Pharmacists and Charcot-Marie-Tooth disease

Adapted by Ann Winkle MPS.

Charcot–Marie–Tooth disease (CMT) is the most commonly inherited neuromuscular disorder, affecting almost 10,000 Australians.^1,2,3

About one in three CMT patients require a mobility aid.² Some are susceptible to medicine-induced neurotoxicity.

Could this be any of your patients?

CMT affects both sensory and motor peripheral nerves, gradually resulting in reduced sensation and muscle weakening. As CMT tends to affect distal points first, symptoms start in the feet and progress proximally.¹ 

Severity, progression and age of onset vary widely. People with more common forms of CMT typically live a normal lifespan.² Those with the rare childhood form of CMT (diagnosed before 10 years of age) usually have profound limitation in activities.

CMT results from mutations in genes involved in peripheral nerve function. Although not fully understood, nerve conduction velocity is reduced. Electrical impulses do not reach target muscles, causing weakness, atrophy and sensory loss.^4,5 

Familial inheritance can be autosomal dominant, autosomal recessive or X-linked recessive, depending on the specific mutation involved.⁶ Cases of sporadic mutations have also been documented.¹  

There are many genetic variations with CMT1 (demyelinating form) being the most common form, followed by CMT2 and CMTX (both axon abnormalities). Many patients don’t know their CMT subtype.^2,7

Symptoms commonly appear in adolescence or early adulthood but can be earlier or later. An Australian survey found that the median age of diagnosis was 33.5 years, with most diagnoses in the age cohort of 45–49.²

Common signs and symptoms:^1,2

• Abnormal gait and balance
• Foot deformities e.g. high arched foot (pes cavus), flat feet, hammer toes
• Foot drop during walking 
• Weakness in extremities
• Decreased sensation in feet, legs, hands and arms
• Burning or pins-and-needles sensation in hands and feet
• Difficulty with fine motor tasks
• Decreased grip strength
• Curling fingers or toes
• Muscle cramping in feet/lower legs
• Neuropathic pain, tremors, fatigue.

Less commonly, sleep apnoea, vocal cord paralysis, scoliosis, kyphosis and hearing loss has occurred. Rarely, breathing can be affected requiring a ventilator.¹ 

CMT is progressive; symptoms usually worsen over time. Although quality of life can be affected, life expectancy is not usually decreased. However, there is no cure.

Neuropathic and postural pain can be significant problems for patients with CMT, causing anxiety and depression.^1,2

Treatments^1,3

Non-pharmacological strategies aim to improve mobilisation and maintain strength and flexibility and include: 

• Physical therapy – general exercise, resistance training, stretching, splinting (for hand function)
•  Occupational therapy – orthotics, mobility aids, foot care
•  Surgery for significant deformities.

There is low-level evidence (based on case studies) that functional surgery plus intensive neurorehabilitation improves walking, balance and pain in adults with CMT.⁸

Short-term pharmacological treatment is considered for symptoms such as musculoskeletal pain, neuropathic pain and fatigue. There is mid–level evidence that botulinum toxin type A slows progression of pes cavus (high arched foot) but may not improve foot posture, ankle flexibility, or strength in children with CMT1A.⁹

Sydney pharmacist Sietel Gill has lived with CMT for nearly 30 years following his diagnosis at age 11. After corrective surgery and ongoing occupational therapy to improve mobility and muscle weakness, his primary concern is chronic and breakthrough pain. The condition has also taken an emotional toll. Mr Gill has fine-tuned management of his condition, particularly with regular OTC NSAIDs for pain, but feels frustrated with health professionals who don’t understand CMT or appreciate that management is not a one-size-fits-all. 

‘I want pharmacists to understand CMT, a disease 1 in 2500 Aussies has. Also [they could] show more compassion, especially for the chronic neuralgic and muscular pain involved because through my career, very few have added value to how I manage the disease, Mr Gill said.

‘CMT is not life-threatening. I can have a good life by managing symptoms and being supported by health professionals who respect my individual needs.’

How can pharmacists help?

Pharmacists are in an ideal position to provide medication safety information to CMT patients and medical practitioners. They can also identify adverse drug reactions if they occur and refer the patient for medical review. 

Patients with peripheral neuropathy, including CMT, have increased susceptibility to medicine-induced neurotoxicity, thereby worsening symptoms.¹⁰ Twenty-five per cent of patients with CMT have reported adverse side effects with prescription medicines, as opposed to 4% of the general population.² 

The American CMT Association (CMTA) developed a list of drugs/drug classes with the potential to worsen neuropathic symptoms.¹¹ For example, there is strong evidence that vincristine causes neurotoxicity in CMT patients, whereas nitrous oxide does not.¹² Alcohol has not been shown to be neurotoxic, but can increase the risk of falls. 

