Dr K. Florian P. ThomasK. Florian P. Thomas, MD, MA, PhD, MS
At the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania, K. Florian P. Thomas, MD, MA, PhD, MS, chair, Neuroscience Institute, chair, Department of Neurology, director, Multiple Sclerosis and Hereditary Neuropathy Centers, and founding chair and professor, Department of Neurology, Seton Hall Hackensack Meridian School of Medicine, sat with NeurologyLive® to discuss an often misdiagnosed hereditary neuropathy: Charcot-Marie-Tooth disease (CMT).

Thomas explained that since many patients oftentimes never reach a diagnosis, it’s important to increase awareness of this disease so clinicians can diagnose earlier and intervene sooner with treatment options. Significant progress has been made, according to Thomas, in alerting both patients and healthcare providers to the multiple treatment options, whether rehabilitative, surgical, comprehensive in terms of disease adjustment, or pharmacological. Thomas spoke about the approach for 2 investigational pharmacological agents being studied for CMT, which were discussed at the AAN meeting, PXT3003 (Pharnext) and ACE-083 (Acceleron), and is hopeful that more patients with hereditary neuropathy will be successfully treated. 

NeurologyLive®: What are some of the latest developments in CMT?

K. Florian P. Thomas, MD, MA, PhD, MS: It's important for my colleagues who are general neurologists as well as sub-specialized neurologists to be very much aware of CMT disease type and of the existing and upcoming treatment options because it turns out it's not a rare illness. It is appropriately classified as a rare disease because it affects only 1 in 2500 people, but at the same time this amounts 125,000 people in this country. It is my belief that many patients go through life without having reached a diagnosis. We have asked people and we've learned that it can take several years for people to reach a diagnosis and that means that during that time they may be subject to unnecessary tests and they may suffer from uncertainty, uncertainty both as it concerns themselves but also into how it affects their parents, their children, their thoughts about having children, so I think it is very important to increase awareness of this disease so that people get diagnosed rapidly and can benefit from the multiple treatment opportunities.

Over the last 30 years or so since we discovered the first chromosomal locations where mutations in genes have been associated with causing the various subtypes of CMT the science of CMT really has exploded. We now are aware of close to 100 different genes that can cause CMT and as all neurologists learned during their residency, we classify CMT along the lines of the speed of nerve conduction, so-called nerve conduction velocity being significantly reduced or relatively normal—people with significantly reduced conduction velocities we classify CMT1, people with a fairly normal conduction velocity we classify as CMT2. Beyond that we also differentiate patients who have autosomal dominant forms of the disease in which having one abnormal copy of a gene suffices to produce the disease, as opposed to a normal recessive, a condition in which a person needs 2 have to abnormal copies of the same gene. Lastly, there are excellent recessive forms in which a person has a mutation on the X Chromosome which typically affects men more severely than women because women have another normal copy of the X chromosome. This classification was very reasonable when we only had to deal with a couple of genotypes, but now that we approach 100 it has become very unwieldy. Furthermore, we have learned that the one genotype, one phenotype paradigm does not apply, it is crucial to know where in a particular gene a person has a mutation because it is the specific mutation that for instance can determine whether a patient has normal or abnormal conduction velocities. Furthermore, we've learned that conduction velocity in a given patient can change over time. A couple of days ago, with colleagues at Saint Louis University, I presented a poster that looked at a 16-year follow-up in patients with a particular type of CMT, also referred to as dominant intermediate Charcot-Marie-Tooth disease type C, which I had first described a couple of years ago, and we were able to show how patients evolve over time—that's another important consideration. We are moving toward a new classification system which is entirely based on the genetic abnormality and that is a work in progress, so stay posted.

Furthermore, we have come to realize that our knowledge of a particular mutation does not fully explain a people's disease severity, and that led to the discovery that they may be modifying genes which in a given family may determine whether a person has severe illness or milder illness. Lastly it is important to recognize that statistical freak incidents do happen, so that patients may have a mutation in more than one gene and that can result in an 80 old mother being much less severely affected than her son and her grandchild.

What efforts can be made to manage neuropathy in this patient population? 

When patients see their primary care doctors or neurologists and they discuss what could be done about their neuropathy, quite often patients leave the visit somewhat disheartened because they often go away with the impression that nothing can be done. I think it's important to realize that a lot can be done in terms of rehabilitative treatment of both arm and leg weakness, specifically I'm thinking about ankle braces which can correct foot drop and allow people to walk much more normally than they would without those ankle braces. There are all kinds of tools that occupational therapists are actually familiar with, which allow patients to cut tomatoes and carrots, to brush their hair, to brush their teeth, to pick up pens and various other tools. It's important to provide patients with appropriate consultations so they can benefit from these devices.

Hereditary neuropathies of the Charcot-Marie-Tooth disease type are typically length dependent neuropathies, which means that the symptoms and signs are more severe the longer the nerve is. For that reason, these neuropathies typically manifest first in the feet, before traveling up the ankle and up the calf muscles, and they typically affect the fingers before they affect the rest, so typically proximal muscles remain strong. The sensory abnormalities result in loss of vibration sense, loss of pinpricks sense, and it's fairly difficult to predict whether patients actually aware of that, quite often patients tell me that they experience no numbness and no tingling when I test them, but typically that is abnormal. CMT is defined as a condition of a peripheral nervous system, but we know that there is a certain degree of overlap in particular subtypes of CMT with conditions of the spinal cord and of the brain, patients may have unexpectedly brisk reflexes, patients may have impaired hearing or vision, those are well described but certainly a very rare. In the various subtypes, there may be a differential preponderance of motor versus sensory symptoms, patients can have severe sensory loss and loss of autonomic function which can result together in foot ulcers that patients may not be aware of, so it's often important to examine the skin not just for foot ulcers but also for development calluses and bunions which result from abnormal configuration of the foot joints relative to one another. The latter issue reflects the differential weakness of muscles that stretch out at a joint or bend at a joint and that is the reason for which patients get hammer toes and high arches, but also occasionally very flat arches. These changes have consequences, they can result in musculoskeletal pain, they can result in abnormal posture due to Achilles tendon shortening, where peoples’ heels no longer touch the ground which makes it necessary in order for them to stand upright, to bend the knees, which can put additional strain on the menisci and lead to degenerative changes. For that reason, it's important for the neurologist to work closely with a foot and ankle orthopedic surgeon or a podiatrist specialized in foot and ankle surgery who will assess patients for the correct timing of surgical interventions as well as for the correct choice of surgical interventions. Unfortunately, we have not yet reached a consensus on both topics, both the timing of surgery and on the type of surgery, so there is a work group ongoing that looks at just that, so one we need to stay posted on that.

