ELECTROMYOGRAPHIC TENDON REFLEX RECORDING: AN ACCURATE AND COMFORTABLE METHOD FOR DIAGNOSIS OF CHARCOT-MARIE-TOOTH DISEASE TYPE 1A ANTONIO GARCIA, MD,1 ANA L. PELAYO-NEGRO, MD,2 SILVIA ALVAREZ-PARADELO, MD,1 3 2 FRANCISCO M. ANTOLIN, MD, and JOSE BERCIANO, MD 1
Service of Clinical Neurophysiology, University Hospital Marqu es de Valdecilla, Instituto de Investigaci on Marqu es de Valdecilla, University of Cantabria and Centro de Investigaci on Biom edica en Red de Enfermedades Neurodegenerativas, Santander, Spain 2 Service of Neurology, University Hospital Marqu es de Valdecilla, Instituto de Investigaci on Marqu es de Valdecilla, University of Cantabria and Centro de Investigaci on Biom edica en Red de Enfermedades Neurodegenerativas, Santander, Spain 3 Service of Epidemiology, University Hospital Marques de Valdecilla and Instituto de Investigaci on Marqu es de Valdecilla, Santander, Spain Accepted 28 October 2014 ABSTRACT: Introduction: We analyzed the utility of tendon reflex (T-reflex) testing in Charcot-Marie-Tooth disease type 1A (CMT1A). Methods: A total of 82 subjects from 27 unrelated CMT1A pedigrees were evaluated prospectively. The series also comprised 28 adult healthy controls. Electrophysiology included evaluation of biceps T-reflex and soleus T-reflex. Results: Seventy-one individuals (62 adults and 9 children) had clinical and electrophysiological features of CMT1A. The remaining 11 (8 adults and 3 children) were unaffected. On electrophysiological testing, the biceps T-reflex was elicited in 58 of 62 (93%) adult CMT1A patients and in all 9 affected children. Latencies of the biceps T-reflex were always markedly prolonged, and a cut-off limit of 16.25 ms clearly separated adult patients and controls or unaffected kin adult individuals. In affected children, the soleus T-reflex latency was also prolonged when compared with age and height normative data. Conclusion: T-reflex testing is an accurate diagnostic technique for CMT1A patients. Muscle Nerve 52: 39–44, 2015
Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating polyneuropathy usually associated with a large DNA duplication in chromosome 17p, which includes the peripheral myelin protein 22 (PMP22) gene.1–3 Currently, the electrophysiological diagnosis of CMT1A is based on detecting the characteristic marked and uniform slowing of motor conduction velocity (MCV).4–10 However, supramaximal nerve stimulation necessary for obtaining MCV can be uncomfortable. Latency measurement of electromyographic deep tendon reflex responses (Treflex) is a simple, painless, and accurate tool for Additional Supporting Information may be found in the online version of this article. Abbreviations: CDN, chronic demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound muscle action potential; CMT1A, Charcot-Marie-Tooth disease type 1A; MCV, motor conduction velocity; NCS, nerve conduction studies; PMP22, peripheral myelin protein 22; ROC, receiver operating characteristic Key words: 17p.11.2 duplication; Charcot-Marie-Tooth disease; CMT1A; hereditary neuropathy; motor nerve conduction velocity; tendon reflexes; T-reflex Correspondence to: J. Berciano; e-mail: [email protected], [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 31 October 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24499
T-Reflex in CMT1A
assessment of proximal nerve conduction,11 which has been applied primarily to the investigation of radicular syndromes.12,13 One study of the role of T-reflex testing in the diagnosis of acquired chronic demyelinating neuropathy (CDN) demonstrated that T-reflex latency was prolonged in the majority of patients.14 The aim of this study was to establish the diagnostic utility of T-reflex testing in CMT1A. METHODS Patients. Eighty-two subjects (57 women, 25 men) from 27 unrelated CMT1A families were studied. Seventy were adults aged 19–88 years (mean 43.1 years, SD 14.9 years, median 42.0 years), and 12 were children aged 2–15 years (mean 9.1 years, SD 4.0 years, median 8.5 years). Seventy-one subjects (62 adults, 9 children) were affected based on clinical features, marked and uniform slowing of nerve conduction velocities (NCVs), and molecular genetic studies showing PMP22 duplication. Eleven subjects were not affected (8 adults, 3 children) (Table 1). Healthy Adult Control Group. T-reflex latencies from the biceps brachii muscle were measured in 28 age- and height-matched, healthy volunteers (17 women and 11 men) (Table 1). The soleus T-reflex was not tested in this group. There were no significant intergroup differences between affected adult CMT patients, unaffected adult patients, and adult controls (Table 1). All adults and parents of underage subjects gave informed consent to participate in the study, which was approved by the ethics committee of the University Hospital “Marques de Valdecilla.” Clinical Assessment. Detailed neurological evaluation was performed as reported elsewhere.6,15 For clinical assessment of tendon reflexes, the following procedures were followed16: (1) we always used the same percussion hammer with a long and flexible handle, ring of thick resilient rubber, and without a heavy center; (2) we tried to keep the patient warm, comfortable, and relaxed; and (3) MUSCLE & NERVE
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Table 1. Subjects from CMT1A pedigrees and adult control group. Age (years)
Height (cm)
Groups
Mean 6 SD
Median
Min
Max
Mean 6 SD
Median
Min
Max
Subjects from CMT1A pedigrees Affected adults (n 5 62) Unaffected adults (n 5 8) Affected children (n 5 9) Unaffected children (n 5 3) Adult control group (n 5 28)
43.9 6 15.3 36.7 6 10.2 9.1 6 4.6 9.0 6 1.7 43.7 6 11.8
42.5 38.5 9.0 8.0 44.0
19 20 3 8 19
88 48 15 11 70
162.7 6 9.2 157.5 6 5.5 135.5 6 25.0 142.0 6 3.6 164.7 6 6.1
160.0 156.5 135.0 143.0 164.5
149 149 100 138 152
182 165 170 145 175
P > 0.05 for multiple comparisons of both age and height between affected adults, unaffected adults, and adult control group.
