Brain Advance Access originally published online on November 29, 2005
Brain 2006 129(2):426-437; doi:10.1093/brain/awh693
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Charcot–Marie–Tooth disease type 1A duplication: spectrum of clinical and magnetic resonance imaging features in leg and foot muscles
Services of 1 Radiology, 2 Clinical Neurophysiology and 3 Neurology, 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
 |
Summary |
|---|
 Top Summary IntroductionPatients and methodsResultsDiscussionReferences |
|---|
MRI is an ideal method for identifying areas of muscle atrophy and fatty infiltration. Studies comparing clinical and MRI features of foot and leg muscle atrophy in Charcot–Marie–Tooth disease type 1A (CMT-1A) duplication are lacking. The aim of this study is to describe clinical and MRI patterns of lower limb amyotrophy in CMT-1A. A total of 10 secondary CMT-1A patients and 1 proband patient with de novo mutation were prospectively evaluated. Ages of patients ranged from 8 to 61 years (median, 24). Disease severity in terms of ability to walk and run was established using a nine-point functional disability scale (FDS). We administered the CMT neuropathy score (CMTNS), based on patient's symptoms, neurological examination and neurophysiological testing. Muscle strength of flexo-extensor ankle and toe muscles was assessed manually with the standard Medical Research Council scale. In all 11 patients, leg MRI study included T1- and T2-weighted spin-echo sequences in coronal and axial planes, and a T1-weighted spin-echo sequence with chemical sift fat suppression before and after paramagnetic contrast agent injection. In seven patients both feet were simultaneously studied in coronal and axial planes. Six patients had pes cavus, an FDS score of 0 (normal), mild CMTNS and normal muscle power of foot flexo-extensors. In these six patients, MRI showed muscle fatty infiltration of intrinsic foot muscles mainly involving the lumbricals, all four leg muscle compartments being preserved. The remaining five patients had FDS scores from 1 (cramps or fatigability) to 3 (walking difficulty), mild to moderate CMTNS and variable weakness of peroneal musculature. In these five patients MRI showed, besides intrinsic foot muscle involvement, variable and distally accentuated fatty infiltration of the lateral, anterior and superficial posterior leg muscle compartments and, to a lesser degree, of the deep posterior compartment. In four patients muscle oedema and post-contrast enhancement was noted. MRI demonstrated fatty infiltration of clinically normal muscles. We conclude that clinical-MRI patterns of lower limb muscle atrophy vary with evolution of semiology. Selective involvement of intrinsic foot muscles is the characteristic pattern of CMT-1A cases with minimal disease signs. Afterwards this pattern usually combines variable involvement of leg muscles. Our findings help to clarity the pathogenesis of pes cavus in the disease.
Key Words: hereditary neuropathy; CMT-1A; 17p11.2 duplication; pes cavus; MRI; muscle denervation; muscle atrophy; muscle fatty infiltration; muscle oedema
Abbreviations: ADH = adductor hallucis; ADM = abductor digiti minimi; AH = abductor hallucis; CMAP = compound muscle action potential; CMT-1A = Charcot–Marie–Tooth disease type 1A; CMTNS = Charcot–Marie–Tooth neuropathy score; EDB = extensor digitorum brevis; EDL = extensor digitorum longus; EHL = extensor hallucis longus; FDS = functional disability scale; FHB = flexor hallucis brevis; GM = gastrocnemius medialis; MCV = motor conduction velocity; MRC = Medical Research Council; PB = peroneus brevis; PL = peroneus longus; TA = tibialis anterior
Received June 9, 2005. Revised September 23, 2005. Accepted October 24, 2005.
|
Introduction |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Charcot–Marie–Tooth disease type 1A (CMT-1A) is an autosomal dominant demyelinating polyneuropathy usually associated with a large DNA duplication on the short arm of chromosome 17 (Lupski et al., 1991
; Raeymaekers et al., 1991; Hallam et al., 1992). The hallmark of the disease is a peroneal muscular atrophy syndrome of variable severity and marked and diffuse slowing of nerve conduction velocity (Dyck and Lambert, 1968; Harding and Thomas, 1980; Berciano et al., 1989; Nicholson, 1991; Harding, 1995; García et al., 1998). Symptoms are present during the first decade of life in over 60% of cases (Harding and Thomas, 1980). The clinical course is quiescent in adult patients (Hoogendijk et al., 1994), though significant age-dependent increase of either mean weakness score (Harding and Thomas, 1980; Berciano et al., 1989) or neuropathic deficit (Dyck et al., 1989) has been reported in cross-sectional studies; furthermore, functional disability increases with disease duration (Birouk et al., 1997). In a longitudinal study of secondary CMT-1A patients performed in infancy and early childhood, we have shown that clinical course in the first two decades is less quiescent, serial examination allowing detection of the appearance of new clinical signs (García et al., 1998; Berciano et al., 2000, 2003).
