Background:

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous group of peripheral nerve disorders that usually present in childhood. Identification of the genetic basis enables genetic counselling, organising surveillance and involvement in clinical trials. Unlike predominantly adult cohorts, there is limited literature on genetic frequencies in a paediatric CMT cohort.

Methods:

We reviewed the database of a tertiary paediatric peripheral neuropathy clinic in Australia to determine the most common genes causing childhood-onset CMT. Genetic testing was performed by a combination of targeted single gene testing, CMT-specific gene panel testing or whole exome sequencing.

Results:

234 individuals (174 probands, 90 males) were diagnosed with CMT or a related neuropathy over a 17 year period. 208 individuals (161 probands) had CMT, with 86% having CMT1 (n=138) and 14% having CMT2 (n=23). 73% of the individuals with CMT1 (n=118) and 43% with CMT2 (n=10) received a genetic diagnosis. Mutations most commonly identified were PMP22 duplication (CMT1A; 70%) or point mutations in MFN2 (CMT2A; 8%), GJB1 (CMTX1; 6%), Xq27.1 insertion (CMTX3; 6%) and SH3TC2 (CMT4C; 3%).

Interpretation:

We have investigated a large paediatric cohort of CMT to understand the frequency of various genetic mutations. The frequency differed from adult cohorts, with a higher proportion of individuals with CMT1A. There was also a lower proportion of individuals with CMTX1, CMT1B and HNPP, likely due to a later age of onset in these disorders. Understanding the frequency of genetic mutations and disease progression enables targeted genetic testing and appropriate rehabilitation and involvement in clinical trials.