Pes cavus pathogenesis in Charcot–Marie–Tooth disease type 1A
Received March 15, 2006. Accepted April 4, 2006.
Sir, We thank Drs Burns and Ouvrier for their interest regarding our article; in their letter, they raise several concerns that we are going to address. But before doing so, we would like to emphasize the rationale of our study (Gallardo et al., 2006
). In previous longitudinal clinico-electrophysiological studies in 12 Charcot–Marie–Tooth disease type 1A duplication (CMT-1A) secondary patients (symptomatic or asymptomatic at-risk relatives affected upon clinico-electrophysiological examination), performed from infancy as the inclusion period (range: 1 month to 5 years; mean: 2 years) to the third decade of life (range: 6–23 years; mean: 13 years), we had found the following outstanding features (García et al., 1998; Berciano et al., 2000, 2003): (i) abnormal post-natal nerve conduction maturation in every patient; (ii) all 12 children had normal milestones; (iii) during the inclusion period only two infants (17%) had already developed symptoms, whereas five (42%) were symptomatic at the end; (iv) number of abnormal examinations at the beginning was 6 (50%) and at conclusion was 10 (83%); (v) during the inclusion period, observed signs comprised lower limb areflexia, nerve enlargement, foot semeiology including pes cavus and shortening of Achilles' tendon, and difficulty in heel walking with no weakness or atrophy of peroneal musculature till the second decade of life; and (vi) progressive atrophy of extensor digitorum brevis (EDB) muscle correlated not with the degree of motor conduction velocity (MCV) slowing of peroneal nerve but with the degree of attenuation of compound muscle action potential (CMAP) of EDB. As pes cavus and intrinsic foot muscle atrophy may precede the appearance of peroneal muscle atrophy, we hypothesized that initial walking difficulties correlate with abnormal foot architecture owing to selective denervation of the intrinsic foot muscles. Upon this background we planned a clinico-MRI study of foot and leg musculature in CMT-1A in two case groups: (i) six patients (one proband and five secondary cases) with no disability on the functional disability scale (FDS) (Birouk et al., 1997) and no weakness of flexo-extensor ankle muscles; and (ii) five patients (all secondary cases) with FDS scores indicative of mild or moderate gait impairment and paresis of ankle dorsiflexor muscles. If we were right, MRI study should show abnormal signal of foot muscles with normal signal of leg muscles in the first group of patients, and abnormal signal of both foot and leg muscles in the second group. And in effect, our MRI study demonstrated that all six patients of the first group showed abnormal muscle signal restricted to intrinsic foot musculature, a fact reinforcing the pathogenetic role of these muscles in the initiation of pes cavus. Nevertheless, it is worth noting that, as stated in our paper, in more severe cases with peroneal paresis, muscle leg imbalance may play a pathophysiological role in walking and in foot semeiology (Gallardo et al., 2006).
As underlined by Burns and Ouvrier, one hypothetical model of leg muscle imbalance as the cause of pes cavus in CMT is a weak peroneus brevis overpowered by a relatively stronger tibialis posterior causing adduction of the forefoot and inversion of the hindfoot. In our six patients with normal FDS scores there was no weakness of peronei, and in each case peroneus brevis muscle MRI signal was normal both in coronal and axial images (Fig. 1). These findings do not support such a hypothetical model of leg muscle imbalance.
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Burns and Ouvrier found it surprising that while all of our CMT-1A patients exhibited pes cavus deformity, 55% of the sample demonstrated normal leg muscle power using the Medical Research Council (MRC) scale. In contrast with their criterion, this is not in contradiction with other CMT-1A series demonstrating leg and foot weakness in 78–93% of cases (Birouk et al., 1997
; Kajeswski et al., 2000; Verhamme et al., 2004). Selection bias of our patients accounts for the difference, as 10 out of the 11 patients were secondary cases with either no or at most moderate punctuation on the FDS. In Birouk's series, non-symptomatic at-risk relatives represented only 27% cases (32 out of 112); in Kajeswski's series just 4 out of 43 patients were asymptomatic, 26 of the 39 symptomatic patients requiring ankle bracing (26 cases) or wheelchair (8 cases); and Verhamme's series comprised 51 patients (28 probands), 86% of them becoming symptomatic in the first two decades of life. Krajewski et al. (2000) found that most electrophysiological potentials in the feet were unobtainable, whereas in our patients attenuated CMAPs were recorded in EDB in all 11 patients and in 10 patients in abductor hallucis. This is an objective demonstration of the differential clinical severity between both series. In our paper, we wrote that wishing to analyse initial semeiology we deliberately selected 10 secondary cases, 6 of them exhibiting no disability on FDS and categorized as mild on CMT neurological score (Gallardo et al., 2006). It is evident that there is no place to compare our limited and selected sample series with any large cohort of patients.