Pes cavus deformity in CMT, a cardinal manifestation of the disease, is defined as pes cavus secondary to a plantar flexion deformity of the first metatarsal with no contribution to the cavus deformity by a dorsiflexion deformity of the calcaneus (Tynan et al., 1992). The theories of aetiology of pes cavus involving muscle balance fall into two main categories: those involving the intrinsic muscles of the foot and those involving the muscles of the legs (Sabir and Lyttle, 1983; Mann and Missirian, 1988; Alexander and Johnson, 1989; Tynan et al., 1992; Holmes and Hansen, 1993; Guyton and Mann, 2000). The role of the intrinsic foot muscle in the aetiology of pes cavus is difficult to decide upon and opposing theories exist (Tynan et al., 1992). In fact, most authors agree with the contention that pes cavus in CMT results from an imbalance between the peroneus longus (PL) and its antagonist, the tibialis anterior (TA). Such contention, however, derives from studies including CMT proband cases with evident weakness of peroneal musculature and not from series analysing secondary cases in early stages of the clinical course where foot deformities occur with no evidence of leg muscle weakness (García et al., 1998; Berciano et al., 2003).
MRI has an important role in the detection and characterization of pathological conditions of the skeletal muscle that cause changes in muscle signal intensity (Fleckenstein et al., 1993; May et al., 2000; Farber and Buckwalter, 2002). Normal skeletal muscle is characterized by intermediate to low signal intensity in all sequences. The MRI finding of high signal intensity within skeletal muscle is, on T2-weighted images, non-specific for any condition and can be seen in cases with oedema, rhabdomyolysis, denervation, muscular dystrophies or inflammatory myopathies (Garcia, 2000; May et al., 2000; Farber and Buckwalter, 2002). Muscle atrophy, regardless of the aetiology, has a characteristic MRI appearance, and T1-weighted spin-echo images are extremely useful in its identification because of the high signal intensity of the fat tissue (May et al., 2000). MRI may also help to evaluate the extent and number of muscle lesions and eventually to follow their evolution under therapy (Garcia, 2000). In the only MRI study of calf musculature performed in 23 CMT patients with no genetic screening, Stilwell et al. (1995) reported muscle atrophy and areas of fatty infiltration in anterior, lateral and posterior compartments; however, clinical-MRI correlation in this study is lacking.
We therefore conducted a clinical, electrophysiological and MRI study in 11 CMT-1A patients with ages ranging from the first to the seventh decade of life. We focused particularly on the lower limb clinical signs and their correlation with MRI muscle lesions. Furthermore, we evaluated MRI involvement of intrinsic foot muscles in selected asymptomatic patients with incipient signs to determine the first muscles implicated in the disease and their pathophysiological role in the appearance of foot deformities.
|
Patients and methods |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients
From our CMT-1A cases under the current serial follow-up, we selected a proband male case with de novo mutation and 10 secondary cases (5 females and 5 males) either asymptomatic and with minimal signs of disease or symptomatic and with evident signs of peroneal muscular atrophy. These patients had proven 11p11.2 duplication and came from six unrelated pedigrees, three of which have already been included in previous studies (Combarros et al., 1983
; Berciano et al., 1989; Middleton-Price et al., 1990; Hallam et al., 1992; García et al., 1998; Berciano et al., 2000, 2003). To avoid the influence of previous surgical procedures on the interpretation of foot semiology, we only included patients with no antecedents of foot orthopaedic surgical corrections. Known causes of acquired polyneuropathy were discounted in each patient. All patients and parents of under age patients gave informed consent to participate in the study, which was approved by the Ethics Committee of the University Hospital ‘Marqués de Valdecilla’.
Clinical assessment
Patients were clinically evaluated by taking a detailed history. Development of motor milestones, presence of cramps, clumsiness in walking or running, shoes not fitting, painful corns or callouses, and difficulty in digital manipulation were specifically questioned. Examination was video-recorded in each patient. We specifically looked for difficulties in heel walking or tiptoe walking, shortening of tendon Achilles, foot deformities (including toe clawing, pes cavus, equinus or varus, flattening of transverse arcus plantaris), atrophy of intrinsic foot muscles [extensor digitorum brevis (EDB), abductor hallucis (AH) and flexor hallucis brevis (FHB)] and presence of callosity. Ankle dorsiflexion and ankle plantar flexion were routinely evaluated by using a goniometer. Although the range of movement varies in different individuals, the normal ankle may be expected to permit dorsiflexion of the foot to 
70° (anatomic, 20°) and plantar flexion to 135° (anatomic, 45°) (Kendall et al., 1974). Muscle strength of flexo-extensor ankle and toe muscles was assessed manually using the standard Medical Research Council (MRC) scale. In each patient muscle power specifically included the following leg muscles: extensor digitorum longus (EDL), TA, extensor hallucis longus (EHL), PL, peroneus brevis (PB) (peronei), long toe flexors (LTF) including flexor digitorum longus (FDL) and flexor hallucis longus (FHL), tibialis posterior (TP), and plantar flexors (PF) including soleus and gastrocnemius medialis (GM) and gastrocnemius lateralis. In patients with severely limited foot dorsiflexion, TA muscle strength was evaluated not starting from foot ankle at the 90° position but allowing the patient a mild plantar flexion.
