Hereditary motor-sensory neuropathies (HMSNs) are a group of slowly progressive neurological disorders affecting the motor and sensory components of the peripheral nervous system. Charcot-Marie-Tooth (CMT) disease is an HMSN and the most commonly inherited form of peripheral neuropathy with an estimated prevalence of one in 2,500 adults and 19 in 100,000 children.1,8 CMT typically presents in childhood or adolescence with symmetric, slowly progressive distal muscular atrophy of the legs and feet, and in most cases, eventually involves the hands.2 The age of onset, severity, and rate of progression can all vary, even within the same family.2
The known genes that are associated with the pathogenesis of inherited peripheral neuropathies are PMP22 encoding peripheral myelin protein of 22kD, MPZ encoding myelin protein zero, Cx-32 encoding connexin-32, and EGR2 encoding early growth response gene 2.1 The list of new genes and various identifiable mutations for the different clinical phenotypes of CMT continues to expand. The most common form of HMSN, CMT1A, accounts for 70-80% of all CMT1 cases, and is caused by a 1.5 megabase duplication including the PMP22 gene on chromosome 17. The reciprocal deletion of the 1.5 megabase region has been shown to be associated with another HMSN, hereditary neuropathy with liability to pressure palsies (HNPP).1
The genetics involved in HMSNs are complex: there are multiple genes that may be involved in a single disorder; the pattern of transmission varies, depending on the gene and sometimes on the specific mutant allele involved; and the genes have a high mutation rate which may result in de novo (sporadic) mutations.2 For example, it is estimated that at least 10% of CMT1A cases are caused by de novo duplications.10 In these situations, negative family histories are not helpful in ruling out HMSN, since the individual's disorder may be the result of a sporadic mutation.
The development of novel genetic tests has assisted physicians in being better equipped to assess the potential causes of various HMSNs and in helping clarify a patient's diagnosis.
Table 1 highlights the complexity of the genetics involved in HMSNs. Note that the various genotypes can produce different phenotypes - i.e., a point mutation in PMP22 can cause CMT-1A, DSS-A, and HNPP.
Table 1: Known Genes of CMT and Related Demyelinating Neuropathies1
Chart adapted from: Schenone, A. and Mancardi, G.L. Molecular basis of inherited neuropathies. Current Opinions in Neurology 1999; 12:603-616.
In addition to classifying HMSNs by their molecular basis, these disorders can be categorized by their clinical features, including: age of onset, major clinical features, electromyography (EMG) findings, and sural nerve biopsy. Table 2 summarizes the clinical presentations of CMT and other related demyelinating neuropathies.
Table 2: Clinical Presentations of CMT and Related Demyelinating Neuropathies
The clinical workup for HMSN can include a medical history, physical and neurological examination, family history, clinical findings, and DNA-based testing.3 The differential diagnosis, based on clinical findings and neurological examination, may include CMT as well as other demyelinating disorders.3 As explained by James R. Lupski, MD, Ph.D., a CMT expert at Baylor College of Medicine,
These inherited demyelinating neuropathies can be difficult to distinguish from acquired demyelinating neuropathies. Molecular diagnostic testing should be considered in CMT and related peripheral neuropathies. These disorders can present with an extremely variable clinical picture.2
In addition to assisting in determining a clearer diagnosis, the molecular information may also allow individuals affected with CMT to avoid contraindicated medications. A 1995 study in the journal Cancer described the detrimental effects of a chemotherapy drug, Vincristine, which was administered to patients with CMT. Three families with CMT1A were reported, each of which had a family member who suffered rapid onset, severe neuropathy after receiving initial doses of Vincristine to treat cancer. These asymptomatic individuals, who had not been clinically diagnosed as having CMT, either died or were severely disabled as a result of taking the drug.4
Subsequent studies have shown that Vincristine causes primary axonal degeneration, disrupting axonal transport, especially in individuals with a genetic defect in the myelin sheath. This defect predisposes them to developing a severe neuropathy when exposed to an axonal toxin.4 The authors of the Cancer report stress, "In patients with unexplained or preexisting familial neuropathy, testing for 17p11.2-12 duplication should be carried out prior to initiating Vincristine therapy."4 Reports such as this have prompted investigators and the Charcot-Marie-Tooth Association (CMTA) to compile a list of medications that may cause a neurotoxic reaction in patients with CMT.
Once an individual is diagnosed with CMT, patient management focuses on supportive measures. Early in the course of the disease, strength and exercise training may be helpful to stabilize gait.14 As CMT progresses, these exercises may no longer be beneficial and the patients may require orthoses to maintain strength and balance. "Ankle-foot orthoses [AFOs] can correct foot drop and improve gait, and special adaptive splints, utensils, and writing instruments can improve hand function."14 Patients who are uncomfortable using AFOs may decide to receive orthopedic surgery to correct foot drop or pes cavus deformity.14 As a patient's condition worsens, use of ambulatory supports, and in extremely severe cases, use of a wheelchair, may be required.14
The following case studies provide examples of the utility of genetic testing for HMSNs.
HMSNs represent a spectrum of clinically heterogeneous disorders. Each has variable clinical and genetic attributes, often making it difficult to clearly identify each disorder based on clinical and electrophysiological features alone. Genetic testing for these disorders can help clarify a complex clinical picture and supplement the diagnosis: "Because of the clinical heterogeneity, the clinical workup of a patient with a peripheral neuropathy requires molecular definition."2 Once a disorder is definitively diagnosed, individuals are then able to learn about their disease, better understand their prognosis, and, in some cases, even avoid harmful medications.
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