we placed the corresponding muscle in the optimum position (see below), slightly stretched but with plenty of room for contraction. Electrophysiological Study. Electrophysiological measurements were carried out using a Synergy EMG system (Oxford Instruments, UK). Room and skin temperature were maintained using an air conditioner and an infrared heater between 25 and 28 C and 32 and 34 C, respectively. T-reflex responses from biceps brachii and triceps surae muscles were evoked with a manually operated trigger hammer using a piezoelectric element to allow fast, accurate triggering of the sweep. Recordings were made from the right side in all patients, but, in 10 (16%) adult CMT1A patients, the biceps T-reflex was recorded bilaterally; over the 3-year study period, test-retest assessment was done in 9 (14.5%) adult CMT1A patients. Compound muscle action potentials (CMAPs; T-waves) were recorded with surface electrodes. Latencies were measured from the start of the sweep to the onset of the first deflection from the baseline caused by the reflex action potential. Subject positions, joints, and electrode positions were standardized following previously published norms.17 In brief, the biceps brachii muscle (biceps T-reflex) was stretched with the patient lying supine, elbow joint at 90 , the active electrode placed on the muscle belly, and the reference electrode fixed 3–5 cm proximally. The triceps surae muscle (soleus T-reflex) was stretched with the patient lying prone, ankle at 90 , the active electrode was placed in line with the Achilles tendon at half the distance between the popliteal fossa crease and the ankle, and the reference electrodes were fixed 3–5 cm distally. The ground electrode was placed in the same extremity. To avoid reflex fatigue and conditioning of subjects, 5–10 reflexes were examined at different time intervals (>5 seconds) between taps in each subject. The sweep display was 10 ms/division. Sensitivity was adjusted according to the amplitude of the response. Filter settings were 2 HZ to 5 kHZ. For adults, the T-reflex latencies were compared with 40
T-Reflex in CMT1A
the results of our healthy adult control group. Normative T-reflex latencies, adjusted for age and height, from previously published data were used in children.11 Only reproducible T-waves over 100-mV amplitude from the baseline to the negative peak were considered. We specifically analyzed the morphology of T-waves, which are biphasic for the biceps T-reflex and bi- or triphasic for the soleus T-reflex.11 Nerve conduction studies (NCS) were performed with surface stimulating and recording electrodes. We studied MCV of the median nerve in all 82 at-risk CMT1A subjects and all healthy adult subjects. MCV was assessed by stimulation at the wrist and at the elbow while recording the CMAP over the abductor pollicis brevis (APB) muscle following standard procedures. Results were compared with previously published data in adults and children.18,19 All 82 individuals at risk for CMT1A were analyzed for the presence of the 17p11.2 duplication as reported elsewhere.3,20
DNA Analysis.
Statistical Analysis. Descriptive analysis of the study variables was performed; their normal distribution was assessed using the Kolmogorov-Smirnov test. Graphic representation was performed using boxplot graphs. Given the small numbers in some groups, comparison of means was performed with the non-parametric Mann-Whitney U-test and the Kruskal-Wallis test with Bonferroni correction for multiple comparisons between groups. To determine the ideal cut-off point of T-reflex latency in adults we used the bisector method in the receiver operating characteristic (ROC) curve. Subsequently, the sensitivity, specificity, and positive and negative predictive values were calculated. In all cases, the significance level was set at P < 0.05. IBM SPSS Statistics v20.0 software was used for data analysis. RESULTS Electromyographic T-Reflexes. On electrophysiological testing, the soleus T-reflex was absent in 46 (74.2%) of the 62 adult CMT1A patients and in 3 MUSCLE & NERVE
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FIGURE 1. Biceps T-reflex recordings in 4 adults. (A) Normal T-reflex in a healthy volunteer from the control group aged 54 with height of 158 cm. (B) Normal T-reflex latency in a kin adult without 17p11.2 duplication, aged 48 years, with height of 156 cm. (C) Prolonged T-reflex latency in a CMT1A patient, aged 60 years, with height of 158 cm, who showed preserved biceps tendon reflex. (D) Prolonged T-reflex latency in an areflexic CMT1A patient, aged 52 years, with height of 165 cm. Median nerve MCV was normal in (A) (56.8 m/s) and (B) (62.8 m/s), and slowed in (C) (20.1 m/s) and (D) (22.7 m/s). Note comparable morphology of T-wave responses, although the CMAP amplitudes are slightly lower in (D).
(33.3%) of the 9 pediatric patients. In contrast, the biceps T-reflex was absent in only 4 (6.5%) of the adult patients; consequently, all statistical comparisons between adult patients and controls were based on the results of electrophysiological evaluation of the biceps T-reflex. Soleus T-reflex and biceps T-reflex were systematically obtained in kin unaffected subjects (8 adults and 3 children) who did not have the 17p duplication. In all 28 healthy controls, the biceps T-reflex was preserved, both clinically and electrophysiologically. Furthermore, the T-wave morphology was almost always normal (Fig. 1, and Fig. S1 in Supplementary Material available online).
adult control group; Figure 1 shows representative recordings of this T-reflex. CMT1A patients had significant prolongation of biceps T-reflex latencies in comparison with controls and at-risk subjects without 17p duplication. In contrast, there was no significant difference between the at-risk nonaffected group and the healthy control group (see Table 2). In adults, the cut-off value of biceps T-reflex latency for CMT1A diagnosis was 16.25
T-Reflex Values in Adults. Table 2 and Figure 2 summarize the results of the electrophysiological recordings of biceps T-reflex in the adult patient group, at-risk adult group without mutation, and
Table 2. Biceps T-reflex latency values in adults (ms). Clinical category
Mean
Median
SD
Min
Max
1. Affected adults (n 5 58)* 2. Unaffected adults (n 5 8) 3. Adult control group (n 5 28)
29.6
29.1
6.7
17.9
48.6
12.1
12.1
0.8
10.9
13.6
12.9
12.9
0.8
10.9
14.6
Category 1 vs. 2: P < 0.0001; category 1 vs. 3: P < 0.0001; category 2 vs. 3: P > 0.05. *Four adults with absence of biceps T-reflex were excluded.