In order to determine physical disability we used two scales. First, disease severity in terms of ability to walk and run was assessed according to a nine-point functional disability scale (FDS) from 0 to 8 as follows: 0 = normal; 1 = normal, but with cramps or fatigability; 2 = inability to run; 3 = walking is difficult but still possible unaided; 4 = able to walk with a cane; 5 = able to walk with crutches; 6 = able to walk with a walker; 7 = wheelchair bound; and 8 = bedridden (Birouk et al., 1997). And secondly, we administered the recently created CMT neuropathy score (CMTNS), based on patient's symptoms, neurological examination and neurophysiological testing (Shy et al., 2005). In short, patients could be divided into mild (CMTNS, 
10 points), moderate (CMTNS, 11–20) and severe (CMTNS, 21–36) categories.
Electrophysiological study
We studied motor conduction velocities (MCVs) of the median, tibial and peroneal nerves in all 11 patients. Recordings were performed by standard methods using surface stimulating and recording electrodes. MCV of the median nerve was assessed by stimulation at the elbow and at the wrist while recording the compound muscle action potentials (CMAPs) over abductor pollicis brevis. In the same way, MCVs of the peroneal and tibial nerves were assessed by stimulation at the knee and ankle while recording the CMAP over the extensor EDB and AH, respectively. CMAP amplitude was measured from the baseline to the negative peak.
MRI study
MRI was performed using a 1.5 T clinical scanner (Sigma, General Electric Medical Systems, Milwaukee, W). All patients were studied using a commercially available phase-array multicoil, centred between both calves at the level of the greatest diameter of the lower leg, the patient being in a supine position. To clearly delimitate all four muscle compartments, imaging was carried out in the transverse (field of view 24–32, slice thickness 10 mm, and slice gap 0.5–1.0 mm) and coronal planes (field of view 38–40, slice thickness 4–5 mm, slice gap 0.5–1.0 mm). We used the following protocol in all patients: T1-weighted fast spin-echo (FSE) sequence (TR/TE 400–540/9–11 and a 512 matrix) and fat-suppressed proton density (PD)-T2 weighted FSE sequence (TR/TE 3000–3500/50–70 and a 512 matrix) in both planes. Except in the youngest patient aged 8 years, we also obtained a T1-weighted spin-echo with chemical shift fat suppression sequence (TR/TE 500/9 and a 512 matrix) before and after paramagnetic contrast agent injection (GdDPTA-BMA, 0.2 ml/kg) in the axial plane.
In all patients with an FDS score of 0 and in one with a score of 2, both feet were also studied. We obtained images in coronal and axial planes with the same T1- and PD-T2 weighted sequences described above, using manufacturer's standard extremity coil. Imaging parameters were optimized to maximize the signal-to-noise ratio in order to obtain better spatial and contrast resolution permitting accurate delimitation of different muscle compartments and increasing muscle signal intensity while maintaining a reasonable imaging time.
In all MRI studies we looked for signal intensity alterations including muscle oedema, fatty infiltration and abnormal contrast enhancement. The distribution of these changes along the longitudinal axis of leg muscles was specifically analysed. Given the large number of examined muscles, we did not attempt to quantify the degree of fatty infiltration in the calf and foot musculature.
Statistical analysis
Correlation study of electrophysiological data was performed using Pearson's correlation coefficient (r). Statistical significance was considered to exist when P-value was <0.05.
DNA analysis
With informed consent, molecular genetic study of 17p duplication was carried out as reported previously (Hallam et al., 1992; García et al., 1998).
