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

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

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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.

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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.

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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.

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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").

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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.

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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 ...

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