T-Reflex in CMT1A
FIGURE 2. Boxplots of biceps T-reflex latency values of the 3 study adult groups. Lines inside the boxes indicate median values; horizontal lines that form the top and bottom of the boxes are the 75th and 25th percentiles, respectively; and horizontal lines above and below the boxes (whiskers) represent maximum and minimum values. Note the absence of whisker overlap between the patient group and the other 2 groups. MUSCLE & NERVE
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Table 3. Clinical settings, T-reflex latency, and median nerve MCV in children from CMT1A pedigrees. Case no. 1 2 3 4 5 6 7 8 9 10 11 12
Age (years)
Gender
Height (cm)
17p dupl.
MCV (m/s)
Biceps T-reflex (ms)
Soleus T-reflex (ms)
2 4 5 7 8 8 9 11 12 13 15 15
W W M W M W W W M W W M
95 100 128 125 143 138 135 145 148 165 154 170
Yes Yes Yes Yes No No Yes No Yes Yes Yes Yes
27.6 19.1 29.0 28.1 59.3 55.7 27.3 61.2 28.6 26.0 25.8 30.4
17.6 21.1 19.6 21.6 11.9 11.6 24.3 11.5 21.5 24.6 22.9 23.9
32.9 A 44.5 43.1 27.6 21.2 53.6 23.6 52.6 A 62.7 A
A, absent; W, woman; M, man; MCV, motor conduction velocity.
ms; all patients with latencies over this value and all at-risk subjects without duplication and healthy controls were below this value (see Fig. 2). The ROC curves (not shown) demonstrated a perfect concordance between the results of T-reflex testing and DNA analysis; the sensitivity, specificity, and positive and negative predictive values at this discriminating cut-off point on the ROC curves were always 100%. In the 10 adult CMT1A patients who had bilateral biceps T-reflex evaluation, the observed latencies were similar (right: 25.9 6 5.4 ms; left: 26.2 6 5.5 ms; P > 0.05). In the same way, testretest evaluation of the right biceps T-reflex in 9 adult CMT1A patients revealed no significant differences (first study: 26.1 6 8.3 ms; second study: 25.9 6 8.5 ms; P > 0.05). T-Reflex Values in Children. In the 6 pediatric CMT1A patients with obtainable soleus T-reflexes, latencies were prolonged when compared with ageand height-adjusted normal values, as reported by P er eon et al.,11 whereas these values were normal in the 3 at-risk children who lacked the 17p duplication (Table 3, and Fig. S1 in Supplementary Material). Biceps T-reflex latencies were systematically prolonged in patients to almost double those observed in at-risk non-affected children (Table 3). There are no normative values for biceps T-reflex latencies in children. Median Nerve Motor Conduction Velocity. All 62 adult CMT1A patients showed severe slowing of median nerve MCV (22.4 6 4.5 m/s), which was systematically lower than 38 m/s10 and significantly lower than that recorded in at-risk non-duplicated adult subjects (59.4 6 2.6 m/s; P < 0.0001). MCV values in the 9 pediatric patients and 3 at-risk nonaffected children are shown in Table 3; the values were below age-adjusted normative values in patients and were normal in non-duplicated 17p children. 42
T-Reflex in CMT1A
Clinical
Tendon
Reflexes
vs.
Electromyographic
On clinical examination, the biceps tendon reflex was absent in 45 (72.6%) of 62 adult CMT1A patients, but the biceps T-reflex was not recordable in only 4. In this adult group, the clinical ankle tendon reflex was absent in 59 (95.1%) patients, and the soleus T-reflex could not be recorded in 46. A notable example is the oldest patient, who was age 88 years and had generalized areflexia, but a biceps T-reflex could still be recorded. All 45 adult patients who lacked clinical biceps tendon reflexes also exhibited generalized areflexia; nevertheless, the combined absence of both soleus and biceps T-reflexes occurred in just 4 (6.5%) patients. There were 3 patients (aged 39, 46, and 58 years) who had preserved clinical biceps and ankle tendon reflexes with recordable although delayed T-reflexes; all 3 exhibited a minimal clinical phenotype of pes cavus.21 Kin unaffected adults and control subjects had normal biceps and soleus reflexes, both on clinical and electrophysiological examination. Clinically, the biceps tendon reflex was absent in 4 (44.4%) of the 9 pediatric patients, although a delayed biceps T-reflex was recordable in all 9 (Table 3). In this pediatric group, clinical ankle tendon reflexes were absent in 7 (77.8%), but delayed soleus T-reflexes could be recorded in 4. A notable example is an 11-year-old at-risk girl (case no. 8 in Table 3) who had generalized areflexia on clinical examination, but exhibited normal biceps and soleus T-reflexes; her NCS and molecular study were normal, indicating that she was not affected. We concluded that the observed areflexia was incidental. T-Reflex Testing.