|
Results |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Clinical findings
Clinical features are summarized in Table 1. There were six males and five females, with ages ranging from 8 to 61 years (median, 24). Except Patient 3, presenting as de novo mutation, the other 10 patients were secondary cases. Cases 4, 6–8, 10 and 11 came from the same pedigree (GV family). Four cases were asymptomatic even after detailed questioning. Symptomatic patients referred to foot deformities (3 cases), difficulty or fatigability in walking, or leg cramps (4 cases). This clinical selection bias explains low FDS scores, either 0 or 1, observed in seven cases, which corresponded in every patient with mild CMTNS category (see Table 1). The remaining four cases had either inability to run (FDS = 2) or difficulty in walking but still possible unaided (FDS = 3), which correlated with moderate disability on CMTNS. Leg muscle power in all six patients with an FDS score of 0 was normal. Case 4, aged 23 years and with an FDS score of 1, showed mild weakness of dorsiflexor and evertor foot muscles; however, severe limitation of passive ankle motion makes it difficult to establish with certainty the possible contribution of foot mechanical problems to this reduced muscle power. Be that as it may, none of these patients with FDS the score 0 showed atrophy of peroneal musculature (Fig. 1A and B). All four patients with FDS scores of 2 or 3 exhibited muscle weakness or amyotrophy involving TA, EHL, EDL and peronei, which was graded 3 or 4 on MRC scale (Fig. 1E and F). It is worth noting that none of them required ankle-foot orthotics. With just two exceptions (Cases 6 and 10), all patients showed difficulty or impossibility in heel walking; furthermore, four cases had difficulty in tiptoe walking despite muscle power of PF being preserved. This apparent discrepancy is explained by the presence of constant foot semiology that included a variable combination of the following signs (see Table 1 and Fig. 1C, D, G and H): atrophy of intrinsic foot muscles, pes cavus with flattening of transverse archus plantaris, inversion of calcaneus with adduction of the forefoot on posterior view (varus deformity), clawing of toes, shortening of the Achilles tendon, presence of callosity and limitation of ankle mobility mainly involving dorsiflexion. Note that EDB atrophy and pes cavus occurred in all 11 patients and that even early in the clinical course foot ankle dorsifexion could be restricted to 10° (Cases 1 and 2). Foot and leg semiology was relatively symmetric except in Patient 6 who exhibited marked atrophy of the right EDB muscle with preservation of the left one (Fig. 2A and B); she denied trauma at the right ankle extensor retinaculi, which could account for lesion of the deep peroneal nerve innervating EDB. The severity of semiology among patients from GV family varied: two members including one aged 60 years had an FDS score of 0, whereas the remaining four scored from 1 to 3 (see Table 1).
|
|
|
Electrophysiological findings
All patients had marked and uniform slowing of MCVs of median, peroneal and tibial nerves (Fig. 3). MCVs ranged from 12 to 37 m/s for the median nerve (21.2 ± 7.3; mean ± SD), from 8.5 to 27 m/s for the peroneal nerve (17.1 ± 6.1) and from 9.3 to 29.5 for the tibial nerve (19.9 ± 6.6). CMAP amplitudes of APB were reduced (
4 mV) in six cases (range, 0.2–3.5 mV; median, 2.2) and were normal in the remaining five cases (range, 4.4–6.3 mV). CMAP amplitudes of EDB were attenuated (<2 mV) in all 11 patients (range, 0.04–1.9 mV; median, 0.6); no correlation was found between the degree of slowing of MCV of peroneal nerve and the degree of EDB-CMAP attenuation (r = 0.3148; P > 0.05). In Case 6, CMAP amplitude of the right EDB was severely attenuated (0.2 mV) and of the left EDB was slightly attenuated (1.7 mV) (Fig. 2C and D); intriguingly, these findings correlated well with clinical findings and MRI findings. CMAP of AH was unobtainable in Case 8 and attenuated (<4 mV) in the remaining 10 cases (range, 0.1–2.4 mV; median, 0.8); no correlation was found between the degree of slowing of MCV of the tibial nerve and the degree of AH-CMAP attenuation (r = 0.631; P = 0.05), but CMAP amplitudes tended to be smaller in patients with lower MCV (data not shown).
|
MRI findings
MRI findings of anterior and lateral leg muscle compartments, which were the most severely involved, are summarized in Tables 2 and 3. No abnormalities were found in all six cases with the FDS score of 0 and normal MRC scores of leg muscles (Fig. 4). The only patient with an FDS score of 1 (No. 4) showed selective, subtle, symmetrical and distal fatty infiltration of both peronei. In the remaining four cases with FDS scores of 2 or 3, the outstanding lesion was bilateral and showed distally accentuated fatty infiltration, systematically involving both peronei and all three muscles of the anterior compartment (Fig. 5). Involvement of muscles of superficial and deep posterior compartments was not so uniform. Two cases (Nos. 9 and 11) showed bilateral fatty infiltration of all three muscles of superficial posterior compartment, whereas the remaining two (Nos. 7 and 8) exhibited involvement of either soleus (Fig. 5D) or GM. Proximal–distal gradient of lesions was lacking in three out of the five involved GM. The deep posterior leg compartment was the least involved, fatty infiltration of TP being observed in three cases (Nos. 7, 9, and 11).
