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

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Abstract
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.
Funding Information
  • Deutsche Gesellschaft für Muskelkranke e.V. (DGM)

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