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.

Rare among Rare: Phenotypes of Uncommon CMT Genotypes

(1) Background: Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations.