Charcot-Marie-Tooth Disease

A hereditary polyneuropathy condition presenting with distal weakness and muscular atrophy (myopathy).

Hereditary Motor and Sensory Neuropathy Type I; Peroneal Muscular Atrophy.

This disorder was first described in 1886 in Paris by the two French neurologists Jean Martin Charcot and Pierre Marie, who identified it as a primary muscle disease, and independently in Cambridge by the English physician Howard Henry Tooth, who correctly interpreted his findings as a primary neurologic disease.

Estimates vary widely between 1:2500 and 1:10,000 live births. Charcot-Marie-Tooth syndrome type I (CMT I) accounts for approximately two thirds of all CMT cases, whereas CMT II constitutes the residual one third. No racial or sexual predilection could be identified.

CMT can be inherited in different patterns: autosomal dominant, autosomal recessive, and X-linked transmission have been described. The dominant form is the most common. Far more than 20 different mutations are known to cause CMT, and new ones are added on a regular basis. The two genes most commonly involved are the PMP22 (peripheral myelin protein 22) gene, located on 17p11.2, and the MPZ (myelin protein zero) gene, which has been mapped to 1q22.

The syndrome can be divided into two types based on electrophysiologic, clinical, and genetic features. CMT I is a demyelinating form of peripheral polyneuropathy characterized by decreased motor nerve conduction velocities, hypertrophy of peripheral nerves with typical onion bulb formation and segmental demyelination. As a result of a mutation in the PMP22 gene, the myelin that is formed is unstable and breaks down easily. Larger motor and sensory axons may be involved. CMT II, the so-called neuronal form, is characterized by normal or only slightly diminished motor nerve conduction velocities and normal myelination and nerve size. The pathoanatomical correlate is direct axonal death and Wallerian degeneration. Because most patients also have sensory nerve involvement, the disorders are now also summarized as hereditary motor and sensory neuropathy type I (see also “Hereditary Motor and Sensory Neuropathies (HMSN): Overview").

Based on the clinical findings of distal muscle weakness and atrophy and supported and confirmed by nerve conduction studies and specialized genetic testing. Nerve biopsy is rarely indicated. Special rare types may require DNA analysis.

Although there is considerable variation in the age of onset, the severity and progression rate of symptoms and the clinical phenotype of all forms of CMT are generally similar. A minority of patients present at birth with hypotonia or later with motor delay. However, the majority of patients present later in life, usually within the first 2 decades. The most common complaint is distal leg weakness, which manifests as frequent tripping and muscle atrophy. Hand involvement follows in most cases. Pregnancy may exacerbate a preexisting weakness in 50% of patients with early-onset disease. The exacerbation is transient in one third of women, but unfortunately is progressive in the other two thirds. Cardiomyopathy and cardiac conduction abnormalities are seen occasionally. Clinical features may include foot dropping, pes cavus deformity, muscle cramping, steppage or equine gait, “champagne bottle” or stork legs, hammer toes, clawhand, and diminished or absent deep tendon reflexes. Pain and temperature sensation are normal. The diaphragm, phrenic nerve, and vocal cords are occasionally involved. Life expectancy usually is not affected, and confinement to the wheelchair is rare.

Charcot-Marie-Tooth Disease Type I

Type IA: Approximately 90% of CMT I patients belong to this group. They all have in common a partial duplication of the PMP22 gene: clinical symptoms appear in the first or early in the second decade of life. In infants and children, the disease presents with patients walking on their toes and severe tightness of the heel cord. Occasionally, these patients are born with clubfoot. Gait anomalies, foot deformities, and loss of balance are the main complaints in these patients and the reason they seek medical help. Distal leg weakness predominantly affects the dorsiflexor muscles (innervated by the peroneal nerve), which may result in frequent tripping over objects lying on the floor. Accordingly, difficulties or inability to walk on the heels usually is one of the early signs of the disease. As the disease progresses, weakness becomes more pronounced and results in foot drops with each step, forcing the patient to flex the hips more, which leads to the steppage or equine gait. The imbalance between intrinsic and extrinsic foot muscles may result in the formation of pes cavus. Peroneal muscle atrophy may lead to inverted “champagne bottle" or stork legs, but may be masked by a thicker layer of subcutaneous fat. At this stage, patients often complain about leg muscle cramps and lumbar back pain. Later, most often the hands also start to show signs of weakness and atrophy that may result in clawhand deformity (marked extension of the fingers in the metacarpophalangeal joints, while the distal and proximal interphalangeal joints are flexed) with serious handicapping in daily life. Involvement of the hand does not appear to be related to the degree of leg weakness. Decreased vibratory sense is common, and mild sensory loss in a stocking distribution is not uncommon. Enlargement of the nerves to the point that they can be seen or palpated occurs in about one fourth of patients and is more common in men, but it seems not to be related to the severity of the disease. Approximately 40% of patients have a tremor, which usually starts in the fourth decade of life. Symptoms of hip dysplasia usually begin in adolescence. Pulmonary symptoms have been reported in CMT patients. Spirometry values and static lung volumes are usually within normal limits, but testing of the inspiratory and expiratory muscles reveals a significantly decreased function.

