Hereditary Motor and Sensory Neuropathies (HMSN, i.e., Charcot-Marie-Tooth Disease)

The classifications of the different types of hereditary polyneuropathy were initially based on clinical and electrophysiologic features. More recently, however, advances in genetics have led to identification of many specific genetic mutations known to produce polyneuropathy, and the classification of hereditary polyneuropathies has hence been modified.

Symptom onset of inherited polyneuropathies tends to be insidious. High arches of the feet, curling of the toes, gradually progressive weakness of the feet and ankles, and mild gait problems are often the initial manifestations, which may first be identified by the patient, a family member, or a health-care provider (in some cases, by a school nurse). On examination, both motor and sensory fibers are usually affected symmetrically and predominantly distally (e.g., ankle dorsiflexion weakness, reduced vibration sensation at the toes). In most cases, negative (e.g., sensory loss) sensory symptoms predominate over positive (e.g., pain, prickling, tingling) sensory symptoms, although these can occur as well. Autonomic features are uncommon. These disorders are chronic, lifelong, and slowly progressive.

Initial classifications of inherited neuropathies affecting motor and large fiber sensory modalities include Charcot-Marie-Tooth disease (CMT). CMT is a very common genetic disorder, affecting approximately 1 in 2,500 people. CMT is also often classified as hereditary motor and sensory neuropathy (HMSN). The most common types of HMSN are type I (demyelinating), type II (axonal), and HMSN X (demyelinating-axonal). Types I and II are both inherited as an autosomal dominant trait. Type III (Déjerine-Sottas disease) has historically been considered an autosomal recessive severe polyneuropathy, although more recently, Déjerine-Sottas disease has been linked to sporadic (“de novo”) mutations in genes that more commonly cause dominant forms of CMT. Consequently, Déjerine-Sottas disease is now thought to be an autosomal dominant disease and is classified as a severe form of HMSN type 1. HMSN X is an X-linked neuropathy, usually with more severe clinical manifestations in males. Type IV usually presents early in life, and can have other associated abnormalities (e.g., deafness, vocal cord paralysis) depending on the subtype and affected gene. Refsum disease is a very rare disorder that causes a relative block in the degradation of phytanic acid and clinically mimics HMSN III in many respects.

Because of all of the advances in medical genetics, the classification of inherited neuropathies has become very complicated and is continually changing. A comprehensive review of these advances is beyond the scope of this book, but a review of some of the more common and more recognized forms is included later.

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