Treatments on the horizon

A greater understanding of the genetic cause of CMT is leading researchers to develop targeted treatments. A fixed-dose combination of baclofen, naltrexone and D-sorbitol has shown promise for mild to moderate CMT Type 1A, and was safe and well-tolerated.^6,13 It may have the potential to change the course of the disease.¹⁴

An experimental treatment in phase 2 trials, known as ACE–083, is injected into the muscle to prevent muscle atrophy, thereby delaying progression of CMT symptoms. Preliminary results are positive.¹³

Other potential treatments are progesterone antagonists, neurotrophic factors, curcumin and ascorbic acid. They have all shown promise in animal studies, but human studies are yet to show benefit.⁶ Gene therapy and stem cell therapy are avenues for future investigation.

Further information

Charcot–Marie–Tooth Association of Australia (CMTAA) at: www.cmt.org.au

Charcot–Marie–Tooth Association of USA (CMTA) provides a list of neurotoxic medications at: www.cmtausa.org¹²

Patient leaflets:

• Moving Forward with CMT at: www.cmt.org.au/uploads/pdf/CMT_Brochure_final_small.pdf
• A Guide to Physical and Occupational Therapy for CMT at: www.cmt.org.au/uploads/pdf/CMTA_PT_OT_Guidel_9_2018_DT.pdf 

References

1. Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009;8:654.
2. Burns J, Denton S, Poynten J, and Stanley J. Reducing the health burden of Charcot-Marie-Tooth in Australia. The University of Sydney. 2015. At: www.cmt.org.au/uploads/pdf/reducing-the-health-burden-of-cmt-in-australia.pdf 
3. McCorquodale D, Pucillo EM, Johnson NE. Management of Charcot-Marie-Tooth disease: improving long-term care with a multidisciplinary approach. J Multidiscip Healthc 2016;9:7–19. At: www.ncbi.nlm.nih.gov/pmc/articles/PMC4725690
4. Timmerman V, Strickland A, Züchner S. Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the human genome project success. Genes 2014;5(1):13–32. At: www.ncbi.nlm.nih.gov/pmc/articles/PMC3978509 
5. Banchs I, Casasnovas C, Albertí A, et al. Diagnosis of Charcot-Marie-Tooth disease. J Biomed Biotechnol 2009;2009:1–10. At: www.ncbi.nlm.nih.gov/pmc/articles/PMC2760395 
6. Hoyle JC, Isfort MC, Roggenbuck J et al. The genetics of Charcot-Marie-Tooth disease: current trends and future implications for diagnosis and management. Appl Clin Genet 2015;8:235–243. At: www.ncbi.nlm.nih.gov/pmc/articles/PMC4621202
7. Saporta AS, Sottile SL, Miller LJ, et al. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol 2011;69:22. At: www.ncbi.nlm.nih.gov/pmc/articles/PMC3058597 
8. Ferraro F, Dusina B, Carantini I et al. The efficacy of functional surgery associated with early intensive rehabilitation therapy in Charcot–Marie–Tooth Type 1A disease. Eur J Phys Rehabil Med;2017:788–92.
9. Burns J, Scheinberg A, Ryan MM, et al. Randomized trial of botulinum toxin to prevent pes cavus progression in pediatric Charcot-Marie-Tooth disease type 1A. Muscle Nerve. 2010 Aug;42(2):262-7. 
10. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci 2006;242(1):47–54.
11. Charcot-Marie-Tooth Association. Neurotoxic medications. 2017. At: www.cmtausa.org/resource-center/treatment-management/neurotoxic-medications 
12. Ibister GK, Burns J, Prior F et al. Safety of nitrous oxide administration in patients with Charcot-Marie-Tooth disease. J Neurol Sci 2008;268(1–2):160–2.
13. Mandel J, Bertrand V, Lehert P, et al. A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment. Orphanet J Rare Dis 2015;10(1):74. At: www.ncbi.nlm.nih.gov/pmc/articles/PMC4482281 
14. Shy M, Herrmann D, Thomas F, et al. CMT and neurogenic disease: Preliminary phase 2 results for ACE-083, local muscle therapeutic, in patients with CMT1 and CMTX. Neuromuscul Disord 2018;28:S132–3.