I’ve talked about rehabilitative efforts, I’ve talked about surgical efforts, but there is more to CMT than that. For a young person to grow up with abnormally thin leg muscles, a young person to grow up feeling off-balance, can be quite stressful. I've talked to many patients about that, who worry about falling when they go to meet friends and being embarrassed about their falls—kids often worry about being picked last for sporting events, patients also suffer from fatigue and some patients suffer from significant pain, so it is important to have a comprehensive approach to CMT and in my center I'm fortunate to be able to offer our patients access to counseling psychologists so that we can help them live well despite the illness.
CMT is a lifelong illness, as any condition that has a genetic basis, onset age varies dramatically, and it sometimes reflects awareness within a family of CMT. I'm thinking about a woman now in her 70s, who when she was 5 could recognize her father's walking because he made an abnormal sound when he walked, and that patient has over her lifetime seen dozens of grandchildren with CMT, she has seen her many children with CMT, and her many siblings with CMT, so in that family the awareness of the symptoms and manifestation is extremely high and that family they make themselves the diagnosis of CMT in some of their little relatives by age 3—and they’re accurate. On the other hand, other people will come to a diagnosis only in their 40s or 50s, I'm thinking about a patient who first noticed that something was wrong when as an industrial worker he noticed that occasionally when his factory floor flooded, he could no longer walk on his heels to keep his shoes dry, so that was a subjective onset age in the 40s or 50s—so anything that the patient says about onset age, one has to take with a grain of salt.

CMT is obviously progressive illness, and we know that people retire a couple of years earlier than people without CMT; there is evidence that disease may progress more rapidly after age 50 and those are all factors that a neurologist should consider and address in a comprehensive approach to taking care of patients. Patients may need to get vocational rehabilitation, thinking about 2 patients of mine, one is an optician the other one is a tool and die maker and they were lucky that they could move into the more commercial side of an opticians work, in the case of one and could move into more of an educator and supervisor capacity in case of the other, because neither can pick up small tools, small screws, and so forth, so vocational rehabilitation is part of an appropriate approach to CMT.

What does the pharmacological treatment landscape of CMT look like?

With the knowledge that we've acquired over last 30 years of the CMT genes, of the cell biology of CMT, of the pathogenic mechanisms through which mutations in these genes cause disease, we have been able to think about treatment options, pharmacological treatment options, gene therapy treatment options, and some of these treatment options are very specific to the particular mutation and others are not. In many neurological illnesses we have looked at neurotrophic factors, body own chemicals, that promote growth of nerves—so that's an example of a treatment option that may be applicable to many types of CMT, there's a compound called NT-3 that has garnered a lot of interest. There are other options that only work for one particular type of CMT, I'm thinking about oligonucleotide-based treatment options where one either supplies the RNA molecule from which a protein is derived, or one corrects the effects of a mutation through gene therapy. There also is quite a bit of work on specific pharmacological agents and during the 2019 meeting of the American Academy Neurology, and I had the opportunity to talk about my work in that regard.

One approach that is the result of research sponsored by a pharmaceutical company called Acceleron focuses on removing a block to muscle synthesis through a medication that is injected into muscle every couple of weeks. What we are showing for that drug during this meeting is preliminary data in a phase 2 study where we found that injection of this agent, which is referred to as ACE-083, the muscle volume of the tibialis anterior muscle increases. The rationale is that an increased amount of contractile muscle tissue will translate into increased strength of the tibialis anterior muscle, which when weak, is one of the main contributors to disability in CMT, i.e. foot drop. This approach is interesting because it is silent as to the disease mechanism of action by which foot drop occurs. While the phase 2 study has not yet been completed, our plan assuming that the study is successful, is to move on to a pivotal phase 3 study.

In a separate study, sponsored by the pharmaceutical company Pharnext, we looked at Charcot-Marie-Tooth disease type 1A, which accounts for fully 50% of all patients with CMT. This condition results from a duplication of the PMP22 gene, which results in an increased amount of PNP22 protein and that in turn seems to be the basis for both degeneration of the axons and of demyelination loss of the normal insulation material around the axons which is produced by the Schwann cells. The approach with this drug is to reduce the amount of PMP22 protein that is made, toward normal levels. We show results from a pivotal phase 3 trial that we met primary endpoint and patients who received the drug actually improved, whereas patients who received placebo got worse, as expected.

In summary, the prospect for more successful treatment of patients with hereditary neuropathy is very good, significant progress is being made in alerting both the patients as well as their healthcare providers to the multiple treatment options, be they rehabilitative, surgical, comprehensive in terms of disease adjustment, or pharmacological, and that makes it even more important to make a diagnosis earlier, because the earlier we make a diagnosis the sooner we can intervene.

For more coverage of AAN 2019, click here.

Transcript has been edited for clarity.