DISCUSSION
In a CMT1A series, lower limb areflexia ranged between 85% and 98% and upper limb areflexia between 59% and 92%.4,22 On clinical examination, we observed that, in adult CMT1A patients, MUSCLE & NERVE
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the biceps tendon reflex was absent in 72.6% of patients, and the ankle tendon reflex was absent in 95.1%; these percentages were lower in pediatric patients, dropping to 44.4% for the biceps tendon reflex and 77.8% for the ankle tendon reflex. T-reflex testing is an electrophysiological method to explore the monosynaptic reflex circuit.11,17 We selected representative lower limb (soleus T-reflex) and upper limb (biceps T-reflex) T-reflexes. From our clinical findings we expected that areflexia would be confirmed by electrodiagnosis. Intriguingly, this was not the case, as the biceps T-reflex was elicited in 58 (93%) of the adult CMT1A patients and in all 9 pediatric patients. Latencies of this T-reflex were always markedly prolonged in the CMT1A patients, including children. A cut-off limit of 16.25 ms clearly separated adult patients and controls or unaffected kin individuals; that is, there was perfect discrimination between subjects with and without PMP22 duplication (100% sensitivity and 100% specificity). As may have been expected, this result paralleled that of MCV and was completely concordant with DNA analysis in separating patients from their unaffected kin.6,8,23 The reason for the observed discrepancy between electrophysiological recordings of tendon reflexes, in which T-reflexes can be recorded in most cases, and clinical examination, in which absent tendon reflexes are common, is not clear. Leaving delay of T-wave responses aside, such responses exhibited the characteristic biphasic or triphasic morphology11 (see Fig. 1, and Fig. S1 in Supplementary Material). Notably, the absence of CMAP temporal dispersion is also characteristic of any inherited neuropathy,24 including CMT1A.25 Clinically absent or almost unappreciable tendon reflexes in CMT1A can be explained to some degree by the demyelinating nature of the underlying neuropathy. There is abnormal input from afferent neurons, but, as observed here, this mechanism in itself probably is not enough to nullify electromyographic responses. In addition, electromyographic amplification of muscle responses aids in recording the T-reflex. This clinical-electrophysiological discrepancy has also been reported in CDN.14 The authors studied the T-reflex in 26 CDN patients, including 22 with chronic inflammatory demyelinating polyneuropathy (CIDP). The T-reflex was abnormal in 25 (96%), including 6 of 7 CIDP patients with brisk or normal reflexes on clinical examination. In these 7 CIDP patients, T-reflex latencies were prolonged beyond 150% of normal means. It was argued that the mechanisms by which clinical reflexes are preserved in some patients who have evidence of demyelination on NCS are not clear. T-Reflex in CMT1A
In any event, T-reflex testing could serve as a useful electrophysiological technique to show that clinically absent tendon reflexes may be accompanied by recordable, yet delayed electromyographic T-reflex responses, and that peripheral neuropathy with preserved tendon reflexes on clinical examination may occur in the context of demyelinating polyneuropathy. In conclusion, T-reflex testing is a simple and accurate technique for CMT1A diagnosis, which, because of its painless nature, may be useful for subjects reluctant to undergo electrical nerve stimulation, especially children at risk for the disease. In particular, a normal T-reflex test finding may rule out CMT1A and make NCS unnecessary. The authors are grateful to Professor Onofre Combarros and Jon Infante for molecular study, Rosario Repoila and Mar Ruiz for technical assistance, Marta de la Fuente for secretarial help, and John Hawkins for stylistic revision. This study was supported by Instituto de Investigaci on Marqu es de Valdecilla, University of Cantabria, and Centro de Investigaci on Biom edica en Red de Enfermedades Neurodegenerativas. REFERENCES 1. 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;66:219–232. 2. Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, et al. Duplication in chromosome 17p11.2 in CharcotMarie-Tooth neuropathy type Ia (CMT Ia). Neuromuscul Disord 1991;1:93–97. 3. 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 1). Ann Neurol 1992;31:570–572. 4. Birouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonobe 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;120:813–823. 5. Thomas PK, Marques W Jr, Davis MB, Sweeney MG, King RH, Bradley JL, et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 1997;120:465–478. 6. Garcıa 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;50:1061–1067. 7. Berciano J, Garcıa A, Combarros O. Initial semeiology in children with Charcot-Marie-Tooth disease 1A duplication. Muscle Nerve 2003; 27:34–39. 8. Kaku DA, Parry GJ, Malamut R, Lupski JR, Garcia CA. Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy type 1. Neurology 1993;43:2664–2667. 9. Hoogendijk JE, De Visser M, Bolhuis PA, Hart AA, Ongerboer BW. Hereditary motor and sensory neuropathy type I: clinical and neurographical features of the 17p duplication subtype. Muscle Nerve 1994;17:85–90. 10. Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980;103:259–280. 11. P er eon Y, Tich TSN, Fournier E, Genet R, Guih eneuc P. Electrophysiological recording of deep tendon reflexes: normative data in children and in adults. Neurophysiol Clin 2004;34:131–139. 12. Schott K, Koenig E. T-wave response in cervical root lesions. Acta Neurol Scand 1991;84:273–276. 13. Miller TA, Pardo R, Yaworski R. Clinical utility of reflex studies in assessing cervical radiculopathy. Muscle Nerve 1999;22:1075–1079. 14. Kuruoglu HR, Oh SJ. Tendon-reflex testing in chronic demyelinating polyneuropathy. Muscle Nerve 1994;17:145–150. 15. Berciano J, Combarros O, Calleja, Polo JM, Leno C. The application of nerve conduction and clinical studies to genetic counseling in hereditary motor and sensory neuropathy type I. Muscle Nerve 1989; 12:302–306. 16. Bickerstaff ER. Neurological examination in clinical practice. Oxford: Blackwell Scientific; 1968.
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17. Stam J, van Crevel H. Measurement of tendon reflexes by surface electromyography in healthy subjects. J Neurol 1989;236:231–237. 18. Garcıa A, Calleja J, Antolın FM, Berciano J. Peripheral motor and sensory nerve conduction studies in normal infants and children. Clin Neurophysiol 2000;111:513–520. 19. Preston DC, Shapiro BE. Electromyography and neuromuscular disorders. Clinical-electrophysiologic correlations. Philadelphia: Elsevier/Butterworth Heinemann; 2005. p 663–666. 20. Infante J, Garcıa A, Combarros O, Mateo JI, Berciano J, Sedano MJ, et al. Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion. Muscle Nerve 2001;24:1149–1155. 21. Berciano J, Gallardo E, Garcıa A, Ram on C, Mateo I, Infante J, et al. CMT1A duplication: refining the minimal adult phenotype. J Peripher Nerv Syst 2008;13:310–312.
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22. Kim YH, Chung HK, Park KD, Choi KG, Kim SM, Sunwoo IN, et al. Comparison between clinical disabilities and electrophysiological values in Charcot-Marie-Tooth 1A patients with PMP22 duplication. J Clin Neurol 2012;8:139–145. 23. Nicholson GA. Penetrance of the hereditary motor and sensory neuropathy Ia mutation: assessment by nerve conduction studies. Neurology 1991;41:547–552. 24. Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology 1982;32:592–596. 25. Berciano J, Garcıa 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;10:419–424.