|
|
|
|
Muscle oedema was also present in one-third of the muscles exhibiting fatty infiltration (see Tables 2 and 3, and Fig. 6A). Oedema did not follow the same topographical pattern to that of fatty infiltration: distal accentuation was not present and the posterior superficial compartment was the most frequently involved (Cases 7, 9 and 11) one. Contrast enhancement was noted in 59% of the muscles showing oedema (Fig. 6B and C), both abnormalities occurring in the same areas of affected muscles.
|
Intrinsic musculature of both feet was studied in coronal and axial planes in seven cases (Nos. 1–3, 5, 6, 8 and 10 in Table 1). All seven studies showed variable and bilateral fatty infiltration of the foot muscles, which was more marked in the severest cases (Figs 7 and 8). We will analyse our findings in accordance with the classical anatomical division of the muscles of the foot (Davies and Coupland, 1967
). MRI evaluation of Case 1, aged 8 years, was difficult due to technical reasons (patient's movement). In this case we were able to accurately illustrate unilateral and subtle involvement of EDB and lumbricals. EDB, the only dorsal muscle of the foot, was systematically wasted with clear asymmetrical involvement only in Case 6 (Fig. 2E). The first foot layer, comprising AH, flexor digitorum brevis (FDB) and abductor digiti minimi (ADM), was the most preserved, evident fatty infiltration of these muscles being only visualized in Case 8 (Figs 7 and 8). In the second foot layer, the lumbricals were systematically involved (Fig. 7C–F), whereas flexor digitorum accessorius was relatively preserved (Fig. 7C). All three muscles of the third foot layer, FHB, flexor digiti minimi brevis (FDMB) and adductor hallucis (ADH), were affected (Fig. 7C–F). Finally the only muscles of the fourth foot layer, the interossei, showed fatty infiltration in four cases (Fig. 7D and F).
|
|
|
Discussion |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
The current work describes clinical-electrophysiological features and MRI patterns of lower limb muscle atrophy in 11 patients with CMT-1A duplication, aged from 8 to 61 years. To our knowledge there are no previous studies correlating clinical and MRI findings in the disease. To analyse initial semiology, we deliberately selected 10 secondary cases, 6 of them exhibiting no disability on FDS (Birouk et al., 1997
) and categorized as mild on CMTNS (Shy et al., 2005). The other secondary cases showed either inability to run or difficulty in walking but still possible unaided and were categorized as moderate according to CMTNS. The remaining one patient (Case 3 in Table 1), aged 17, was with a de novo mutation who reported only foot deformities with no functional disability.
All six patients with an FDS score of 0, including one patient aged 60 years, showed neither atrophy nor weakness of peronei or TA muscles. These patients had foot deformities essentially consisting of a variable combination of pes cavus, toe clawing, flattening of transverse arcus plantaris, shortening of the Achilles tendon, or atrophy of EDB and AH muscles. Other foot findings included reduced range of ankle dorsiflexion and difficulties or impossibility in heel walking. In established CMT cases, forefoot cavus and heel walking difficulties have been correlated to muscle imbalance between peronei and TA muscles (Mann and Missirian, 1988; Alexander and Johnson, 1989; Tynan et al., 1992; Holmes and Hansen, 1993; Guyton and Mann, 2000). Our findings, however, argue against this contention and give support to the notion that forefoot cavus is initiated by selective weakness of intrinsic foot muscles (Sabir and Lyttle, 1983; Berciano et al., 2000, 2003). The first event would be atrophy and weakness of the lumbricals and other intrinsic foot muscles causing dorsiflexion of metatarsophalangeal joints, initially manifested as clawing of the toes and flattening of the transverse arcus plantaris. During gait, prior to toe-off, as metarsophalangeal joints extend, the plantar aponeurosis is wrapped around the metatarsal heads and the short flexors contract, approximating the pillars of the longitudinal arch and shortening the Achilles tendon that limits ankle dorsiflexion. Therefore initial foot deformities and walking difficulties correlate with abnormal foot architecture due to selective denervation of the intrinsic foot muscles (Berciano et al., 2003). In the remaining five patients with FDS scores of 1 to 3, categorized as mild to moderate on CMTNS, foot deformities were accompanied by weakness of peroneal musculature and hence muscle imbalance may play a pathophysiological role here in walking and foot semiology (Tynan et al., 1992; Guyton and Mann, 2000).
Our electrophysiological findings showed a striking uniformity of conduction slowing in all three nerves studied, which was always in the range established for CMT-1 and CMT-1A (Harding and Thomas, 1980; Kaku et al., 1993; Birouk et al., 1997; García et al., 1998). CMAP amplitudes of AH and EDB were bilaterally and markedly attenuated in all 11 cases, but were not significantly correlated with MCV of tibial and peroneal nerves, respectively (Hoogendijk et al., 1994). As might be expected from such CMAP attenuation, bilateral atrophy of EDB and AH muscles was almost systematically identified. Case 6 is an exception as apparent asymmetry of EDB wasting was corroborated by electrophysiological and MRI findings. Although muscular weakness has been considered symmetrical in patients with the hypertrophic type of CMT and asymmetrical in 20% of patients with the neuronal type of CMT (Buchthal and Behse, 1977), our findings indicate that in CMT-1A there may be not only intra-familial variability (Birouk et al., 1997; Garcia et al., 1995), as illustrated here in patients coming from GV family, but also intra-individual phenotypic variation.
