Charcot Marie Tooth Disease

Charcot-Marie-Tooth disease is the single most common diagnosis associated with cavus foot. The imbalance involving intrinsic and extrinsic muscles has been suggested as the main pathogenetic cause of cavus foot in this disease. The goal of surgical treatment is to correct the deformity to obtain a plantigrade foot. In the presence of a flexible deformity and the absence of degenerative arthritis, preserving as much as possible of the overall range of motion of the foot and ankle is advisable. Twenty-four cavus feet in twelve patients with Charcot-Marie-Tooth disease were included in the study. Clinical evaluation was summarized with the Maryland Foot Score. Radiographic evaluation assessed calcaneal pitch, Meary angle, Hibb angle, and absence of degenerative joint changes. Only patients who had a flexible deformity, with varus of the heel reducible in the Coleman-Andreasi test, and did not have degenerative joint arthritis were included in this study. Surgical treatment consisted i...

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predict...

Peripheral nerve axons require a well-organized axonal microtubule network for efficient transport to ensure the constant crosstalk between soma and synapse. Mutations in more than 80 different genes cause Charcot-Marie-Tooth disease, which is the most common inherited disorder affecting peripheral nerves. This genetic heterogeneity has hampered the development of therapeutics for Charcot-Marie-Tooth disease. The aim of this study was to explore whether histone deacetylase 6 (HDAC6) can serve as a therapeutic target focusing on the mutant glycyl-tRNA synthetase (GlyRS/GARS)-induced peripheral neuropathy. Peripheral nerves and dorsal root ganglia from the C201R mutant Gars mouse model showed reduced acetylated a-tubulin levels. In primary dorsal root ganglion neurons, mutant GlyRS affected neurite length and disrupted normal mitochondrial transport. We demonstrated that GlyRS co-immunoprecipitated with HDAC6 and that this interaction was blocked by tubastatin A, a selective inhibitor of the deacetylating function of HDAC6. Moreover, HDAC6 inhibition restored mitochondrial axonal transport in mutant GlyRS-expressing neurons. Systemic delivery of a specific HDAC6 inhibitor increased a-tubulin acetylation in peripheral nerves and partially restored nerve conduction and motor behaviour in mutant Gars mice. Our study demonstrates that a-tubulin deacetylation and disrupted axonal transport may represent a common pathogenic mechanism underlying Charcot-Marie-Tooth disease and it broadens the therapeutic potential of selective HDAC6 inhibition to other genetic forms of axonal Charcot-Marie-Tooth disease. Abbreviations: CMAP = compound muscle action potential; CMT = Charcot-Marie-Tooth disease; DRG = dorsal root ganglion; GlyRS = glycyl-tRNA synthetase; SNAP = sensory nerve action potential