Cardiac Abnormalities Associated With Charcot-Marie-Tooth Disease

June 12, 2007

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.

Conclusion
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)

References
1. Garcia CA. A clinical review of Charcot-Marie-Tooth. Ann N Y Acad Sci. 1999;883:69-76.

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 www.emedicine.com/pmr/topic29.htm.

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.

Researchers Discover Gene Crucial for Nerve Cell Insulation

April 16, 2007

Researchers funded by the National Institutes of Health have discovered how a defect in a single master gene disrupts the process by which several genes interact to create myelin, a fatty coating that covers nerve cells and increases the speed and reliability of their electrical signals.

The discovery has implications for understanding disorders of myelin production. These disorders can affect the peripheral nervous system — the nerves outside the brain and spine. These disorders are known collectively as peripheral neuropathies. Peripheral neuropathies can result in numbness, weakness, pain, and impaired movement. They include one of the most common genetically inherited disorders, Charcot-Marie-Tooth disease, which causes progressive muscle weakening.

The myelin sheath that surrounds a nerve cell is analogous to the insulating material that coats an electrical cord or wire, keeping nerve impulses from dissipating, allowing them to travel farther and faster along the length of the nerve cell.

The researchers discovered how a defect in just one copy of the gene, known as early growth response gene 2 (EGR2) affects the normal copy of the gene as well as the functioning of other genes, resulting in peripheral neuropathy.

“The researchers have deciphered a key sequence essential to the assembly of myelin,” said Duane Alexander, M.D., Director of the NICHD, the NIH institute that funded the study. “Their discovery will provide important insight into the origins of disorders affecting myelin production.”

The study appears in the online version of Molecular and Cellular Biology.

John Svaren, Ph.D., an associate professor in the Department of Comparative Bioscience at the University of Wisconsin — Madison’s School of Veterinary Medicine, worked with colleagues Scott E. LeBlanc, and Rebecca M. Ward, to conduct the study. Dr. Svaren is an affiliate of NICHD-funded mental retardation and developmental disabilities research center at the Waisman Center at the University of Wisconsin.

Until this discovery, researchers did not fully understand the complex genetic process that enables Schwann cells, found in the peripheral nervous system, to coat nerves with myelin.

The Newly Discovered Role of EGR2

During this study, the scientists found that EGR2 produces a protein that activates several other genes necessary for myelin production. Some of these genes contain the information needed to make peripheral myelin protein-22 (PMP-22) and myelin protein zero (MPZ). MPZ is the most abundant protein in myelin in the peripheral nervous system.

The overproduction or underproduction of the proteins PMP22 and MPZ account for the majority of inherited peripheral neuropathies, Dr. Svaren said.

Ultimately, the sequence of activating genes “switches on” the Schwann cell, which wraps the nerve axon, the arm-like projection that conveys nerve impulses, in a myelin sheath.

The scientists’ research also resolved a long-standing mystery surrounding why a single mutant copy of the EGR2 gene disrupts the functioning of the normal EGR2 gene, leading to a disorder of the nervous system.

In many genetic conditions, the unaffected copy of an affected gene continues to produce its protein. However, the researchers found that the mutant EGR2 copy interferes with the interaction between the normal EGR2 gene and another myelin gene, SOX10, as the two try to work together to produce the myelin protein MPZ.

Therapeutic Potential

By understanding the process which creates myelin, researchers may now be able to investigate new therapies for disorders affecting myelin.

“Our research has uncovered a whole new mechanism for regulating myelin genes,” said Dr. Svaren. “Our hope is to exploit this knowledge so that we can adjust the levels of myelin genes such as PMP22 and MPZ, and thereby create an effective treatment for myelin diseases.”

Understanding the process by which nerve cells are myelinated also could be applied to other disorders as well, Dr. Svaren said. Diabetic neuropathy, which results in a loss of feeling in the extremities, also is thought to involve myelin production.

Dr. Svaren added that it is possible that the current study’s findings about myelin production in the peripheral nervous system could lead to greater understanding of how myelination takes place in the central nervous system (the brain and spinal cord). Myelination in the central nervous system is not well understood. Multiple sclerosis, a degenerative muscular disorder that can be fatal, results from the destruction of myelin in the central nervous system.

Information about peripheral neuropathies is available from the National Library of Medicine, at: http://www.nlm.nih.gov/medlineplus/ency/article/000593.htm and http://www.nlm.nih.gov/medlineplus/ency/article/000727.htm.

