Preventing Deterioration from Charcot-Marie-Tooth Disease

This report was commissioned by one of my freelancing clients and published with permission.

Bottom Lines

The standard treatment for CMT is physical therapy and orthotics, and these do help improve strength and ankle stability.  Everything else is experimental.

A combination drug made of low-dose baclofen, naltrexone, and sorbitol improves CMT symptoms in a Phase II human trial, and seems to slow deterioration.  

Neurotrophin-3, a nerve growth factor, improved symptoms of neuropathy in a pilot study, and caused regeneration of myelin-producing cells.  

Modafinil relieves fatigue.  

Standard pain medication includes NSAIDs, lidocaine, tricyclic antidepressants, or anticonvulsants. There have been case studies of acupuncture and spinal stimulation being effective for pain.


Physical Therapy

20 patients given a resistance training regimen (with wrist and ankle weights and a squeeze ball) for 12 weeks, and receiving either creatine or placebo, significantly increased muscle fiber thickness, grip strength, and knee mobility, as well as ability to perform ADLs.  Creatine compared to placebo had no effect.[1]

Stretching does not improve short or long-term joint mobility in people with neurological disorders.[2]

In a case study of a CMT patient given physical therapy exercises to balance on an unstable surface, balance and gait significantly improved after 3 weeks of exercise.[3]



In a study of 14 CMT patients, wearing night splints does not increase range of motion or ankle strength.[4]

In a case study of a woman with CMT, made-to-measure orthopedic shoes ended her pattern of falling and foot pain, and her walking speed increased.[5]

Ankle-foot orthoses stiffen the ankle and prevent foot drop compared to shoes alone.[6]

A hand splint significantly (p = 0.006) improved manual dexterity and ADL performance  in CMT patients.[7]

Custom semirigid AFOs are more effective than leaf spring AFOs in normalizing gait in CMT, and leaf spring AFOs are more effective than silicone AFOs.[8]

Vitamin C

Vitamin C appeared to slow the progression of CMT in mouse models, but the effect failed to replicate in humans.

In a mouse model of CMT, created by mutations in the PMP22 gene (one of the genes involved in CMT), mice improved with a high dose of vitamin C (57 mg/kg).  After 3 months of treatment, the placebo mice lost locomotor skills while the vitamin C mice improved.  Effects were significant at p < 0.01 for all tests.  The nerves of the mice treated with vitamin C had thicker myelin sheaths than the untreated ones (though still thinner than the myelin sheaths on healthy mice.)[9]

In a randomized placebo-controlled study of vitamin C given at 1g/day or 3 g/day, there was no significant improvement in CMTNS scores after 12 months of treatment.  There was a small p<0.02 improvemnt in CMTES scores (just the examination without the EMG studies) between the placebo and the 3g group; but there was no improvement in limb strength or overall disability.[10]

In a randomized placebo-controlled study of 174 CMT patients treated with 4g/day vitamin C, both placebo and vitamin C performed better over 24 years on the CMTNS score than a natural history control; there was no effect of treatment compared to placebo.[11]

In a randomized trial of 277 CMT patients given 1.5g/day vitamin C or placebo for 24 months, there was no difference in CMTNS or secondary outcomes.[12]


Progesterone Antagonists

Male mice with a PMP22 model of CMT were given either progesterone or a progesterone antagonist (onapristone.) Administration of progesterone worsened the CMT phenotype, while onapristone improved it. PMP22 expression is higher in mutant mice than in wild-type mice, and progesterone further raises it by 30%; progesterone also raises the fraction of unmyelinated axons. Onapristone improved performance on all motor tests (at a p-value of p < 0.05 for 5 weeks of treatment and p < 0.01 for 7 weeks.)  Unfortunately, onapristone is too toxic to use as a therapy in humans.[13]


Baclofen, Naltrexone, and Sorbitol

This combination of drugs, dubbed PXT3003, has been found to improve myelination and motor performance in rat models of CMT. In a placebo-controlled study of 80 CMT patients, there was significant improvement in the high dose group compared to placebo on neuropathy and some measures of nerve conduction velocity.  There were significantly more patients in the high-dose group who didn’t deteriorate after 1 year (79% vs. 48%).[14]

In mouse models of CMT, PXT3003 improves myelination, reduces Pmp22 expression, improves nerve conduction velocity, and improves time-to-falling on the bar test and the inclined plane test.  It also promotes axon regrowth after nerve crush.[15]



In a case series of 4 patients, all who had significant daytime fatigue due to CMT, all found their fatigue completely reversed by taking 200 mg/day of modafinil.[16]


In two mouse models of CMT, nerves regenerated more in the NT-3 treated group than in the placebo or BDNF-treated groups.   In an 8-patient trial of NT-3 on CMT patients, over 24 weeks, the treatment group showed a significant decrease in neuropathy (p < 0.005); when subscores were examined, it was found that NT-3 significantly improved sensory and reflex scores but not motor scores.  NT-3 also increased the density of Schwann cells, which produce myelin.[17]

In a phase I study of 70 healthy subjects, NT-3 was found to be well tolerated, with the most common side effects being mild injection-site pain and diarrhea.[18]

Mice with a model of CMV given NT-3 gene therapy (in AAV viruses) had significant improvement in grip strength, both with and without nerve crush, and significantly more myelinated fiber density (p < 0.01). There was also significantly (p < 0.03) higher nerve conduction velocity in treated vs. control mice.


