Hereditary Motor and Sensory Neuropathy Types I and II

Nerve conduction studies (NCS) distinguish predominantly demyelinating diseases, such as CMT1, from axonal neuropathies. In demyelinating neuropathies (e.g., CMT1a), conduction velocities are generally less than 60% of normal and may be as low as 15% of normal. Slowing of nerve conduction can be used to identify affected family members before they are symptomatic. The degree of conduction slowing is relatively uniform across nerves. Distal latencies may be significantly prolonged, consistent with slowing along the entire course of the nerve. Temporal dispersion and conduction block are usually not present.

In contrast to CMT1, CMT2 (i.e., HMSN I) is predominantly an axonal neuropathy. NCS show lowamplitude motor and sensory responses, with relatively preserved conduction velocities and latencies. Needle electromyography in patients with CMT2 shows a greater degree of axonal changes, (e.g., fibrillations or positive sharp waves, long-duration motor units).

Nerve biopsies are usually not used diagnostically, but may be useful when genetic testing is negative and other etiologies need to be ruled out. In CMT1, nerve biopsy specimens may demonstrate a decrease in the number of myelinated nerve fibers associated with an increased fascicular area, producing onion bulbs (circumferentially arranged Schwann cell processes), which are caused by repeated episodes of demyelination and attempted remyelination. It is also common to see thinly myelinated nerve profiles as well as “naked axons” that have become denuded of myelin. Teased fiber preparations on the nerve biopsy will show areas of segmental demyelination and remyelination. Although both inherited and acquired forms of demyelinating polyradiculoneuropathy may show similar findings of demyelination and remyelination, acquired forms are more likely to show inflammatory changes. CMT2 nerve biopsies predominantly show axonal loss in a diffuse pattern, with degenerating profiles, and with teased fibers showing axonal degeneration in varying stages, consistent with an indolent process. Genetic testing has a progressively greater role in the diagnosis of inherited neuropathies. Early in research, duplication of the PMP22 gene was found to be a cause of CMT1a, but subsequently, other genetic abnormalities were also found to produce an CMT1 phenotype, including defects in the genes myelin protein zero (MPZ), EGR2, and GJB1. Similarly, several gene abnormalities have been found to cause CMT2, including MFN2, MPZ, EGR2, PRX, NFL, LITAF, and GJB1. Identification of a specific genetic abnormality is important, both for genetic counseling of the patient and family members, and for implicating potential targets for research in future therapeutics.

There is currently no curative treatment available for the underlying genetic processes at this time, and no treatment consistently found to be effective in slowing the progression of the disease process. Because the genetic defects are variable and new genes continue to be identified, it is unlikely a single treatment strategy will be effective for all these entities. The degree of disability acquired can vary dramatically, with some patients wheelchair-bound but others minimally affected, and many cases are only identified after a more affected family member has been diagnosed. Many patients with severe foot drop benefit from ankle-foot orthoses to avoid muscle fatigue and falls. Painless injury, particularly to the feet, is a risk in these patients, and care of the feet is important. In extreme cases, patients can develop a Charcot joint. In some cases, the use of a cane or other gait aid can markedly improve quality of life.

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