Information about Charcot-Marie-Tooth syndrome and multiple sclerosis is available from The National Institute of Neurological Disorders and Stroke at: http://www.ninds.nih.gov/disorders/charcot_marie_tooth/charcot_marie_tooth.htm and http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s website at http://www.nichd.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

New microscope allows scientists to track a functioning protein with atomic-level precision

December 14, 2005

A Stanford University research team has designed the first microscope sensitive enough to track the real-time motion of a single protein down to the level of its individual atoms. Writing in the Nov. 13 online issue of the journal Nature, the Stanford researchers explain how the new instrument allowed them to settle long-standing scientific debates about the way genes are copied from DNA—a biochemical process that's essential to life. [Read more]

Glomerular Permeability Is Altered by Loss of P0, a Myelin Protein Expressed in Glomerular Epithelial Cells

September 17, 2005

Journal of the American Society of Nephrology

[Note: P0 is one of the genes implicated in a form of Dejerine-Sottas, though the mutation itself is different. You can read more about P0 here.]

The myelin protein 0 (MPZ or P0) is a transmembrane glycoprotein that represents the most abundant myelin component. Mutations in the P0 gene are associated with one form of autosomal dominant demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (CMT1B). Because CMT1 may be associated with renal involvement, mostly focal segmental glomerulosclerosis, we hypothesized that P0 could be expressed in the kidney. P0 mRNA was detected by reverse transcriptase-PCR in the human and mouse renal cortex. P0 transcripts were identified by in situ hybridization at different stages of the mouse kidney development, especially in embryonic structures that give rise to the glomerulus. P0 protein was also detected by Western blot in human and rat glomerular extracts and in a human podocyte cell line using a monoclonal anti-P0 antibody. Immunofluorescence studies on human kidney sections showed that the podocytes were intensely labeled. Immunogold electron microscopy disclosed a predominant staining of the membranes of intracellular vesicles in podocytes. P0 was also detected in the podocyte cell membrane, including at the foot processes. P0-/- mice exhibited mild growth retardation and demyelinating neuropathy similar to the one observed in patients with CMT1B. They also presented mild albuminuria, without significant ultrastructural change of the glomerular basement membrane or the podocytes. These results demonstrate that P0, the major myelin protein, is also expressed during nephrogenesis and in mature kidney, mostly in podocytes. They suggest that P0 gene mutations might be involved in renal diseases.

Role of toxins in inherited disease, Washington State University study

June 04, 2005

From Medical News Today: A disease you are suffering today could be a result of your great-grandmother being exposed to an environmental toxin during pregnancy.

Researchers at Washington State University reached that remarkable conclusion after finding that environmental toxins can alter the activity of an animal's genes in a way that is transmitted through at least four generations after the exposure. Their discovery suggests that toxins may play a role in heritable diseases that were previously thought to be caused solely by genetic mutations. It also hints at a role for environmental impacts during evolution.

"It's a new way to think about disease," said Michael K. Skinner, director of the Center for Reproductive Biology. "We believe this phenomenon will be widespread and be a major factor in understanding how disease develops."

The work is reported in the June 3 issue of Science Magazine.

Skinner and a team of WSU researchers exposed pregnant rats to environmental toxins during the period that the sex of their offspring was being determined. The compounds - vinclozolin, a fungicide commonly used in vineyards, and methoxychlor, a pesticide that replaced DDT - are known as endocrine disruptors, synthetic chemicals that interfere with the normal functioning of reproductive hormones.

Skinner's group used higher levels of the toxins than are normally present in the environment, but their study raises concerns about the long-term impacts of such toxins on human and animal health. Further work will be needed to determine whether lower levels have similar effects.

Pregnant rats that were exposed to the endocrine disruptors produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however, and when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems. The effect persisted through all generations tested, with more than 90 percent of the male offspring in each generation affected. While the impact on the first generation was not a surprise, the transgenerational impact was unexpected.

Scientists have long understood that genetic changes persist through generations, usually declining in frequency as the mutated form of a gene gets passed to some but not all of an animal's offspring. The current study shows the potential impact of so-called epigenetic changes.

Epigenetic inheritance refers to the transmission from parent to offspring of biological information that is not encoded in the DNA sequence. Instead, the information stems from small chemicals, such as methyl groups, that become attached to the DNA. In epigenetic transmission, the DNA sequences - the genes - remain the same, but the chemical modifications change the way the genes work. Epigenetic changes have been observed before, but they have not been seen to pass to later generations.

While this research focused on the impact of these changes on male reproduction, the results suggested that environmental influences could have multigenerational impacts on heritable diseases. According to Skinner, epigenetic changes might play a role in diseases such as breast cancer and prostate disease, whose frequency is increasing faster than would be expected if they were the result of genetic mutations alone.