Spinal Cord Stimulation

In a case study of a man already taking high doses of narcotics for CMT pain with little relief, upon receiving spinal cord stimulation implants, saw his pain go from a 7.5 to a 3 over 6 months.  He had improved ability to sit, stand, sleep, work, exercise, and have sex.[19]


Intravenous Immunoglobulin

One Japanese family with a history of X-linked CMT type 1 found that 2 of 3 patients had a rapid deterioration of their symptoms, which were significantly alleviated with IVIG.[20]


In a single case study of a patient with neuropathic pain from CMT, 4 weeks of acupuncture took her from a 5 on the pain scale to a 2.[21]



[1]Chetlin, Robert D., et al. "Resistance training exercise and creatine in patients with Charcot–Marie–Tooth disease." Muscle & nerve 30.1 (2004): 69-76.

[2]Katalinic, Owen M., Lisa A. Harvey, and Robert D. Herbert. "Effectiveness of stretch for the treatment and prevention of contractures in people with neurological conditions: a systematic review." Physical therapy 91.1 (2011): 11-24.

[3]Kobesova, Alena, et al. "Effect of functional stabilization training on balance and motor patterns in a patient with Charcot-Marie-Tooth disease." Neuroendocrinol. Lett 33 (2012): 101-108.

[4]Refshauge, Kathryn M., et al. "Night splinting does not increase ankle range of motion in people with Charcot-Marie-Tooth disease: a randomised, cross-over trial." Australian Journal of Physiotherapy 52.3 (2006): 193-199.

[5]Guzian, M. C., et al. "Orthopaedic shoes improve gait in a Charcot-Marie-Tooth patient: a combined clinical and quantified case study." Prosthetics and orthotics international 30.1 (2006): 87-96.

[6]Ramdharry, Gita M., et al. "Foot drop splints improve proximal as well as distal leg control during gait in Charcot‐Marie‐Tooth Disease." Muscle & nerve 46.4 (2012): 512-519.

[7]Videler, Annemieke, et al. "A thumb opposition splint to improve manual dexterity and upper-limb functioning in Charcot-Marie-Tooth disease." Journal of rehabilitation medicine 44.3 (2012): 249-253.

[8]Del Bianco, James, and Stefania Fatone. "Comparison of silicone and posterior leaf spring ankle-foot orthoses in a subject with Charcot-Marie-Tooth disorder." JPO: Journal of Prosthetics and Orthotics 20.4 (2008): 155-162.

[9]Passage, Edith, et al. "Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease." Nature medicine 10.4 (2004): 396-401.

[10]Micallef, Joëlle, et al. "Effect of ascorbic acid in patients with Charcot–Marie–Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial." The Lancet Neurology 8.12 (2009): 1103-1110.

[11]Lewis, Richard A., et al. "High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial." JAMA neurology 70.8 (2013): 981-987.

[12]Pareyson, Davide, et al. "Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial." The Lancet Neurology 10.4 (2011): 320-328.

[13]Sereda, Michael W., et al. "Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A)." Nature medicine 9.12 (2003): 1533-1537.

[14]Attarian, Shahram, et al. "An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A." Orphanet journal of rare diseases 9.1 (2014): 199.

[15]Chumakov, Ilya, et al. "Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy." Orphanet journal of rare diseases 9.1 (2014): 201.

[16]Carter, Gregory T., et al. "Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series." American Journal of Hospice and Palliative Medicine® 23.5 (2006): 412-416.

[17]Chumakov, Ilya, et al. "Polytherapy with a combination of three repurposed drugs (PXT3003) down-regulates Pmp22 over-expression and improves myelination, axonal and functional parameters in models of CMT1A neuropathy." Orphanet journal of rare diseases 9.1 (2014): 201.

[18]Chaudhry, V., et al. "Tolerability of recombinant‐methionyl human neurotrophin‐3 (r‐metHuNT3) in healthy subjects." Muscle & nerve23.2 (2000): 189-192.

[19]Skaribas, Ioannis M., and Stephanie N. Washburn. "Successful Treatment of Charcot‐Marie‐Tooth Chronic Pain with Spinal Cord Stimulation: A Case Study." Neuromodulation: Technology at the Neural Interface 13.3 (2010): 224-228.

[20]Miki, Yasuo, et al. "A family with IVIg-responsive Charcot–Marie–Tooth disease." Journal of neurology 260.4 (2013): 1147-1151.

[21]Taleço, Tiago Marques, et al. "Acupuncture for pain treatment in Charcot-Marie-Tooth disease." Medical Acupuncture 26.1 (2014): 57-63.