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Service of Clinical Neurophysiology, University Hospital Marqu es de Valdecilla, Instituto de Investigaci on Marqu es de Valdecilla, University of Cantabria and Centro de Investigaci on Biom edica en Red de Enfermedades Neurodegenerativas, Santander, Spain 2 Service of Neurology, University Hospital Marqu es de Valdecilla, Instituto de Investigaci on Marqu es de Valdecilla, University of Cantabria and Centro de Investigaci on Biom edica en Red de Enfermedades Neurodegenerativas, Santander, Spain 3 Service of Epidemiology, University Hospital Marques de Valdecilla and Instituto de Investigaci on Marqu es de Valdecilla, Santander, Spain Accepted 28 October 2014 ABSTRACT: Introduction: We analyzed the utility of tendon reflex (T-reflex) testing in Charcot-Marie-Tooth disease type 1A (CMT1A). Methods: A total of 82 subjects from 27 unrelated CMT1A pedigrees were evaluated prospectively. The series also comprised 28 adult healthy controls. Electrophysiology included evaluation of biceps T-reflex and soleus T-reflex. Results: Seventy-one individuals (62 adults and 9 children) had clinical and electrophysiological features of CMT1A. The remaining 11 (8 adults and 3 children) were unaffected. On electrophysiological testing, the biceps T-reflex was elicited in 58 of 62 (93%) adult CMT1A patients and in all 9 affected children. Latencies of the biceps T-reflex were always markedly prolonged, and a cut-off limit of 16.25 ms clearly separated adult patients and controls or unaffected kin adult individuals. In affected children, the soleus T-reflex latency was also prolonged when compared with age and height normative data. Conclusion: T-reflex testing is an accurate diagnostic technique for CMT1A patients. Muscle Nerve 52: 39–44, 2015
Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating polyneuropathy usually associated with a large DNA duplication in chromosome 17p, which includes the peripheral myelin protein 22 (PMP22) gene.1–3 Currently, the electrophysiological diagnosis of CMT1A is based on detecting the characteristic marked and uniform slowing of motor conduction velocity (MCV).4–10 However, supramaximal nerve stimulation necessary for obtaining MCV can be uncomfortable. Latency measurement of electromyographic deep tendon reflex responses (Treflex) is a simple, painless, and accurate tool for Additional Supporting Information may be found in the online version of this article. Abbreviations: CDN, chronic demyelinating polyneuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; CMAP, compound muscle action potential; CMT1A, Charcot-Marie-Tooth disease type 1A; MCV, motor conduction velocity; NCS, nerve conduction studies; PMP22, peripheral myelin protein 22; ROC, receiver operating characteristic Key words: 17p.11.2 duplication; Charcot-Marie-Tooth disease; CMT1A; hereditary neuropathy; motor nerve conduction velocity; tendon reflexes; T-reflex Correspondence to: J. Berciano; e-mail: [email protected], [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 31 October 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24499
T-Reflex in CMT1A
assessment of proximal nerve conduction,11 which has been applied primarily to the investigation of radicular syndromes.12,13 One study of the role of T-reflex testing in the diagnosis of acquired chronic demyelinating neuropathy (CDN) demonstrated that T-reflex latency was prolonged in the majority of patients.14 The aim of this study was to establish the diagnostic utility of T-reflex testing in CMT1A. METHODS Patients. Eighty-two subjects (57 women, 25 men) from 27 unrelated CMT1A families were studied. Seventy were adults aged 19–88 years (mean 43.1 years, SD 14.9 years, median 42.0 years), and 12 were children aged 2–15 years (mean 9.1 years, SD 4.0 years, median 8.5 years). Seventy-one subjects (62 adults, 9 children) were affected based on clinical features, marked and uniform slowing of nerve conduction velocities (NCVs), and molecular genetic studies showing PMP22 duplication. Eleven subjects were not affected (8 adults, 3 children) (Table 1). Healthy Adult Control Group. T-reflex latencies from the biceps brachii muscle were measured in 28 age- and height-matched, healthy volunteers (17 women and 11 men) (Table 1). The soleus T-reflex was not tested in this group. There were no significant intergroup differences between affected adult CMT patients, unaffected adult patients, and adult controls (Table 1). All adults and parents of underage subjects gave informed consent to participate in the study, which was approved by the ethics committee of the University Hospital “Marques de Valdecilla.” Clinical Assessment. Detailed neurological evaluation was performed as reported elsewhere.6,15 For clinical assessment of tendon reflexes, the following procedures were followed16: (1) we always used the same percussion hammer with a long and flexible handle, ring of thick resilient rubber, and without a heavy center; (2) we tried to keep the patient warm, comfortable, and relaxed; and (3) MUSCLE & NERVE
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Table 1. Subjects from CMT1A pedigrees and adult control group. Age (years)
Height (cm)
Groups
Mean 6 SD
Median
Min
Max
Mean 6 SD
Median
Min
Max
Subjects from CMT1A pedigrees Affected adults (n 5 62) Unaffected adults (n 5 8) Affected children (n 5 9) Unaffected children (n 5 3) Adult control group (n 5 28)
43.9 6 15.3 36.7 6 10.2 9.1 6 4.6 9.0 6 1.7 43.7 6 11.8
42.5 38.5 9.0 8.0 44.0
19 20 3 8 19
88 48 15 11 70
162.7 6 9.2 157.5 6 5.5 135.5 6 25.0 142.0 6 3.6 164.7 6 6.1
160.0 156.5 135.0 143.0 164.5
149 149 100 138 152
182 165 170 145 175
P > 0.05 for multiple comparisons of both age and height between affected adults, unaffected adults, and adult control group.
