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What You Don’t Know…The Risk of Undiagnosed Hereditary Peripheral Neuropathy

When it came to needing chemotherapy, what Allison Moore didn’t know really did hurt her. Moore was a healthy 29-year-old in training for the New York marathon when her doctors discovered a malignant but treatable tumor in her leg. She underwent combination chemotherapy with vincristine, adriamycin, and cytoxan. While her cancer was treated successfully, she developed severe peripheral neuropathy. Peripheral neuropathy is a recognized side effect of several potent chemotherapy agents, including vincristine, and she was assured she would likely improve over time. But she didn’t.

What she didn’t know at the time was that the chemotherapy had unmasked a previously asymptomatic hereditary neuropathy called Charcot-Marie-Tooth disease (CMT). As months turned into years with no improvement, she began to look for other causes of her symptoms. Finally, she saw a neurologist who recognized the symptoms and the connection to the chemotherapy. “It took me two-and-a-half years to finally get a diagnosis,” Ms. Moore says. “It’s the biggest disease no one has ever heard of.”

CMT, named for its three co-discoverers, is not one but actually many different genetic disorders with similar symptoms. There are multiple clinical types and subtypes, which differ in their underlying gene, the mode of inheritance, and the spectrum of symptoms produced. The most common is duplication of the peripheral myelin protein 22 (PMP22) gene, causing overexpression of the protein and myelin abnormalities. It is inherited as an autosomal dominant condition.

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Symptoms include weakness, reduced deep tendon reflexes, loss of muscle bulk, and foot deformities, including hammer toes and high arches. “CMT is the most common cause of inherited peripheral neuropathy with a prevalence of 1 in 2,500 people. It is unfortunate that the genetic diagnosis is not considered more frequently because it identifies medications that are potentially toxic to CMT patients.” according to Joseph Higgins, MD, FAAN, Medical Director of Neurology for Athena Diagnostics.

Taking a detailed family history can help avoid problems. “Questions about whether there are relatives who use a cane, or braces, have an orthopedic problem with their feet, or have seen a podiatrist should raise the suspicion.  Some medications are hazardous and should be avoided by all CMT patients including those with no symptoms.” Dr. Higgins said. “It is important to ask questions about hereditary peripheral neuropathies before prescribing such medications.” In Ms. Moore’s case, there were clues in her family history—her father had peripheral neuropathy—and she herself had high arches and poor reflexes. “My leg never would go up when they tapped my knee,” she noted, but neither she nor her family were informed of the possible implications. “We didn’t know it was genetic.”

When there is a possibility of a history of peripheral neuropathy, or if medications worsen a neuropathy, a referral to a genetic counselor or a neurologist is indicated. In years past, the wide array of potential genetic diagnoses meant that much effort and expense, including electromyography and nerve conduction studies, went into narrowing the diagnosis by CMT type before ordering a genetic test. That is still good medical practice, Dr. Higgins said. “But with the cost of sequencing coming down, it is now easier to screen for the majority of the CMT types all at once.” Genetic counseling is still a vital part of the testing protocol, since the hereditary information and the implications of the test results can still be complex.

What to do when the patient tests positive for a peripheral neuropathy and still needs chemotherapy? There are important guidelines every oncologist should know. Most significantly, vincristine should never be used in a patient at risk for CMT type 1a, the form due to PMP mutations. This precaution is outlined on a “black box” warning on the drug’s prescribing information.  There is a long list of other drugs that carry less severe risks, including other chemotherapy agents, antibiotics, and anesthetics. With each, it is important to weigh the risks and benefits for the individual patient in light of their genetic diagnosis. A full discussion and list of drugs of concern can be found at the National CMT Resource Center website, help4cmt.com/factsheets/?t=Neurotoxic Drugs

Ms. Moore can no longer run marathons, but she does ride in bike-a-thons and remains physically active despite her CMT. She is the founder and president of the Hereditary Neuropathy Foundation, and serves as the Consumer Advisor to the National CMT Resource Center. Educating physicians about these unrecognized risks “is one of our missions,” she says. “The oncology community needs to know.”

Additional Resource

Allison Moore shares her experiences with CMT and sheds light on why genetic diagnosis is so important.

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