Charcot-Marie Tooth Syndrome

Definition and Causes – the Charcot-Marie-Tooth Syndrome or CMT is an inherited peripheral polyneuropathy first described independently by French professor Jean-Martin Charcot and his student Pierre Marie in 1886 and later by Howard Henry Tooth in his dissertation in the same year (PatientPlus 2005, Kedlaya 2005). This inherited neurological disease is characterized by a slowly progressive degeneration of the muscles in the foot, the lower leg, hand and forearm and also a mild loss of sensation in the limbs, fingers and toes (National Human Genome Research Institute 2004). Genetic mutations in this heterogeneous disorder cause the deterioration of nerves that control the muscles of the hand, arm, foot and leg (Avicena 2005). This progressive deterioration of the muscles results in a range of symptoms from mild to severe deformities. The disease is usually not fatal and does not shorten life span or affect one’s intellectual capability (Avicena).

This most common inherited neurologic disorder was first described in 1886 by Charcot and his student Marie as distal muscle weakness and wasting that begins in the legs and first called it peroneal muscular atrophy (Kedlaya 2005). In the same year, Tooth described the same disease in his Cambridge dissertation as peroneal progressive muscular atrophy and was the first to correctly identify the symptoms to neuropathy rather than to myelopathy, which earlier physicians did. The same condition was identified by Hoffman in 1912 as peroneal muscular atrophy with thickened nerves. The disease was then called Hoffman disease and later the Charcot-Marie-Tooth-Hoffman disease (Kedlaya).

CMT is the most common inherited disorder of the peripheral nervous system, which affects 36 in every 100,000 population (PatientPlus 2005). The prevalence in the U.S. is one person per 2,500 or about 125,000 people (Kedlaya 2005). Because it is often misdiagnosed, experts agree that as many as 300,000 may actually harbor the disease (Avicena 2004). It affects all races and ethnic groups. CMT was subdivided into CMT 1 and CMY 2 in 1968, based on pathologic and physiologic criteria and further subdivided according to the genetic cause (Kedlaya). Type 1 is a peripheral myelination, which results from a mutation in the peripheral myelin protein-22 gene. The mutation produces an abnormal and unstable myelin, which spontaneously breaks down, a process that leads to demyelination and the uniform slowdown of conduction velocity. Medical experts believed that the slowdown of conduction in motor and sensory nerves caused weakness and numbness. A more recent study by Krajewski and his group tended to attribute neurological dysfunction and clinical disability in Type 1 to a loss of or damage to diameter motor and sensory axons. In response to demyelination, Schwann cells proliferate and form concentric rays of remyelination. The repeated and alternating cycles of demyelination and remyelination produce a thick layer of abnormal myelin around the peripheral axons and create an onion bulb appearance (Kedlaya).

Type 2 is a primarily neuronal rather than a demyelinating disorder and results in peripheral neuropathy through direct axonal death and Wallerian degeneration (Kedlaya 2005). There is also a Type 3, called Dejerine-Sottas disease, which begins in infancy and is characterized by severe demyelination and delayed motor skills. There is maked segmental demyelination with the myelin thinning around the nerve. CMT S. And CMT 4 have also been identified as demyelinating neuropathies (Kedlaya).

Research points to a GARS gene as behind CMT type 2D (National Human Genome Research Institute 2005). This is a form of CMT that primarily affects the hands and the forearms and is inherited in an autosomal-dominant environment. The GARS gene has been linked by the study to only two specific types of CMT, but this will guide further research into other forms of disease and neurological disorders.

Scientists and researchers may also investigate the connection between the GARS gene and the carpal tunnel syndrome (National Human Genome Research Institute 2005). Two defective forms of the gene have been identified and implicated in Lou Gehrig’s disease as interacting with the GARS strain. The GARS gene is viewed as a rich new resource for scientists studying inherited and non-inherited neurological diseases (NHGRI).