The finding that an environmental toxin can permanently reprogram a heritable trait also may alter our concept of evolutionary biology. Traditional evolutionary theory maintains that the environment is primarily a backdrop on which selection takes place, and that differences between individuals arise from random mutations in the DNA. The work by Skinner and his group raises the possibility that environmental factors may play a much larger role in evolution than has been realized before. This research was supported in part by a grant to Skinner from the U.S. Environmental Protection Agency's STAR Program.

Mosaic Mouse Technique Offers A Powerful New Tool To Study Diseases And Genetics

May 07, 2005

From Science Daily:

A powerful laboratory technique used by fruit fly geneticists for more than a decade is now available to scientists studying genes and diseases in mice.

Writing in the May 6 edition of the journal Cell, researchers from Stanford University describe a streamlined method for creating a "genetic mosaic mouse"--a rodent whose body is genetically engineered to produce small clusters of cells with mutated genes.

The new technique, called Mosaic Analysis with Double Markers (MADM), was developed in the laboratory of Liqun Luo, professor of biological sciences at Stanford who was recently named an investigator with the Howard Hughes Medical Institute.

"With MADM, you can look at a tiny subset of cells and study gene function at a very high resolution," says Luo, who also is affiliated with the Neuroscience Institute at the Stanford School of Medicine. "Our method can be used to study a variety of tissues, such as the skin, heart and nervous system."

Mosaics are designed to give researchers an opportunity to observe what happens when a specific gene is removed from a small cluster of cells in a living animal. With MADM, cells carrying an altered gene of interest actually turn green for easier observation.

"We use a green fluorescent protein," Luo says. "So now if you mutate a gene, you'll know in which cell the normal gene is lost. For example, if you delete a tumor suppressor gene, the green cells will proliferate, and you can actually study the tumor's progression. If you can image these cells in a live animal, you can potentially watch the tumor grow."

Luo points out that MADM is more precise than the widely used "knockout mouse" technique, in which a gene of interest is removed ("knocked out") of every cell in the animal's body. The knockout method can have unwanted, deleterious consequences for the mouse and the experiment, Luo adds, whereas MADM acts more like a scalpel, creating a handful of mutant cells in an otherwise normal animal.

Geneticists have been using mosaic fruit flies for decades. In the early 1990s, scientists developed a more efficient technique that allows researchers to control when and where mutant cells are generated in the fly's body. However, scientists have had a much more difficult time designing mosaic vertebrates, such as mice. The mouse has long been considered an ideal laboratory model for studying human development and disease, primarily because mouse DNA and human DNA are remarkably alike.

The MADM technique, which Luo and his colleagues developed for mice, works on the same principal as the method currently used to create mosaic fruit flies. The researchers begin with two embryonic stem cells whose chromosomes have been engineered to carry two inactivated segments of a green fluorescent protein molecule. Mice derived from these embryonic stem cells are mated to each other. As their offspring grow, the cells in their body begin to divide--a normal process that results in the duplication of each chromosome. Before cell division is complete, a special enzyme causes the exchange, or recombination, of the two engineered chromosomes. If one of those chromosomes contains a bad copy (mutation) of a gene, the recombination event could cause an offspring to inherit two bad copies of the gene, which would result in a mutant cell. This process simultaneously activates the green fluorescent protein, which turns the mutant cell green.

"If there is no recombination, there are neither green nor mutant cells," Luo explains. "So even if only one cell turns green, we know it has to contain the mutated gene of interest."

In their study, the Stanford team focused on the cerebellum, the part of the brain whose main function is to coordinate motor activity and maintain balance. The researchers used MADM to study the development of cerebellum granule cells, which are the most abundant cells in the brains of mice and humans.

"Usually people think that all cerebellum granule cells are the same--they are born, and their final function is determined by their interaction with other neurons," Luo says. "But we found that there appears to be a certain degree of predisposition to these cells by their lineages. This comes back to an interesting problem in developmental neurobiology as to whether the brain is wired by genetics or by environment--nature or nurture. Our discovery makes us feel that cerebellum wiring is more genetically determined than previously thought."

In a companion article published in the same edition of Cell, scientists Todd E. Anthony and Nathaniel Heintz of Rockefeller University describe MADM as "an elegant method" that brings mouse geneticists "one step closer to the enviable experimental facility available to invertebrate geneticists."

There are "many potential applications of this powerful approach," Anthony and Heintz wrote, including the "opportunity for in-depth studies of molecular mechanisms that underlie the dynamic properties of specific neuronal populations." MADM also could prove important for analysis of complex developmental or degenerative diseases resulting from genetic mutations, they added.

In light of its potential commercial applications, Luo has begun the process of licensing MADM through Stanford University's Office of Technology Licensing. Meanwhile, he and his colleagues are returning to the lab to see if the technique can be applied to other aspects of developmental biology and disease in mice.