Abstract
Objective: The description of a new genetic association with late-onset axonal Charcot-Marie-Tooth disease (CMT). Method. A 57-year-old Brazilian woman presented with a slowly progressive history of paresthesia, muscle wasting and weakness in her lower limbs since age 50 years. Examination disclosed peroneal amyotrophy, bilateral pes cavus, mild distal weakness, reduced vibration, pain and temperature sensation in the the lower limbs and brisk tendon reflexes. Results. Neurophysiological studies showed chronic sensorimotor axonal polyneuropathy. Whole-genome sequencing showed compound heterozygous pathogenic variants in the TECPR2 gene (14q32.31). Conclusion. This novel genetic presentation of late-onset axonal CMT with brisk tendon reflexes associated with TECPR2.
Highlights
Axonal Charcot-MarieTooth disease (CMT) represents a complex expanding group of neurodevelopmental and neurodegenerative disorders which has been related to more than 40 distinct genetic loci and 20 different pathophysiological mechanisms[1], including intraneuronal disturbances of autophagy (i.e. CMT2B, CMT2O) showing a common monogenic basis with some subtypes of Hereditary Spastic Paraplegia (HSP) and other neurodegenerative disorders[2]
As an atypical late-onset presentation of axonal Charcot-Marie-Tooth disease (CMT) was suspected, wholegenome sequencing was performed and showed compound heterozygous pathogenic variants c.3076-62G>A (p.(=)) and c.3316+112T>C (p.(=)) in two intronic regions of the TECPR2 gene (14q32.31), both predicted as probably pathogenic according to 1000G (1000 genomes) and present in the dbSNP (Single Nucleotide Polymorphism) database and in the BIPMed (Brazilian Initiative on Precision Medicine)
The TECPR2 protein is involved in intraneuronal autophagy pathways by targeting proteins to the lysosome and autophagosome nucleation as a positive regulator[2]
Summary
Axonal CMT represents a complex expanding group of neurodevelopmental and neurodegenerative disorders which has been related to more than 40 distinct genetic loci and 20 different pathophysiological mechanisms[1], including intraneuronal disturbances of autophagy (i.e. CMT2B, CMT2O) showing a common monogenic basis with some subtypes of Hereditary Spastic Paraplegia (HSP) and other neurodegenerative disorders[2]. Despite the presence of a common clinical and neurophysiological basis for most genetic subtypes, neurological and systemic involvement is. Heterogeneous among subtypes and there is marked overlapping with HSP and distal hereditary motor neuronopathies[1,3]
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