A high arched foot or gait disturbance is generally the first sign of CMT (National Human Genome Research Institute 2004). Other symptoms include foot-bone abnormalities, like high arches and hammer toes, hand malfunction and imbalance, occasional muscle cramping in the lower leg or forearm, loss of normal reflexes, occasional partial loss of sight or hearing and scoliosis in some persons. Some people with CMT usually recognize the symptoms in adolescence or early adulthood. The axons of the peripheral nerves in Type 1 lose their protective outer covering called myelin sheaths, a condition that disturbs the axons’ function. In Type 2, a defect within the axons themselves reduces their response. Type 2 is the less common and grouped into at least six subdivisions, based on the defects in different genes.

Complications – Foot ulcers and laryngeal dysfunction with aspiration pneumonia are some of these (Avicena 2005). Besides foot drop and foot deformity or scoliosis, there can be pressure palsies (ParentPlus 2005). Ankle sprains and fractures also occur because us muscular weakness. A person with CMT must lift his or her leg in an exaggerated way to clear the foot off the ground (Kedlaya 2005). Foot muscle weakness often leads to foot deformity called pes cavus, characterized by calluses, ulcers, cellulites and lymphangitis, poor handwriting, difficulty in using zippers and buttons and clumsiness in handling small objects. Other complaints are musculoskeletal and neuropathic pains, muscle cramps, impotence, stork leg or inverted champagne bottle appearance, bony abnormalities for those with long-standing CMT, ulnar nerve lesions and oher foot deformities. There may also been spinal deformities, such as thoracic scoliosis, that have been observed among 37-50% of those with Type 1. CMT significantly reduces or eliminates deep tension reflexes and vibration sensation. It can also produce sensory gait ataxia, essential tremor, sensory neuronal hearing loss, enlarged peripheral nerves, phrenic nerve and vocal cord involvements in a few (Keldaya). Other patients have exhibited hyperhidrosis, nausea, vomiting, diarrhea and heart block (PatientPlus).

Other problematic conditions that have been associated with CMT are acquired non-genetic causes of peripheral neuropathies, alcoholism, Vitamin B12 deficiency thyroid diseases, diabetes mellitus, HIV, leprosy, vasculitis, neurosyphilis, amyloid associated with chronic inflammation, occult malignancy, heavy-metal intoxication, chronic demyelinating polyneuropathy, and motor neuropathy with multiple conduction block. Other genetic neuropathies that have been associated with CMT are blindness, seizures, dementia and mental retardation, familial brachial plexus neuropathy autosomal recessive genetic disorders, x-linked recessive genetic disorders and amyloid neuropathies (Keldaya).

Treatment – There is as yet no known treatment to reverse or slow down the natural progression of the disorder (Keldaya 2005). Nothing has been developed or known that can correct the abnormal myelin, prevent or stop its degeneration or axonal degeneration. Only better understanding of genetics and biochemistry of the disorder offers any hope for future treatment. However, physical therapy and moderate physical activity have been shown to have some benefits by helping maintain muscle strength and endurance (Avicena 2005). Custom shoes and shoe inserts have been of value in preventing ankle sprains and as an aid in walking. Corrective foot surgery may also help maintain mobility. Research also suggests that hand-specific exercises, adaptive devices and surgery can help maintain hand function and movements (Avicena).

In the meantime, conventional management of CMT requires the evaluation and symptomatic treatment by a medical team, including a neurologist, a physiatrist, an orthopedic surgeon, a physical therapist and an occupational therapist (Keldaya 2005). Orthopedic surgery may be the option to correct severe pes cavus deformities, scoliosis and other joint deformities, according to the age of the patient, the cause and severity of the disorder. This may consist of soft tissue surgical procedures, osteotomy, and joint stabilizing procedures. These procedures occur in stages, beginning with a radical plantar or plantar-medial release. The Coleman Block test is sometimes used in deciding the best surgical option (Keldaya)

