Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a large Swiss family with Charcot–Marie–Tooth neuropathy Thierry Kuntzer a, * , Murielle Dunand a , Daniel F. Schorderet b , Jean-Michel. Vallat c , Angelika F. Hahn d , Julien Bogousslavsky a a Service de Neurologie, Centre Hospitalier Universitaire Vaudois, BH 7/306, 1011, Lausanne, Switzerland b Division de Ge ´ne ´tique Me ´dicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland c Service de Neurologie, Centre Hospitalier Universitaire Dupuytren, Limoges, France d Department of Neurological Sciences, London, Ontario, Canada Received 25 October 2001; received in revised form 23 September 2002; accepted 15 October 2002 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. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Hereditary motor and sensory neuropathies; X-linked Charcot – Marie – Tooth; CMTX; Connexin 32 mutation 1. Introduction Charcot and Marie [1], Tooth [2], and subsequently, Hoff- mann [3] and Herringham [4] were the first to study what came to be known as Charcot – Marie – Tooth (CMT) disease. They recognized the characteristic clinical phenotype of distal leg weakness and atrophy, decreased sensation, and absent reflexes, and appreciated the fact that the disease was hereditary. Little new was added until the late 1950s, when it was found that some patients with CMT neuropathy had slow nerve conduction velocities (NCVs) [5]. In the 1960s and 1970s, the CMT1 and two subtypes were defined by NCVs, with CMT1 having markedly slow velocities in the range of 15–30 m/s and CMT2 having near-normal veloc- ities over 40 m/s [6]. Some investigators [7,8] recognized families with ‘‘intermediate’’ NCVs, suggesting a third en- tity. The conduction changes in CMT1 were further defined as being uniformly slow in contrast to the multifocal slowing seen in chronic acquired demyelinating neuropathies [9]. This observation proved clinically useful in distinguishing familial and acquired disorders, and has subsequently been shown to hold true for patients with CMT1a [8,10 – 13]. However, it is less clear whether conduction changes are uniform in other forms of CMT disease [14]. Electrophysio- logical studies have provided important information about the cause of weakness in CMT patients; there is increasing awareness that weakness and disability are less correlated with NCVs than with the compound muscle action poten- tial (CMAP) amplitude, a marker of axonal degeneration [13,15]. 0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII:S0022-510X(02)00394-5 * Corresponding author. E-mail address: thierry.kuntzer@chuv.hospvd.ch (T. Kuntzer). www.elsevier.com/locate/jns Journal of the Neurological Sciences 207 (2003) 77 – 86