Charcot-Marie-Tooth (CMT) disease encompasses a heterogeneous group of inherited, severe, debilitating, progressive and chronic peripheral neuropathies. Charcot-Marie-Tooth disease type 1A (CMT1A), the most common type of CMT, is an orphan disease with a prevalence of 1/5000 people affecting at least 150,000 people in Europe and the U.S. and about 1,500,000 people worldwide.
The genetic mutation responsible for CMT1A is a duplication of the PMP22 gene coding for a peripheral myelin protein. The duplication of this gene results in overexpression of the PMP22 protein and failure of Schwann cells to produce normal myelin (neuronal sheath). The lack of a normal myelin structure and function leads to abnormal peripheral nerve conduction and axonal loss. As a result of peripheral nerve degradation, patients suffer from progressive muscle atrophy in both the legs and arms causing problems with walking, running and balance as well as abnormal hand functioning. They might also suffer from mild to moderate sensory disorders.
First symptoms usually appear during adolescence and will progressively evolve throughout life. Patients with the most severe form of CMT1A end up in wheelchairs, representing at least 5% of cases.
To date, no curative or symptomatic medications have been approved and treatment consists of supportive care such as orthotics, leg braces, physical and occupational therapy or surgery.
Sarah, 38-year-old, diagnosed with CMT1A when she was 2-year-old
Kendall, 61-year-old, diagnosed with CMT1A when he was 16-year-old
Amy, 45-year-old, diagnosed with CMT1A when she was 36-year-old
Yvette, 67-year-old, diagnosed with CMT1A when she was 57-year-old
Arched foot/feet and hammer toes
Weakness of the hips, legs, or feet
Loss of lower leg muscle, which leads to skinny calves
Difficulty lifting the foot at the ankle (foot drop)
Numbness in the feet or hands
Leg and hand cramps
Loss of balance, frequent tripping and falling
Fatigue and pain
Speech and swallowing difficulties
Breathing difficulties, especially when lying flat
Vocal cord paralysis
55-year-old, diagnosed with CMT1A when she was 31-year-old
CEO of the Hereditary Neuropathy Foundation
Kochański A: Molecular genetics studies in Polish Charcot-Marie-Tooth families. Folia Neuropathol. 2005;42:65–73.
Patzkó A, Shy ME: Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep. 2011;11:78–88.
DiVincenzo C, Elzinga CD, Medeiros AC, et al. The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy. Mol Genet Genomic Med. 2014;2:522–529.
Shy ME, Chen L, Swan ER, et al. Neuropathy progression in Charcot-Marie-Tooth disease type 1A. Neurology. 2008;70:378–383.
Hereditary Neuropathy Foundation Website. What is Charcot-Marie-Tooth Disease?
Available at: https://www.hnf-cure.org/charcot-marie-tooth-disease. Accessed Oct. 10, 2019.
Charcot JM, Marie P. Sur une forme particulière d’atrophie musculaire progressive, souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains. Revue Médicale. 1886;6:97–13.
Bird TD. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. 1998 Sep 28 [Updated 2019 Jan 24]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2019.
CMTA Website. Inheritance patters and CMT.
Available at: https://www.cmtausa.org/understanding-cmt/types-of-cmt/genetics-and-inheritance. Accessed Oct. 10, 2019.
Raeymaekers P, Timmerman V, Nelis E, et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a): the HMSN Collaborative Research Group. Neuromuscul Disord. 1991;1:93–97.
Lupski JR, Wise CA, Kuwano A, Pentao L: Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nat Genet. 1992;1:29–33.
Van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Orphanet J Rare Dis. 2014;;9:38.
Vaeth S et al. BMJ Open 2017;7;e018048