we placed the corresponding muscle in the optimum position (see below), slightly stretched but with plenty of room for contraction. Electrophysiological Study. Electrophysiological measurements were carried out using a Synergy EMG system (Oxford Instruments, UK). Room and skin temperature were maintained using an air conditioner and an infrared heater between 25 and 28 C and 32 and 34 C, respectively. T-reflex responses from biceps brachii and triceps surae muscles were evoked with a manually operated trigger hammer using a piezoelectric element to allow fast, accurate triggering of the sweep. Recordings were made from the right side in all patients, but, in 10 (16%) adult CMT1A patients, the biceps T-reflex was recorded bilaterally; over the 3-year study period, test-retest assessment was done in 9 (14.5%) adult CMT1A patients. Compound muscle action potentials (CMAPs; T-waves) were recorded with surface electrodes. Latencies were measured from the start of the sweep to the onset of the first deflection from the baseline caused by the reflex action potential. Subject positions, joints, and electrode positions were standardized following previously published norms.17 In brief, the biceps brachii muscle (biceps T-reflex) was stretched with the patient lying supine, elbow joint at 90 , the active electrode placed on the muscle belly, and the reference electrode fixed 3–5 cm proximally. The triceps surae muscle (soleus T-reflex) was stretched with the patient lying prone, ankle at 90 , the active electrode was placed in line with the Achilles tendon at half the distance between the popliteal fossa crease and the ankle, and the reference electrodes were fixed 3–5 cm distally. The ground electrode was placed in the same extremity. To avoid reflex fatigue and conditioning of subjects, 5–10 reflexes were examined at different time intervals (>5 seconds) between taps in each subject. The sweep display was 10 ms/division. Sensitivity was adjusted according to the amplitude of the response. Filter settings were 2 HZ to 5 kHZ. For adults, the T-reflex latencies were compared with 40
T-Reflex in CMT1A
the results of our healthy adult control group. Normative T-reflex latencies, adjusted for age and height, from previously published data were used in children.11 Only reproducible T-waves over 100-mV amplitude from the baseline to the negative peak were considered. We specifically analyzed the morphology of T-waves, which are biphasic for the biceps T-reflex and bi- or triphasic for the soleus T-reflex.11 Nerve conduction studies (NCS) were performed with surface stimulating and recording electrodes. We studied MCV of the median nerve in all 82 at-risk CMT1A subjects and all healthy adult subjects. MCV was assessed by stimulation at the wrist and at the elbow while recording the CMAP over the abductor pollicis brevis (APB) muscle following standard procedures. Results were compared with previously published data in adults and children.18,19 All 82 individuals at risk for CMT1A were analyzed for the presence of the 17p11.2 duplication as reported elsewhere.3,20
DNA Analysis.
Statistical Analysis. Descriptive analysis of the study variables was performed; their normal distribution was assessed using the Kolmogorov-Smirnov test. Graphic representation was performed using boxplot graphs. Given the small numbers in some groups, comparison of means was performed with the non-parametric Mann-Whitney U-test and the Kruskal-Wallis test with Bonferroni correction for multiple comparisons between groups. To determine the ideal cut-off point of T-reflex latency in adults we used the bisector method in the receiver operating characteristic (ROC) curve. Subsequently, the sensitivity, specificity, and positive and negative predictive values were calculated. In all cases, the significance level was set at P < 0.05. IBM SPSS Statistics v20.0 software was used for data analysis. RESULTS Electromyographic T-Reflexes. On electrophysiological testing, the soleus T-reflex was absent in 46 (74.2%) of the 62 adult CMT1A patients and in 3 MUSCLE & NERVE
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FIGURE 1. Biceps T-reflex recordings in 4 adults. (A) Normal T-reflex in a healthy volunteer from the control group aged 54 with height of 158 cm. (B) Normal T-reflex latency in a kin adult without 17p11.2 duplication, aged 48 years, with height of 156 cm. (C) Prolonged T-reflex latency in a CMT1A patient, aged 60 years, with height of 158 cm, who showed preserved biceps tendon reflex. (D) Prolonged T-reflex latency in an areflexic CMT1A patient, aged 52 years, with height of 165 cm. Median nerve MCV was normal in (A) (56.8 m/s) and (B) (62.8 m/s), and slowed in (C) (20.1 m/s) and (D) (22.7 m/s). Note comparable morphology of T-wave responses, although the CMAP amplitudes are slightly lower in (D).
(33.3%) of the 9 pediatric patients. In contrast, the biceps T-reflex was absent in only 4 (6.5%) of the adult patients; consequently, all statistical comparisons between adult patients and controls were based on the results of electrophysiological evaluation of the biceps T-reflex. Soleus T-reflex and biceps T-reflex were systematically obtained in kin unaffected subjects (8 adults and 3 children) who did not have the 17p duplication. In all 28 healthy controls, the biceps T-reflex was preserved, both clinically and electrophysiologically. Furthermore, the T-wave morphology was almost always normal (Fig. 1, and Fig. S1 in Supplementary Material available online).
adult control group; Figure 1 shows representative recordings of this T-reflex. CMT1A patients had significant prolongation of biceps T-reflex latencies in comparison with controls and at-risk subjects without 17p duplication. In contrast, there was no significant difference between the at-risk nonaffected group and the healthy control group (see Table 2). In adults, the cut-off value of biceps T-reflex latency for CMT1A diagnosis was 16.25
T-Reflex Values in Adults. Table 2 and Figure 2 summarize the results of the electrophysiological recordings of biceps T-reflex in the adult patient group, at-risk adult group without mutation, and
Table 2. Biceps T-reflex latency values in adults (ms). Clinical category
Mean
Median
SD
Min
Max
1. Affected adults (n 5 58)* 2. Unaffected adults (n 5 8) 3. Adult control group (n 5 28)
29.6
29.1
6.7
17.9
48.6
12.1
12.1
0.8
10.9
13.6
12.9
12.9
0.8
10.9
14.6
Category 1 vs. 2: P < 0.0001; category 1 vs. 3: P < 0.0001; category 2 vs. 3: P > 0.05. *Four adults with absence of biceps T-reflex were excluded.
