Cardiac Abnormalities Associated With Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. The association between Charcot-Marie-Tooth syndrome and cardiac involvement is controversial. Although patients with this disease may have cardiac conduction abnormalities, such abnormalities are often not recognized. Increasing numbers of case reports attest to the association between CMT and cardiac problems. We discuss the current understanding of the relationship between Charcot-Marie-Tooth disease and cardiac irregularities.

Hereditary peripheral neuropathies are one of the most common genetic degenerative disorders. These clinically and genetically heterogeneous group of conditions produce progressive deterioration of the peripheral nerves.l The most common hereditary peripheral neuropathy is Charcot-Marie-Tooth (CMT) disease, with an estimated prevalence of 1:2500.2 This slowly progressive neurologic atrophy predominantly affects the distal muscles of the legs and sometimes the intrinsic muscles of the hands.l CMT disease, also called Charcot-Marie atrophy (or syndrome), is a hereditary familial neuromuscular condition showing mostly an autosomal dominant mode of inheritance. This demyelinating neuropathy is associated with striking motor and sensory abnormalities of the affected muscles.1Table 1 summarizes the different CMT types and some of their associated features.
Illustrative Case
A 50-year-old white woman with CMT disease presents with an irregular pulse (88 beats/min) and palpitations. She complains of recent intermittent coughlike sensations. Her medical history includes normal coronary arteries, documented by cardiac catheterization and normal ventricular function. She has never been diagnosed with hypertension, diabetes, or any electrolyte imbalance. Physical examination findings are normal, with the exception of prominent peroneal dystrophy. Her electrocardiogram (ECG) is abnormal (Figure 1), and the rhythm strips demonstrate cardiac arrhythmias (Figures 2, 3,). Based on the assumption that the cough could be a manifestation of the palpitations, she is prescribed beta-blocker therapy, which significantly improves her symptoms. Follow-up 24-hour Holter monitoring shows a significant reduction in the frequency and grade of the premature ventricular contractions.
Cardiovascular Manifestations of CMT Disease
Peroneal muscle atrophy seldom affects the heart. Arrhythmias, conduction disturbances, and dilated heart failure have occasionally been reported in patients with peroneal muscle atrophy,3 but they are believed to be chance occurrences.4 Some investigators consider that cardiac involvement in CMT disease is fortuitous, although a growing number of such patients is now being reported.3 There appears to be a high frequency of associated conduction disturbances. Episodes of supraventricular tachycardia in isolated cases of children suffering from congenital peripheral neuropathies have also been reported.5
It is tempting to speculate about the significance of ventricular arrhythmias in patients with CMT disease. The possibility that this association is merely coincidental is doubtful, in light of the increasing numbers of case reports, including our case, which involve cardiovascular manifestations associated with CMT disease.
One report described a 41-year-old woman with CMT disease who had been prescribed sumatriptan (Imitrex) and soon after suffered a sudden loss of consciousness that was associated with ventricular fibrillation.6Sumatriptan-induced coronary spasm could not be excluded in this case. Sumatriptan is among the medications known to have cardiac side effects in patients who have CMT disease (Table 2).
Another case report described a boy with CMT disease who had arrhythmias during anesthesia. 7The disease has also been linked to dilated cardiomyopathy and conduction disturbances.8 Complete heart block was reported in a 57-year-old patient whose family had 3 generations of CMT disease; the patient’s mother also had complete heart block.3It is not known whether this association is genetically determined or fortuitous. Premature atrial contractions, for instance, are reportedly the most common form of cardiac arrhythmia in CMT disease.
The incidence of ventricular arrhythmias (eg, ventricular tachycardia) is particularly interesting, because they may cause sudden cardiac death. In a study of 68 patients with CMT disease who were evaluated prospectively for evidence of cardiac involvement, 5 had conduction defects, 2 had supraventricular tachycardia, 2 had ischemic heart disease, and 20 had mitral valve prolapse.5
Mechanisms of Cardiac Involvement in CMT
Cardiac disorders appear to be the rule rather than the exception in virtually every hereditary and acquired skeletal myopathy. Some experts point to the frequent occurrence of cardiac disorders in the pseudohypertrophic, myotonic, limb girdle, and facioscapulohumeral dystrophies.9,10 Evidence of pathologically confirmed, clinically evident cardiomyopathy or conduction disturbances is scant, but fibrotic replacement of the myocardium was reported in 1 patient with CMT disease who died from dilated cardiomyopathy.11An autopsy revealed diffuse left ventricular fibrosis, most prominent in the posterior wall. On light microscopic examination, the left ventricular myo­cardium demonstrated diffusely scattered muscular degeneration interlaced with fibrosis.