There is electrophysiological and pathological evidence indicating that predominantly distal muscle weakness and atrophy in CMT-1A is due to slowly evolving length-dependent degeneration of motor axons (Gabreëls-Festen et al., 1992; Berciano et al., 2000; Krajewski et al., 2000). Therefore MRI study in CMT-1A should detect alterations of signal muscle intensity seen in the chronic stages of muscle denervation, which is manifested as fatty infiltration (May et al., 2000). Whether subacute muscle denervation occurs in the disease process, oedema with or without contrast enhancement, could be visualized (May et al., 2000; Farber and Buckwalter, 2002).
In our six patients with an FDS score of 0 and normal leg muscle balance, MRI study showed that fatty muscle infiltration and atrophy was limited to intrinsic foot muscles with preservation of leg muscles. Thus, MRI corroborates that in mild cases pathological findings may be restricted to the feet (Sabir and Lyttle, 1983; Berciano et al., 2000, 2003). There are no previous MRI studies analysing foot muscle semiology in CMT. Together with EDB, the most severely affected plantar foot muscles observed here, such as lumbricals, FHB, ADH, FDMB, interossei and ADM, are those which are anatomically more distal and therefore receiving the longest branches from peroneal or tibial nerves, a fact concurring with the proposal of a length-dependent degeneration of motor axons as the mechanism of muscle denervation in CMT-1A (Gabreëls-Festen et al., 1992; Berciano et al., 2000; Krajewski et al., 2000). The predominant wasting of lumbrical muscles, these being selectively atrophic in the youngest patient of this series aged 8 years, underlines their pathophysiological role in the initiation of foot semiology. In fact, weakening of lumbricals causes hyperextension of metatarsophalangeal joints and flexion of the inter-phalangeal joints (Kendall et al., 1974) leading to toe clawing and flattening of transverse arcus plantaris, which are outstanding signs early in the clinical course (Sabir and Lyttle, 1983; Berciano et al., 2003).
In five patients in this series with FDS scores ranging between 1 and 3 and with weakness of peroneal musculature, MRI showed fatty infiltration of leg muscles. Two kinds of selectivity of muscle involvement were observed. In the only patient with an FDS score of 1, fatty infiltration was restricted to peronei, a feature giving support to the original disease's designation of peroneal type of progressive muscular atrophy (Tooth, 1886). Together with peronei involvement, the remaining four patients had constant fatty infiltration of all three muscles of the anterior leg compartment and variable fatty infiltration of other muscles of the superficial and deep posterior compartments. As reported by Stilwell et al. (1995), fatty infiltration was either symmetrical or asymmetrical, increased from upper to lower sections in all quadrants except the GM and varied from patient to patient. This proximal-to-distal gradient of muscle changes again concurs with the proposal of a length-dependent degeneration of motor axons as the mechanism of muscle denervation in CMT-1A. The lack of distal migration of lesions in the GM remains unexplained (Stilwell et al., 1995).
Although clinical-MRI correlation was good in terms of differentiating patients with or without leg muscle involvement, several discrepancies are worth noting. Case 4 had marked limitation of foot dorsiflexion making it difficult to evaluate muscle power of ankle and toe dorsiflexors and evertors, which was graded as 4 on the MRC scale. MRI showed, however, that fatty infiltration involved only peronei. Cases 7 and 11 had severe second to fifth toe clawing again making it difficult to evaluate muscle power of EDL, which was graded as 3. On MRI, however, fatty infiltration was restricted to the distal third of the muscle, the degree of involvement being no different from other more powerful muscles. MRI showed subclinical changes of several muscles (graded as 5 on the MRC scale), such as peronei in Case 8, and GM, soleus, FHL or TP in Cases 7–9 and 11. In short, MRI examination might help to better interpret clinical signs and to delineate an accurate extent of muscle involvement in the disease.
