A hereditary polyneuropathy condition presenting with
distal weakness and muscular atrophy (myopathy).
Hereditary Motor and Sensory Neuropathy Type I; Peroneal
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 ...