Treatment and Side Effects -Drugs and medications known to cause nerve damage should be avoided. Examples of these drugs and medication are vincristine, isoniazid and nitrofurantoin (Keldaya 2005). The physician or therapist should identify the cause of any pain as accurately as possible. A CMT patient who complains of musculoskeletal pain may respond to acetaminophen or non-steroidal anti-inflammatory drugs, or NSAIDs, or to tricyclic anti-depressants or antiepileptic drugs, such as carbamazepine or gabapentin, if he complains of neuropathic pain. Ibuprofen may be given for mild to moderate pain, to inhibit inflammatory reactions and pain and to decrease prostaglandin synthesis. Ibuprofen, however, is contraindicated to documented hypersensitivity, peptic ulcer, recent gastrointestinal bleeding or perforation, renal insufficiency andr high risk of bleeding. Administration of aspirin also increases the risk of inducing serious NSAID-related adverse side effects. Probenecid may also increase the concentration or toxicity of NSAIDs, reduce the effect of hydralazine, captopril and beta-blockers; the diuretic effects of furosemide and thiazides; increase the risk of methotrexate toxicity and also increase phenytoin levels when administered at the same time.

These conventional drugs and medications are usually safe when prescribed and administered to pregnant patients, but the benefits must outweigh the risks (Keldaya 2005). In the third trimester of pregnancy, caution must be taken concerning congestive heart failure, hypertension and decreased renal and hepatic function, interstitial nephritis, hyperkalemia, hyponatremia and renal papillary necrosis, anticoagulation abnormalities, leucopenia, granulocytopenia and thrombocytopenia. The use of Celecoxib is aimed primarily at suppressing pain and inflammatory stimuli, but it may contribute to NSAID gastrointestinal toxicity. The lowest possible dose of celecoxib should be prescribed and taken. On the whole, NSAIDs can mask the usual signs of infection, therefore, caution must be taken in the presence of existing controlled infection. The physician should investigate symptoms and signs, which suggest liver dysfunction or abnormal liver lab results.

On September 30, 2004, Merck and Company voluntarily withdrew rofecoxib from the American and world markets because of its association with an increase in cardiovascular incidence (Keldaya 2005). A major Food and Drug Administration study linked the medication to a three-fold rise in the risk of sudden cardiac death or heart attack among patients taking higher doses of rofecoxib compared to those not taking it. The study showed that even patients taking standard dose had he greater risk of heart attack or sudden cardiac death than those taking any dose of celecoxib. This study was conducted on account of the medical records of 1.4 million people who were insured by the Kaiser Permanente in Oakland, California between 1999 and 2001. The study was observational, rather than randomized and controlled (Keldaya).

On April 7, 2005, Pfizer, Inc. also voluntarily withdrew its valdecoxib product name, Bextra, from the American and world markets, pending talks with the FDA on the link of the drug to potentially life-threatening risks, including myocardial infarction, stroke and serious skin reactions (Keldaya 2005). The drug offers a very fast start of pain relief and prolonged efficacy. New information was given on the cardiovascular risks to more than 1,500 patients treated with valdecoxib, who showed increased cardiovascular risks as compared with those who were given placebos. These observed cardiovascular risks included myocardial infarction, cerebrovascular accident, deep vein thrombosis and pulmonary embolism. Pfizer, Inc. submitted its own report on November 5, 2004, confirming the risk of the intravenous form of valdecoxib but that the oral form was associated with lower risk.

CMT is also managed with the use of anti-depressants, a complex group of drugs, which assert central and peripheral anti-cholinergic and sedative effects (Keldaya 2005). Tricyclic anti-depressants have substantial effect on pain transmission and block the ctive re-uptake of norepinephrine and serotonin. Analgesics, on the other hand, are the most commonly prescribed for certain chronic and neuropathic pain. They inhibit membrane pump that is responsible for the uptake of norepinephrine and serotonin in adrenergic and serotonergic neuron. Analgesics are contraindicated to hypersensitivity to these drugs and for patients who have taken MAO inhibitors in the previous 14 days or who have a history of seizures, cardiac arrhythmias, glaucoma or urinary retention. Nortriptyline is another analgesic that has demonstrated effectiveness in treating chronic pain by increasing the synaptic concentration of neurotransmitters in the central nervous system. Desipramine has a similar action in creasing synaptic concentration of norepinephrine at the central nervous system by inhibiting the re-uptake by pre-synaptic neuronal membrane.