The established association between cardiac and neuromuscular disease suggests that cardiac abnormalities may also be an implicit feature of CMT disease. The cardiac conduction disturbances associated with peroneal muscle atrophy are not necessarily secondary to cardiomyopathy but may represent a primary degeneration of the conducting tissue. Significant cardiac conduction system disease can occur secondary to mutations in the gene encoding lamin A/C, a component of the nuclear envelope.12 Mutations in LMNA, which encodes lamin A/C nuclear-envelope proteins, has also been identified as a cause of axonal CMT disease.13
Although peripheral nerve conduction is based on nerve cells, and cardiac conduction is based on specialized myocardial cells, this anatomic difference does not imply that there are direct physiologic differences in the electrochemical transmission of impulses by specialized myocardial cells as opposed to nerve cells.
The treatment of cardiac conduction disorders in CMT disease is the same as for any cardiac conduction disorder. Treatment, therefore, includes antiarrhythmic medications and pacemakers, as needed.
Evidence from the growing number of case reports suggests an association between cardiovascular abnormalities and CMT disease. Physicians should be aware of, and anticipate, the possibility of serious cardiovascular manifestations in any patient with CMT disease. Lack of recognition of this association may delay treatment and could even be fatal.
Self-assessment test
1. All these statements about CMT disease are true, except:
A. It predominantly affects the distal leg muscles
B. Affected muscles have both motor and sensory abnormalities
C. It is a demyelinating neuropathy
D. Inheritance is primarily autosomal recessive
2. Which of these features is NOT associated with CMT disease?
A. Blindness
B. Deafness
C. Scoliosis
D. Restless legs syndrome
3. Which of these cardiac abnormalities is most frequently reported in CMT disease?
A. Supraventricular tachycardia
B. Conduction defects
C. Ischemic heart disease
D. Complete heart block
4. Which one of the following medications would be the most likely to cause cardiac conduction disturbances in CMT disease?
A. Thiopental
B. Nortriptyline
C. Carbamazepine
D. Sumatriptan
5. What is the common cardiac side effect of naproxen in a patient with CMT disease?
A. QT prolongation
B. Cardiac arrhythmia
C. Ventricular fibrillation
D. Exacerbation of congestive heart failure
(Answers at end of reference list)
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2. Roa BB, Garcia CA, Suter U, et al. Charcot-Marie-Tooth disease type 1a – association with a spontaneous point mutation in the pmp22 gene. N Engl J Med. 1993;329:96-101.
3. Rosselot E, Brinck G. Conduction system disease and Charcot-Marie-Tooth syndrome [in Spanish]. Rev Med Chil. 1989;117: 914-917.
4. Dyck PJ, Swanson CJ, Nishimura RA, et al. Cardiomyopathy in patients with hereditary motor and sensory neuropathy. Mayo Clin Proc. 1987;62:672-675.
5. Isner JM, Hawley RJ, Weintraub AM, et al. Cardiac findings in Charcot-Marie-Tooth disease. A prospective study of 68 patients. Arch Intern Med. 1979;139:1161-1165.
6. Rubinstein J, Moghe R, Mizrachi A, et al. Triptan use preceding life-threatening arrhythmias in Charcot-Marie-Tooth: a case report and review of the literature. Clin Neuropharmacol. 2004;27: 14-16.
7. Tetzlaff JE, Schwendt I. Arrhythmia and Charcot-Marie-Tooth disease during anesthesia [letter]. Can J Anaesth. 2000;47:829.
8. Sevillano Fernandez JA, Paz Fraile A, Cano Ballesteros JC, et al. Charcot-Marie-Tooth disease, dilated myocardiopathy and cardiac conduction disorders [in Spanish]. An Med Interna. 1994;11:455-456.
9. Muchir A, Bonne G, van der Kooi AJ, et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet. 2000;9:1453-1459.
10. Laforet P, de Toma C, Eymard B, et al. Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy. Neurology. 1998;51:1454-1456.
11. Yoshida H, Inagaki M, Shukuya M, et al. Charcot-Marie-Tooth disease associated with dilated cardiomyopathy: an autopsy case report [in Japanese]. Kokyu To Junkan. 1991;39:295-298.
12. MacLeod HM, Culley MR, Huber JM, et al. Lamin A/C truncation in dilated cardiomyopathy with conduction disease. BMC Med Genet. 2003;4:4.
13. De Sandre-Giovannoli A, Chaouch M, Kozlov S, et al. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002; 70: 726-736.
14. Kedlaya D. Charcot-Marie-Tooth disease. e-Medicine. October 1, 2004. Available at
15. Baur CP, Schara U, Schlecht R, et al. Anesthesia in neuromuscular disorders. Part 2: specific disorders [in German]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2002;37:125-137.
Answers: 1. D; 2. A; 3. B; 4. B; 5. D.

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