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

Abstract

IntroductionCharcot–Marie–Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur.MethodsWe studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision.ResultsPatients 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.ConclusionsIn 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.

Charcot–Marie–Tooth disease Type 2E/1F mutant neurofilament proteins assemble into neurofilaments

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Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

“…CMT patients usually present with weakness and atrophy in the feet and then hands, indicating that peripheral neurons with longer axons are more impacted by the disease. However, mutations in a few genes, including GARS1, can cause an upper limb predominance 7,8,47 . This suggests that while axon length is important, additional characteristics contribute to pathogenesis and the spectrum of motor neuron involvement.…”

Inverted formins: A subfamily of atypical formins

“…Some inf2 mutations appear specific for FSGS or for CMT-FSGS, but others can result in either disease (Fig 5), depending on the individual [Caridi et al, 2014; Jin et al, 2015]. To date, inf2 mutations are the only known genetic cause for cases of CMT accompanied by kidney disease, and these cases can also be accompanied by other phenotypes, including cognitive impairment, deafness, and hand deformities [Werheid et al, 2016]. Considering that CMT symptoms arise before FSGS symptoms [Mademan et al, 2013], it has been suggested that CMT patients be screened for proteinuria (a sign of kidney dysfunction) and, potentially, genotyped for inf2 , as a guide to the appropriate treatment [De Rechter et al, 2015].…”