Other drugs and medications prescribed for the management of CMT are doxepin with histamine and acetylcholine function in the treatment of depression because of chronic and neuropathic pain. It is, however, contraindicated to sensitiivity, urinary retention, acute recovery phase following myocardial infarction and glaucoma. It decreases anti-hypertensive effects but increases the effects of sympathomimetics and benzodiazepines and those of desipramine with phenytoin, carbamazepine and barbiturates. Anti-convulsants are also used to manage pain and sedate neuropathic pain. One example is gabapentin, which is a membrane stabilizer (Keldaya).

No inpatient care is generally required for CMT, except in surgical cases (Keldaya 2005). Further outpatient care includes check-ups for deterioration in function and contractures, deterrence and prevention. Genetic counseling may be useful in providing families with information on the nature, inheritance patterns and the genetic implications of the disorder. Genetic counseling gives parents a chance to make informed decisions on reproduction.

Failure to make accurate and proper diagnosis of CMT and its genetic patterns has serious medico-legal consequences (Keldaya 2005). This need can be met by providing genetic counseling to parents and avoid these medico-legal consequences.

Diagnosis of CMT requires a series of tests, including an evaluation of muscle atrophy and nerve condition, examination of muscle and nerve sensory responses, and electromyograpic studies as well as a thorough review of the patient’s family history as regards CMT (Keldaya 2005). A DNA blood test may also be used in detecting or ruling out the 1A and 1X CMT types (Keldaya 2005). All routine laboratory tests must be conducted on all CMT patients. Other procedures should include special genetic tests, nerve biopsy in cases of dilemma, electromyography or nerve conduction study.

The Avicena Group (2005) has explored the usefulness of a new drug in the treatment of CMT. A pilot study was conducted by the group on the drug, which aims at increasing muscle size and the level of total muscle creatine concentration. The compound under study addresses increased muscle strength and increased aerobic capacity and the overall reduction of the severity of symptoms (Avicena)

Prognosis – the progression of CMT depends on the subtype, but most CMT patients live a normal life expectancy and the disease progresses slowly with little disability (Avicena 2005). Those who develop the most severe forms of CMT, such as Dejerine-Sotta, are afflicted with the disorder as early as two years old and die young (PatientPlus 2005). Prognosis also depends on the clinical severity. In general, CMT is a slowly progressive neuropathy, which eventually leads to disability secondary to distal muscle weakness and deformities. it, however, does not shorten one’s life span (Keldaya 2005).

CMT is marked by progressive nerve degeneration and muscle atrophy (Avicena 2005). As the nerves of the feet, legs, hands and arms degenerate, the CMT patient slowly loses normal use of his or her extremities. As mentioned earlier, among the earliest signs is a high arched foot. As the disorder progresses, more structural foot deformities and frequent ankle sprains occur as consequent injuries. This condition of progressive muscle atrophy leads to problems with walking, running and maintaining balance. In rare conditions, muscle weakness extends to upper legs. This progressive muscle atrophy also affects hand function, so that fine acts, like writing and holding utensils, become hard. In the latter stages, the degeneration of nerve function leads to the loss of senses in the hands and feet. The patient soon loses the ability to distinguish between hot and cold, along with the tactile sense. In the majority of cases, CMT symptoms reach full expression by the age of 30 (Avicenia).

Bibliography

Avicena. (2005). Charcot-Marie-Tooth Syndrome. Disease Targets. Avicena Group. http://www.avidenagroup.com/disease_targets/neuromuscular/cmt_php?print=on

Kedlaya, D. (2005). Charcot-Marie=Tooth Syndrome. eMedicine.com, Inc. http://www.emedicine.com/arthoped/topic43.ht

National Center for Biotechnology Information (2005). Charcot-Marie-Tooth Syndrome. Genes and Diseases. U.S. National Library of Medicine. http://www.ncbi.nlm.nih.gov/books/bv_fcgi?call=bv.view.ShowSection&rid=gnd.section.197

National Human Genome Researc Institute. (2004). Learning About Charcot-Marie-Tooth Disease. National Institutes of Health. http://www.genome.gov/11009201

PatientPlus. (2005). Charcot-Marie-Tooth Syndrome. EMIS: Patient Information Publications. http://www.patient.co.uk/showdoc/40001212