The next concern manifested by Burns and Ouvrier is related to our interpretation of difficulties in heel walking and tiptoe walking, and the limitation of ankle dorsal flexion that they considered within normal range. We disagree with their criterion. It is generally held that the normal ankle may be expected to permit dorsiflexion 
70° (from 90° to 70°; anatomical, 20°). In our patients, ankle dorsal flexion ranged between 70° (normal, 2 cases) and 80° or 85° (reduced to half or quarter normal) in the remainder. Only one of our four patients with difficulty, but not impossibility, in tiptoe walking showed mild paresis of plantar flexors. MRI demonstrated mild changes in three cases in the superficial posterior leg compartment (see Fig. 6A in Gallardo et al., 2006). In the absence of ankle flexo-extensor muscle weakness or frank fatty muscle infiltration on MRI, our ‘sound’ interpretation is that alteration of foot architecture is essential for determining difficulties in heel walking and to a much lesser degree in tiptoe walking.
We recorded leg muscle strength using the MRC scale as we planned to correlate clinical-MRI findings in all 11 muscles of anterior, lateral and posterior leg compartments, which are gathered together in 7 groups in Table 1 (Gallardo et al., 2006). To achieve this objective using hand-held dynamometry would have been cumbersome. In any case, in CMT-1A there is evidence of good correlation between quantitative motor testing and clinical motor examination (Krajewski et al., 2000). And more importantly to our objective, we demonstrated an excellent clinico-MRI correlation in terms of differentiating patients with or without leg muscle involvement, though some discrepancies were duly commented on (Gallardo et al., 2006). Wishing to further clarify the issue, we have reviewed the electrophysiological recordings to determine CMAP amplitudes of tibialis anterior obtained after stimulating the peroneal nerve at the knee. CMAPs were recorded in nine patients (Nos. 2–7 and 9–11); intriguingly, CMAP amplitudes were normal (
5 mV) in patients with FDS of 0 or 1, and attenuated (1.4–2.6 mV) in patients with FDS of 2 or 3. These data prove the excellent clinico-electrophysiological correlation of our study. Accepting that our findings call for confirmation, we do not share the view manifested by Burns and Ouvrier that our ‘method of clinical examination may have been inaccurate’ or ‘possibly imprecise’. Furthermore, the quotation from the paper by Thomas et al. (1997), describing 61 apparently CMT-1A proband cases, is not applicable to secondary cases, as by no means all secondary cases show ‘almost universal weakness of the leg and foot muscles’.
We entirely agree with Burns and Ouvrier that longitudinal studies of the natural history of CMT-1A are needed to understand the pathogenesis of pes cavus and develop new treatments for this disabling foot deformity. Longitudinal studies in a disorder with very slow clinical course, such as CMT-1A, are not an easy task. As it took us two decades of observation to demonstrate the clinico-electrophysiological evolution of EDB muscle atrophy in CMT-1A children, we wrote that a similar study for other muscles not so distal (e.g. tibialis anterior or abductor pollicis brevis) would probably require two generations of neurologists observing (Berciano et al., 2000). In the meantime, it is our sincere belief that cross-sectional studies with fresh nosological ideas are worthwhile.
1 Services of Neurology, University Hospital ‘Marqués de Valdecilla’, University of Cantabria Santander, Spain 2 Services of Radiology, University Hospital ‘Marqués de Valdecilla’, University of Cantabria Santander, Spain 3 Clinical Neurophysiology, University Hospital ‘Marqués de Valdecilla’, University of Cantabria Santander, Spain
Correspondence to: Prof. José Berciano, Service of Neurology, University Hospital ‘Marqués de Valdecilla’ (UC), 39008 Santander, Spain E-mail: jaberciano{at}humv.es
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