May 2017

Genetic mutations in CMT help predict phenotypic differences      

Image courtesy of the Charcot-Marie-Tooth Association.

Ankle strength commonly affected

By Greg Gargiulo

Researchers are inching closer to being able to predict specific symptoms of Charcot-Marie-Tooth disease (CMT) based on a child’s genotype, but the variability found in a recent Australian study suggests that, for now, patients should still be assessed and managed individually.

The cross-sectional study identified notable phenotypic differences within and among several common CMT genotypes, including functional limitations and self-reported impairments.

“We were able to demonstrate that significant impairment occurs from the earliest stages of the disease, with ankle dorsiflexion strength and functional hand dexterity being the most affected of all measurements,” said Kayla Cornett, a PhD student who conducts research with the Sydney Children’s Hospital Network at the University of Sydney in Australia. “Furthermore, the mutation-specific manifestations provide additional information on the difficulties experienced by the different genetic subtypes.”

CMT is characterized by distal weakness, foot deformity, sensory loss, and gait difficulties, but it is not completely clear how frequently and to what extent these manifestations and functional limitations occur in different CMT genotypes.

The study evaluated 520 children and adolescents (246 girls) aged 3 to 20 years using the 44-point CMT Pediatric Scale (CMTPedS). The CMTPedS measured hand dexterity, strength of hand grip, ankle dorsiflexion and plantar flexion, lower limb sensation, gait, balance, and function. The resulting raw scores were compared with age- and sex-matched normative reference values.

The most prevalent CMT genotypes in the sample group were CMT1A (48.5%), CMT2A (6%), CMT1B (2.9%), CMT4C (2.5%), and CMTX1 (1.9%). Disease severity according to the CMTPedS represented almost the entire spectrum of the scale, and scores differed significantly among each of the five most common genotypes.

More frequent follow-up with patients with CMT genotypes linked to greater symptom severity may be warranted.

The most affected items on the CMTPedS for all genotypes were ankle dorsiflexion strength (82.3%) and hand dexterity (56.5%), but certain physical impairments were more prevalent in some genotypes than others.

“Although ankle dorsiflexion strength was the most affected, it is not the only affected aspect, and different children will have different goals and outcomes they want to achieve,” Cornett said. “Therefore, specific clinical recommendations should still be made on a patient-by-patient basis.”

The findings were published in June 2016 by JAMA Neurology. A longitudinal study on the same study group is ongoing.

Participants with CMT2A and CMT4C had significantly weaker ankle plantar flexion and dorsiflexion strength, as well as lower long jump and 6-minute walk test scores, than those with CMT1A and CMTX1. Genotypes CMT1A and CMTX1 had significantly better balance and were less severely affected than the other three genotypes, while participants with CMT2A were significantly weaker for all strength measurements and were most severely impaired, with a CMTPedS mean score of 30.

CMTPedS scores for children with CMT4C and CMX1 were also found to progress quicker in childhood than adolescence, while the progression was faster in adolescence for CMT1B and CMT2A.

“According to this, if a five-year-old child with CMT4C does not yet have balance issues, we might expect them to develop them within the next five years. However, there is individual variability,” Cornett said. “Patients with CMT1B also had significantly impaired balance compared to other types, so we would expect similar difficulties to arise in them.”

The findings suggest clinicians may want to have more frequent follow-ups when dealing with genotypes associated with greater symptom severity, Cornett said. Ultimately, however, treatment should still be decided on an individual level, she said.

This is equally true for the study findings that have implications for orthotic management, said David Misener, CPO, of Clinical Prosthetics and Orthotics in Albany, NY, who has CMT himself and whose son was a CMT1B participant in the study.

“I don’t think I’ll change my treatment recommendations at all for CMT patients based on this study, as I just don’t think there’s enough delineation between all the different types here,” Misener said. “So, I’ll still base treatment on phenotype over genotype: basically how do they present and how do they look, and then it’s always important to see patients on a pretty routine basis after I give them a device.”

More long-term data on the topic are still needed, he said.

“It’s an awesome starting point, but we just need more people in these studies to make them more statistically significant,” he said. “I’d love to see more in-depth research on phenotypic variability, and I’d love to get a better understanding of time and rate of change and know what the rate of change really is. I don’t think we have enough here to garner that information.”

In the meantime, the longitudinal, natural history study may help Cornett and her team to better answer some of the many remaining questions.

“When we follow individual children over time and look at progression, we will be better suited to answer the questions on progression and where to target treatment,” she said.

Greg Gargiulo is a freelance medical writer based in San Francisco.


Cornett KM, Menezes MP, Bray P, et al. Phenotypic variability of childhood Charcot-Marie-Tooth Disease. JAMA Neurol 2016;73(6):645-651.

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