Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?

Introduction Charcot–Marie–Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur. Methods We studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision. Results Patients harbored a PMP22 gene alteration (n = 28) or a mutation in MPZ (n = 11), GJB1 (n = 4), LITAF (n = 2), MFN2 (n = 2), INF2 (n = 1), NEFL (n = 1). We identified four novel mutations (3 MPZ, 1 GJB1). A total of 88% presented at least one additional feature. In MPZ patients, we detected hypertrophic nerve roots in 3/4 cases that underwent spinal MRI, and pupillary abnormalities in 27%. In our cohort, restless legs syndrome (RLS) was present in 18%. We describe for the first time RLS associated with LITAF or MFN2 and predominant upper limb involvement with LITAF. Cold‐induced hand cramps occurred in 10% (PMP22, MPZ, MFN2), and autonomous nervous system involvement in 18% (PMP22, MPZ, LITAF, MFN2). RLS and respiratory insufficiency were mostly associated with severe neuropathy, and pupillary abnormalities with mild to moderate neuropathy. Conclusions In CMT patients, additional features occur frequently. Some of them might be helpful in orienting genetic diagnosis. Our data broaden the clinical spectrum and genotype–phenotype associations with CMT. We studied a large cohort of patients with genetically confirmed Charcot–Marie–Tooth neuropathy and particularly focused on a wide range of associated features that occur in addition to the classical CMT‐phenotype. Furthermore, we performed a systematic revision of the literature comprising 280 publications. We showed that in CMT patients, additional features are much more common than previously thought, and that the occurrence of some additional symptoms might be helpful in identifying the underlying gene. Our data broaden the clinical spectrum and genotype–phenotype associations with CMT. Moreover, we identified four novel mutations, three in MPZ and one in GJB1.