T-Reflex in CMT1A
FIGURE 2. Boxplots of biceps T-reflex latency values of the 3 study adult groups. Lines inside the boxes indicate median values; horizontal lines that form the top and bottom of the boxes are the 75th and 25th percentiles, respectively; and horizontal lines above and below the boxes (whiskers) represent maximum and minimum values. Note the absence of whisker overlap between the patient group and the other 2 groups. MUSCLE & NERVE
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Table 3. Clinical settings, T-reflex latency, and median nerve MCV in children from CMT1A pedigrees. Case no. 1 2 3 4 5 6 7 8 9 10 11 12
Age (years)
Gender
Height (cm)
17p dupl.
MCV (m/s)
Biceps T-reflex (ms)
Soleus T-reflex (ms)
2 4 5 7 8 8 9 11 12 13 15 15
W W M W M W W W M W W M
95 100 128 125 143 138 135 145 148 165 154 170
Yes Yes Yes Yes No No Yes No Yes Yes Yes Yes
27.6 19.1 29.0 28.1 59.3 55.7 27.3 61.2 28.6 26.0 25.8 30.4
17.6 21.1 19.6 21.6 11.9 11.6 24.3 11.5 21.5 24.6 22.9 23.9
32.9 A 44.5 43.1 27.6 21.2 53.6 23.6 52.6 A 62.7 A
A, absent; W, woman; M, man; MCV, motor conduction velocity.
ms; all patients with latencies over this value and all at-risk subjects without duplication and healthy controls were below this value (see Fig. 2). The ROC curves (not shown) demonstrated a perfect concordance between the results of T-reflex testing and DNA analysis; the sensitivity, specificity, and positive and negative predictive values at this discriminating cut-off point on the ROC curves were always 100%. In the 10 adult CMT1A patients who had bilateral biceps T-reflex evaluation, the observed latencies were similar (right: 25.9 6 5.4 ms; left: 26.2 6 5.5 ms; P > 0.05). In the same way, testretest evaluation of the right biceps T-reflex in 9 adult CMT1A patients revealed no significant differences (first study: 26.1 6 8.3 ms; second study: 25.9 6 8.5 ms; P > 0.05). T-Reflex Values in Children. In the 6 pediatric CMT1A patients with obtainable soleus T-reflexes, latencies were prolonged when compared with ageand height-adjusted normal values, as reported by P er eon et al.,11 whereas these values were normal in the 3 at-risk children who lacked the 17p duplication (Table 3, and Fig. S1 in Supplementary Material). Biceps T-reflex latencies were systematically prolonged in patients to almost double those observed in at-risk non-affected children (Table 3). There are no normative values for biceps T-reflex latencies in children. Median Nerve Motor Conduction Velocity. All 62 adult CMT1A patients showed severe slowing of median nerve MCV (22.4 6 4.5 m/s), which was systematically lower than 38 m/s10 and significantly lower than that recorded in at-risk non-duplicated adult subjects (59.4 6 2.6 m/s; P < 0.0001). MCV values in the 9 pediatric patients and 3 at-risk nonaffected children are shown in Table 3; the values were below age-adjusted normative values in patients and were normal in non-duplicated 17p children. 42
T-Reflex in CMT1A
Clinical
Tendon
Reflexes
vs.
Electromyographic
On clinical examination, the biceps tendon reflex was absent in 45 (72.6%) of 62 adult CMT1A patients, but the biceps T-reflex was not recordable in only 4. In this adult group, the clinical ankle tendon reflex was absent in 59 (95.1%) patients, and the soleus T-reflex could not be recorded in 46. A notable example is the oldest patient, who was age 88 years and had generalized areflexia, but a biceps T-reflex could still be recorded. All 45 adult patients who lacked clinical biceps tendon reflexes also exhibited generalized areflexia; nevertheless, the combined absence of both soleus and biceps T-reflexes occurred in just 4 (6.5%) patients. There were 3 patients (aged 39, 46, and 58 years) who had preserved clinical biceps and ankle tendon reflexes with recordable although delayed T-reflexes; all 3 exhibited a minimal clinical phenotype of pes cavus.21 Kin unaffected adults and control subjects had normal biceps and soleus reflexes, both on clinical and electrophysiological examination. Clinically, the biceps tendon reflex was absent in 4 (44.4%) of the 9 pediatric patients, although a delayed biceps T-reflex was recordable in all 9 (Table 3). In this pediatric group, clinical ankle tendon reflexes were absent in 7 (77.8%), but delayed soleus T-reflexes could be recorded in 4. A notable example is an 11-year-old at-risk girl (case no. 8 in Table 3) who had generalized areflexia on clinical examination, but exhibited normal biceps and soleus T-reflexes; her NCS and molecular study were normal, indicating that she was not affected. We concluded that the observed areflexia was incidental. T-Reflex Testing.
