Abnormal Bone Morphology in Charcot-Marie-Tooth Disease

Background: Although long suspected, it has yet to be shown whether the foot and ankle deformities of Charcot-Marie-Tooth disease (CMT) are generally associated with abnormalities in osseous shape. Computed tomography (CT) was used to quantify morphologic differences of the calcaneus, talus, and navicular in CMT compared with healthy controls. Methods: Weightbearing CT scans of 21 patients (27 feet) with CMT were compared to those of 20 healthy controls. Calcaneal measurements included radius of curvature, sagittal posterior tuberosity-posterior facet angle, and tuberosity coronal rotation. Talar measurements included axial and sagittal body-neck declination angle, and coronal talar head rotation. Surface-mesh model analysis of the hindfoot was performed comparing the average of the CMT cohort to the controls using a CT analysis software (Disior Bonelogic 2.0). Means were compared with a t test ( P < .05). Results: CMT patients had significantly less talar sagittal declination vs controls (17.8 vs 25.1 degrees; P < .05). Similarly, CMT patients had less talar head coronal rotation vs controls (30.8 vs 42.5 degrees; P < .001). The calcaneal radius of curvature in CMT patients was significantly smaller than controls (822.8 vs 2143.5 mm; P < .05). CMT sagittal posterior tuberosity–posterior facet angle was also significantly different from that of controls (60.3 vs 67.9 degrees respectively; P < .001). Surface-mesh model analysis demonstrated the largest differences in morphology at the navicular tuberosity, medial talar head, sustentaculum tali, and anterior process of the calcaneus. Conclusion: This is the first study to quantify the morphologic differences in hindfoot osteology seen in CMT patients. Patients identified with osseous changes of the calcaneus, especially a smaller axial radius of curvature, may benefit from a 3-dimensional osteotomy for correction.

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Intraepidermal nerve fibre density as biomarker in Charcot–Marie–Tooth disease type 1A

Brain Communications ◽

10.1093/braincomms/fcaa012 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Beate Hartmannsberger ◽

Kathrin Doppler ◽

Julia Stauber ◽

Beate Schlotter-Weigel ◽

Peter Young ◽

...

Keyword(s):

Nerve Fibre ◽

Disease Severity ◽

Chronic Inflammatory Demyelinating Polyneuropathy ◽

Healthy Controls ◽

Merkel Cells ◽

Fibre Density ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Tooth Type ◽

Tooth Disease

Abstract Charcot–Marie–Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case–control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot–Marie–Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot–Marie–Tooth type 1A was assessed by the Charcot–Marie–Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot–Marie–Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = −0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot–Marie–Tooth type 1A (P < 0.01, R = −0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot–Marie–Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot–Marie–Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot–Marie–Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot–Marie–Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot–Marie–Tooth type 1A disease progression on cutaneous innervation.

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