Variants of CMT Ia

Roussy-Levy Syndrome: This phenotypic variant has some features in common with Friedreich Ataxia and presents with pes cavus, distal limb weakness, areflexia, tremor in the hands, and distal sensory loss with ataxia. Genetic analysis in these patients has shown a duplication of the PMP22 gene.

Davidenkow Syndrome (Scapuloperoneal Atrophy): Scapuloperoneal muscle atrophy with pes cavus, areflexia, and distal sensory loss. Motor nerve conduction velocities are decreased, and hypertrophic changes of the nerves are present. These patients have the partial duplication of 17p11.2, supporting the fact that this is another variant of CMT IA.

Type IB: This group accounts for the residual 10% of CMT I patients, which share a point mutation in the MPZ gene. In comparison with CMT IA, symptoms start much earlier with delayed ability to walk, proximal leg weakness, and slower nerve conduction velocities than in CMT IA. Sural nerve biopsy reveals the demyelinating process with onion bulb formation.

Variants of CMT Ib

Dejerine-Sottas Syndrome: Characterized by onset in infancy or early childhood with delayed motor development, rapid progression, and often profound nerve hypertrophy. This form is most often caused by either de novo point mutations in the PMP22 or MPZ gene.

Congenital Hypomyelination: Infantile hypotonia secondary to distal muscle weakness, areflexia, and very slow nerve conduction velocities. The combination with joint contractures and Arthrogryposis Multiplex has been described. Sural nerve biopsy reveals hypomyelination without signs of active myelin breakdown. This form is caused by mutations in the MPZ gene.

Charcot-Marie-Tooth Disease Type II

This genetically heterogenous form of CMT, also called the neuronal type of CMT, is clinically similar to CMT I (with the same wide variability). However, the age of onset is more variable and in general is later than in CMT I. Motor nerve conduction velocities are normal or only slightly diminished, the nerves show no signs of hypertrophy, and nerve biopsy lacks the typical onion bulb formation seen in CMT I. Distal leg weakness with muscular atrophy, pes cavus deformity, and steppage gait are similar to CMT I, while the hand muscles are less often affected and deep tendon reflexes are intact. Genetically, several different mutations have been identified and mapped to chromosomes 1, 3, and 7.

CMTX/X-Linked HMSN: In approximately 90%, CMTX is inherited in an X-linked dominant transmission; the remaining 10% show X-linked recessive transmission. The clinical signs are similar to those of CMT IA, but males are more severely affected than females. The significantly decreased nerve conduction velocity supports a demyelinating process.

Assess the patient neurologically and ask about respiratory and cardiac problems. Pulmonary function tests including chest radiography and arterial blood gas analysis should be performed if respiratory involvement (secondary to respiratory muscle weakness) is suspected. An electrocardiogram is recommended for all patients, and an echocardiogram may be indicated depending on the clinical findings.

Anesthesia may exacerbate preexisting respiratory disease, and prolonged postoperative mechanical ventilation may be required. A peripheral nerve stimulator should be used to monitor neuromuscular blockade if muscle relaxants are to be used. However, care should be taken to place the electrodes on an unaffected nerve to prevent erroneous results. Regional anesthesia has been used successfully in multiple cases. Involvement of the autonomic nervous system may result in abnormal temperature regulation.

The literature suggests the induction dose of thiopentone may need to be reduced in Charcot-Marie-Tooth disease. A small number of case reports indicate use of succinylcholine in CMT may result in hyperkalemia or malignant hyperthermia-like reactions. However, this finding has not been confirmed by a larger, retrospective series of a total of 161 procedures in 86 patients, of whom 48% received succinylcholine and 90% received malignant hyperthermia triggering agents without significant adverse effects. It has been suggested, however, that individuals with acute exacerbations of the disease represent a subset of patients who have altered responses to muscle relaxants and that, in such a scenario, succinylcholine should be avoided and other muscle relaxants used in small incremental doses with neuromuscular monitoring.

Cowchock Syndrome: An X-linked form of sensory and motor neuropathy characterized by atrophy of the peroneal muscles but also involving other distal muscles of the legs and arms.