Subacute muscle denervation causes oedema that does not usually become evident on MRI images until 2–4 weeks after denervation has occurred (Fleckenstein et al., 1993; May et al., 2000). The mechanism of this finding is probably due to shifting of water from intracellular to extracellular spaces (West et al., 1994). We found that leg muscle fatty infiltration was accompanied by oedema, sometimes with contrast enhancement, in four patients. This finding mainly involved peronei, gastrocnemius or soleus muscles. In a chronic disorder with minimal clinical progression over decades, such as CMT-1A, the presence of these lesions is difficult to interpret. Acute or subacute deterioration following long periods of stabilization or even stepwise progression of the disease has occasionally been reported in CMT-1A patients and correlated with a superimposed inflammatory component on the genetic condition (Gabriel et al., 2002; Ginsberg et al., 2004). None of our patients, however, showed any of these clinical courses. Accepting that our findings call for confirmation in future studies we can merely speculate that subclinical and superimposed nerve inflammation may be an operative pathogenic mechanism of muscle denervation in CMT-1A. Whether muscle oedema observed here is a preceding phenomenon to fatty infiltration in the course of chronic denervation remains another possibility; elucidation of this question also calls for future longitudinal MRI studies.
|
Acknowledgements |
|---|
The authors are grateful to Dr Rosario García Barredo for constructive support, to Mar Ruiz and Rosario Repoila for technical assistance and to Marta de la Fuente for secretarial help. This study was supported by ‘Centro de Investigación de Enfermedades Neurólogicas (CIEN), Nodo CO3/CO6, (ISCIII, Madrid, Spain)’ and ‘Instituto de Formación e Investigación Marqués de Valdecilla’ (IFIMAV, Santander, Spain).
|
References |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Alexander IJ, Johnson KA. Assessment and management of pes cavus in Charcot-Marie-Tooth disease. Clin Orthop Relat Res 1989; 246: 273–81.
Berciano J, Combarros O, Calleja J, Polo JM, Leno C. The application of nerve conduction and clinical studies to genetic counseling in hereditary motor and sensory neuropathy. Muscle Nerve 1989; 12: 302–6.[CrossRef][Web of Science][Medline]
Berciano J, García A, Calleja J, Combarros O. Clinico-electrophysiological correlation of extensor digitorum brevis muscle atrophy in children with Charcot-Marie-Tooth disease 1A duplication. Neuromuscul Disord 2000; 10: 419–24.[CrossRef][Web of Science][Medline]
Berciano J, García A, Combarros O. Initial semeiology in children with Charcot-Marie-Tooth disease. Muscle Nerve 2003; 27: 34–9.[CrossRef][Web of Science][Medline]
Birouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonabe T, et al. Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain 1997; 120: 813–23.
Buchthal F, Behse E. Peroneal muscular atrophy (PMA) and related disorders. 1. Clinical manifestations as related to biopsy findings, nerve conduction and electromyography. Brain 1977; 100: 41–66.
Combarros O, Calleja J, Figols J, Cabello A, Berciano J. Dominantly inherited motor and sensory neuropathy type I. Genetic, clinical, electrophysiological and pathological features in four families. J Neurol Sci 1983; 61: 181–91.[CrossRef][Web of Science][Medline]
Davies DV, Coupland RE. Gray's anatomy. Descriptive and applied. London: Longmans; 1967. 727–36.
Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol 1968; 39: 1032–8.
Dyck PJ, Karnes JL, Lambert EH. Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology 1989; 39: 1302–8.
Farber JM, Buckwalter KA. MR imaging in nonneoplastic muscle disorders of the lower extremity. Radiol Clin N Am 2002; 40: 1013–31.[CrossRef][Web of Science][Medline]
Fleckenstein JL, Watumull D, Conner KE, Ezaki M, Greenlee RG Jr, Bryan WW, et al. Denervated human skeletal muscle: MR imaging evaluation. Radiology 1993; 187: 213–8.
Gabreëls-Festen AA, Joosten EM, Gabreëls FJ, Jennekens FG, Janssen-van Kempen TW. Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN) type 1. J Neurol Sci 1992; 107: 45–54.
Gabriel CM, Gregson NA, Wood NW, Hughes RAC. Immunological study of hereditary motor and sensory neuropathy type 1a (HMSN type I). J Neurol Neurosurg Psychiatry 2002; 72: 230–5.
Garcia J. MRI in inflammatory myopathies. Skeletal Radiol 2000; 29: 425–38.[CrossRef][Web of Science][Medline]
Garcia CA, Malamut RE, England JD, Parry GS, Liu P, Lupski JR. Clinical variability in two pairs of identical twins with the Charcot-Marie-Tooth disease type 1A duplication. Neurology 1995; 45: 2090–3.
García A, Combarros O, Calleja J, Berciano J. Charcot-Marie-Tooth disease type 1A with 17p duplication in early infancy and childhood. A longitudinal clinical and electrophysiological study. Neurology 1998; 50: 1061–7.
Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB, et al. Coexistent hereditary and inflammatory neuropathy. Brain 2004; 127: 193–202.
