Charcot-Marie-Tooth neuropathy (CMT) is a disease affecting both motor and sensory neurons1. The distal hereditary motor neuropathies (dHMN) are a related group of diseases affecting only the motor neurons2. Both CMT and dHMN are clinically and genetically heterogeneous with genetic and clinical overlap between the two diseases. To date, over 40 genes are reported to cause CMT and dHMN3,4. Most genes are rare and account for 1-2% of disease.
Here we describe an autosomal dominant pedigree with convergence of dHMN and CMT2 phenotypes from the founder generation combining to cause a more severe phenotype in generation II. One founder has a mild CMT2 phenotype with late onset and slow progression. The second founder has a dHMN phenotype with juvenile onset, lower limb weakness and later muscle wasting, with inferred family history. Three of five siblings in generation II show a more severe CMT2 phenotype with earlier onset and more severe progression than either of the two parents from generation I. The third generation shows reduced penetrance, with one of eight at risk individuals affected with a CMT2 phenotype.
We performed exome sequence analysis to identify independent candidate variants segregating from the founder individuals. We hypothesise that two autosomal dominant genes are inherited in this pedigree. A reported MFN2
mutation segregates with the disease from the founder with mild CMT2. However, this mutation shows reduced penetrance, with two unaffected at risk individuals carrying the mutation. No mutations in known genes were identified segregating from the founder with dHMN phenotype. Novel sequence variants were identified in two genes segregating from the founder with dHMN. We propose that the combination of two mutations causes a more severe phenotype than the mutations individually. These candidate CMT/dHMN genes will be explored further with additional families.