foothills Hosp, Dept Neurol Sci, Calgary, AB, Canada
[5] New England Med Ctr, Dept Neurol, Boston, MA USA
[6] London Hlth Sci Ctr, Dept Biochem, London, ON N6A 5A5, Canada
来源
CHARCOT-MARIE-TOOTH DISORDERS | 1999年 / 883卷
关键词
D O I
10.1111/j.1749-6632.1999.tb08598.x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:366 / 382
页数:17
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