Guyton GP, Mann RA. The pathogenesis and surgical treatment of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin 2000; 5: 317–26.[Medline]
Hallam PJ, Harding AE, Berciano J, Barker DF, Malcolm S. Duplication of part of chromosome 17 is commonly associated with hereditary motor and sensory neuropathy type I (Charcot-Marie-Tooth disease type I). Ann Neurol 1992; 31: 570–2.[CrossRef][Web of Science][Medline]
Harding AE. From the syndrome of Charcot, Marie and Tooth to disorders of peripheral myelin proteins. Brain 1995; 118: 809–18.
Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980; 103: 259–80.
Holmes JR, Hansen ST. Foot and ankle manifestations of Charcot-Marie-Tooth disease. Foot Ankle 1993; 14: 477–86.
Hoogendijk J, de Visser M, Bolhuis PA, Hart AAM, Ongerboer de Visser BM. Hereditary motor and sensory neuropathy type I: clinical and neurographical features of the 17p duplication subtype. Muscle Nerve 1994; 17: 85–90.[CrossRef][Web of Science][Medline]
Kaku DA, Parry GJ, Malamut R, Lupsky JR, Garcia CA. Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy. Muscle Nerve 1993, 43: 2664–7.
Kendall HO, Kendall FP, Wadsworth GE. Músculos: pruebas y funciones. Barcelona: JIMS; 1974.
Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, et al. Neuronal dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 2000; 123: 1516–27.
Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L, Guzzetta V, Trask BJ, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 1991; 66: 219–32.[CrossRef][Web of Science][Medline]
Mann RA, Missirian J. Pathophysiology of Charcot-Marie-Tooth disease. Clin Orthop Relat Res 1988; 234: 221–38.
May DA, Disler DG, Jones EA, Balkissoon AA, Manaster BJ. Abnormal signal intensity in skeletal muscle at MR imaging: patterns, pearls, and pitfalls. RadoGraphics 2000; 20: S295–313.
Middleton-Price HR, Harding AE, Monteiro C, Berciano J, Malcolm S. Linkage of hereditary motor and sensory neuropathy type I to the pericentromeric region of chromosome 17. Am J Hum Genet 1990; 46: 92–4.[Web of Science][Medline]
Nicholson GA. Penetrance of the hereditary motor and sensory neuropathy Ia mutation: assessment by nerve conduction studies Neurology 1991; 41: 547–52.
Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type Ia (CMT Ia). Neuromuscul Disord 1991; 1: 93–7.[CrossRef][Medline]
Sabir M, Lyttle D. Pathogenesis of pes cavus in Charcot-Marie-Tooth disease. Clin Orthop Relat Res 1983; 175: 173–8.
Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 2005; 64: 1209–14.
Stilwell G, Kilcoyne RF, Sherman JL. Patterns of muscle atrophy in the lower limbs in patients with Charcot-Marie-Tooth disease as measured by magnetic resonance imaging. J Foot Ankle Surg 1995; 34: 583–6.[Medline]
Tooth HH. The peroneal type of progressive muscular atrophy. London: H.K. Lewis; 1886.
Tynan MC, Klenerman L, Helliwell TR, Edwards RHT, Hayward M. Investigation of muscle imbalance in the leg symptomatic forefoot pes cavus: a multidisciplinary study. Foot Ankle 1992; 13: 490–501.
West GA, Haynor DR, Goodkin R, Tsuruda JS, Bronstein AD, Kraft G, et al. Magnetic resonance imaging signal changes in denervated muscles after peripheral nerve injury. Neurosurgery 1994; 35: 1077–85.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in Brain:
- Editorial
- Alastair Compston
Brain 2006 129: 283-284.[Extract] [FREE Full Text]
This article has been cited by other articles:
|
|
 |
|
  C. Verhamme, I. N. van Schaik, J. H. T. M. Koelman, R. J. de Haan, and M. de Visser The natural history of Charcot-Marie-Tooth type 1A in adults: a 5-year follow-up study Brain, December 1, 2009; 132(12): 3252 - 3262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Berciano, E Gallardo, R Dominguez-Perles, E Gallardo, A Garcia, R Garcia-Barredo, O Combarros, J Infante, and I Illa Autosomal-dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype J. Neurol. Neurosurg. Psychiatry, February 1, 2008; 79(2): 205 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Berciano, E Gallardo, A Garcia, J Infante, I Mateo, and O Combarros Charcot-Marie-Tooth disease type 1A duplication with severe paresis of the proximal lower limb muscles: a long-term follow-up study J. Neurol. Neurosurg. Psychiatry, October 1, 2006; 77(10): 1169 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Burns and R. Ouvrier Pes cavus pathogenesis in Charcot-Marie-Tooth disease type 1A. Brain, July 1, 2006; 129(Pt 7): E50 - E50. [Full Text] [PDF]
|
|
|
|
|
|
J. Berciano, E. Gallardo, A. Garcia, and O. Combarros Pes cavus pathogenesis in Charcot-Marie-Tooth disease type 1A. Brain, July 1, 2006; 129(Pt 7): E51 - E51. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||