A rare disease a day: Charcot-Marie-Tooth disease

In honor of rare disease day, I am using my Monday-Friday posts to raise awareness of some of the rare diseases. Following on from past installments of “A rare disease a day” Hunter syndrome, Gaucher disease, Tay-Sachs, Morquio syndrome, Fabry disease, Sanfilippo syndrome, Krabbe Disease, Niemann-Pick Disease , Batten disease , Hurler Syndrome the focus today is Charcot-Marie-Tooth. This also coincides with the release of a short video at the giving library for the Hereditary Neuropathy Foundation with whom I consult. 


Charcot–Marie–Tooth disease (CMT), also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA) — is a  disorder of the peripheral nervous system characterised by progressive loss of muscle tissue and touch sensation across various parts of the body. It is one of the most common rare disorders affecting approximately 1 in 2,500 people. Some drugs can exacerbate CMT and are contraindicated.


Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. CMT is also divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with frequent overlap. CMT can be categorized by both the clinical category and genetic subtype. Peripheral Myelin Protein 22 (PMP22) duplication gene phenotype is the most common form of CMT called CMT1A comprising 68.7% of CMT Type 1’s (demyelinating). Of the axonopathies, Charcot-Marie-Tooth 2A (CMT2A) is the most common form. CMT2A is caused by mutations in the MFN2 gene, which is the most common form of all CMT Type 2’s. Mutations or rearrangements in PMP22, GJB1, MPZ or MFN2 account for 90% of molecular diagnoses, with the MFN2 gene implicated in 33% of CMT Type 2 cases.


Symptoms of CMT include foot drop, wasting of muscle tissue of the lower parts of the legs, weakness in the hands and forearms, loss of touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms.  High arched feet (pes cavus) are a classic symptom.  There are many other symptoms including affects on breathing,  hearing, vision, Scoliosis, malformed Hip sockets ,gastrointestinal problems, difficulty chewing, swallowing, and speaking, tremor and neuropathic pain. More symptoms can be found here.


There is no cure for CMT. Surgery and braces can be useful to improve the physical condition and gait abnoramalities, respectively.


The causal gene duplication defect for the most common form of CMT (PMP22) was identified in 1991, and confirmation that the elevated gene dosing resulting in the pathology of the disease was established in 1993, yet the first high throughput screen (HTS) to search for a small molecule therapeutic wasn’t published until 2012This  HTS identified FDA approved compounds that downregulate transcription of the PMP22 protein. The S16 SC rat reporter assays revealed four small molecule hits from screening, including fenretinide, olvanil, and the anticancer drug bortezomib (Velcade, which can itself cause  neuropathy). Two companies hyave announced work on preclinical and clinical compounds for CMT.  It was recently reported that the preclinical compound Addex ADX71441 dose dependently reduced PMP22 expression comparable to baclofen in a pre-clinical transgenic model of Charcot-Marie-Tooth 1A disease . Pharnext is a French company which has a phase II trial for a combination therapy (baclofen, naltrexone and sorbitol) for CMT 1A. One group has published on HDAC6 inhibitors (tubacin and tubastatin A) for rescuing the CMT2 phenotype in mutant heat shock protein B1 mice.


The recent clinical studies for Charcot-Marie-Tooth 1A have not been successful including the high dose of ascorbic acid which exemplified the need for better outcome measures. Further, a 5-year longitudinal study in subjects with CMT1A failed to identify a physiologically significant biomarker in patients vs. controls, yet, at the end of the study, 30 patients (68%) and 2 controls (8%) stated that their physical condition had deteriorated during the 5-year study period. A longitudinal study for CMT2A has not yet been published.There are limited efforts to find additional outcome measures for Chartcot-Marie-Tooth including in vivo confocal microscopy of meissner corpuscles, Anterior Tibialis CMAP amplitude, CMT neuropathy score (second version) and patient identified quality of life.

These preclinical and clinical efforts would suggest there is scope to readily develop treatments for this disease as there is significant unmet need.

There are 2 major groups that support research on CMT, Charcot-Marie-Tooth Association and the Hereditary Neuropathy Foundation (HNF) which just put out the CMT update.


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