DISCUSSION
In a CMT1A series, lower limb areflexia ranged between 85% and 98% and upper limb areflexia between 59% and 92%.4,22 On clinical examination, we observed that, in adult CMT1A patients, MUSCLE & NERVE
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the biceps tendon reflex was absent in 72.6% of patients, and the ankle tendon reflex was absent in 95.1%; these percentages were lower in pediatric patients, dropping to 44.4% for the biceps tendon reflex and 77.8% for the ankle tendon reflex. T-reflex testing is an electrophysiological method to explore the monosynaptic reflex circuit.11,17 We selected representative lower limb (soleus T-reflex) and upper limb (biceps T-reflex) T-reflexes. From our clinical findings we expected that areflexia would be confirmed by electrodiagnosis. Intriguingly, this was not the case, as the biceps T-reflex was elicited in 58 (93%) of the adult CMT1A patients and in all 9 pediatric patients. Latencies of this T-reflex were always markedly prolonged in the CMT1A patients, including children. A cut-off limit of 16.25 ms clearly separated adult patients and controls or unaffected kin individuals; that is, there was perfect discrimination between subjects with and without PMP22 duplication (100% sensitivity and 100% specificity). As may have been expected, this result paralleled that of MCV and was completely concordant with DNA analysis in separating patients from their unaffected kin.6,8,23 The reason for the observed discrepancy between electrophysiological recordings of tendon reflexes, in which T-reflexes can be recorded in most cases, and clinical examination, in which absent tendon reflexes are common, is not clear. Leaving delay of T-wave responses aside, such responses exhibited the characteristic biphasic or triphasic morphology11 (see Fig. 1, and Fig. S1 in Supplementary Material). Notably, the absence of CMAP temporal dispersion is also characteristic of any inherited neuropathy,24 including CMT1A.25 Clinically absent or almost unappreciable tendon reflexes in CMT1A can be explained to some degree by the demyelinating nature of the underlying neuropathy. There is abnormal input from afferent neurons, but, as observed here, this mechanism in itself probably is not enough to nullify electromyographic responses. In addition, electromyographic amplification of muscle responses aids in recording the T-reflex. This clinical-electrophysiological discrepancy has also been reported in CDN.14 The authors studied the T-reflex in 26 CDN patients, including 22 with chronic inflammatory demyelinating polyneuropathy (CIDP). The T-reflex was abnormal in 25 (96%), including 6 of 7 CIDP patients with brisk or normal reflexes on clinical examination. In these 7 CIDP patients, T-reflex latencies were prolonged beyond 150% of normal means. It was argued that the mechanisms by which clinical reflexes are preserved in some patients who have evidence of demyelination on NCS are not clear. T-Reflex in CMT1A
In any event, T-reflex testing could serve as a useful electrophysiological technique to show that clinically absent tendon reflexes may be accompanied by recordable, yet delayed electromyographic T-reflex responses, and that peripheral neuropathy with preserved tendon reflexes on clinical examination may occur in the context of demyelinating polyneuropathy. In conclusion, T-reflex testing is a simple and accurate technique for CMT1A diagnosis, which, because of its painless nature, may be useful for subjects reluctant to undergo electrical nerve stimulation, especially children at risk for the disease. In particular, a normal T-reflex test finding may rule out CMT1A and make NCS unnecessary. The authors are grateful to Professor Onofre Combarros and Jon Infante for molecular study, Rosario Repoila and Mar Ruiz for technical assistance, Marta de la Fuente for secretarial help, and John Hawkins for stylistic revision. This study was supported by Instituto de Investigaci on Marqu es de Valdecilla, University of Cantabria, and Centro de Investigaci on Biom edica en Red de Enfermedades Neurodegenerativas. REFERENCES 1. 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;66:219–232. 2. Raeymaekers P, Timmerman V, Nelis E, De Jonghe P, Hoogendijk JE, Baas F, et al. Duplication in chromosome 17p11.2 in CharcotMarie-Tooth neuropathy type Ia (CMT Ia). Neuromuscul Disord 1991;1:93–97. 3. 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 1). Ann Neurol 1992;31:570–572. 4. Birouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonobe 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;120:813–823. 5. Thomas PK, Marques W Jr, Davis MB, Sweeney MG, King RH, Bradley JL, et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 1997;120:465–478. 6. Garcıa 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;50:1061–1067. 7. Berciano J, Garcıa A, Combarros O. Initial semeiology in children with Charcot-Marie-Tooth disease 1A duplication. Muscle Nerve 2003; 27:34–39. 8. Kaku DA, Parry GJ, Malamut R, Lupski JR, Garcia CA. Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy type 1. Neurology 1993;43:2664–2667. 9. Hoogendijk JE, De Visser M, Bolhuis PA, Hart AA, Ongerboer BW. Hereditary motor and sensory neuropathy type I: clinical and neurographical features of the 17p duplication subtype. Muscle Nerve 1994;17:85–90. 10. Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 1980;103:259–280. 11. P er eon Y, Tich TSN, Fournier E, Genet R, Guih eneuc P. Electrophysiological recording of deep tendon reflexes: normative data in children and in adults. Neurophysiol Clin 2004;34:131–139. 12. Schott K, Koenig E. T-wave response in cervical root lesions. Acta Neurol Scand 1991;84:273–276. 13. Miller TA, Pardo R, Yaworski R. Clinical utility of reflex studies in assessing cervical radiculopathy. Muscle Nerve 1999;22:1075–1079. 14. Kuruoglu HR, Oh SJ. Tendon-reflex testing in chronic demyelinating polyneuropathy. Muscle Nerve 1994;17:145–150. 15. Berciano J, Combarros O, Calleja, Polo JM, Leno C. The application of nerve conduction and clinical studies to genetic counseling in hereditary motor and sensory neuropathy type I. Muscle Nerve 1989; 12:302–306. 16. Bickerstaff ER. Neurological examination in clinical practice. Oxford: Blackwell Scientific; 1968.
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17. Stam J, van Crevel H. Measurement of tendon reflexes by surface electromyography in healthy subjects. J Neurol 1989;236:231–237. 18. Garcıa A, Calleja J, Antolın FM, Berciano J. Peripheral motor and sensory nerve conduction studies in normal infants and children. Clin Neurophysiol 2000;111:513–520. 19. Preston DC, Shapiro BE. Electromyography and neuromuscular disorders. Clinical-electrophysiologic correlations. Philadelphia: Elsevier/Butterworth Heinemann; 2005. p 663–666. 20. Infante J, Garcıa A, Combarros O, Mateo JI, Berciano J, Sedano MJ, et al. Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion. Muscle Nerve 2001;24:1149–1155. 21. Berciano J, Gallardo E, Garcıa A, Ram on C, Mateo I, Infante J, et al. CMT1A duplication: refining the minimal adult phenotype. J Peripher Nerv Syst 2008;13:310–312.
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22. Kim YH, Chung HK, Park KD, Choi KG, Kim SM, Sunwoo IN, et al. Comparison between clinical disabilities and electrophysiological values in Charcot-Marie-Tooth 1A patients with PMP22 duplication. J Clin Neurol 2012;8:139–145. 23. Nicholson GA. Penetrance of the hereditary motor and sensory neuropathy Ia mutation: assessment by nerve conduction studies. Neurology 1991;41:547–552. 24. Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology 1982;32:592–596. 25. Berciano J, Garcıa 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;10:419–424.
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