Histopathology of Skeletal Muscle in a Distal Motor Neuropathy Associated with a Mutant CCT5 Subunit: Clues for Future Developments to Improve Differential Diagnosis and Personalized Therapy

Simple Summary The morphological alterations of the tissues caused by genetic chaperonopathies are scarcely known. Therefore, the histopathological identification of these diseases is a frustrating task, likely to end in misdiagnosis. Consequently, genetic chaperonopathies appear to be rare but, with more histopathological information and better diagnostic accuracy, assessment of their incidence will certainly reveal that they are not that rare and will most likely unveil many cases with mild clinical manifestations. However, progress in this area is impeded by the lack of illustrative publications describing the histopathology of genetic chaperonopathies. As a contribution to remedy this situation, in this brief review, we summarize data from the few previous publications on this topic that are available. The bulk of the data discussed comes from our earlier report on a chaperonopathy associated with a missense mutation in the gene encoding the CCT5 subunit of the chaperonin CCT. The case was diagnosed as a distal motor neuropathy of early onset, and we carried out a detailed histopathological analysis of the abnormalities present in the patient’s striated muscle. Here, we discuss a few of those results that we think offer the best outlook for further exploration to elucidate pathogenic mechanisms and provide clues for diagnosis. Abstract Genetic chaperonopathies are rare but, because of misdiagnosis, there are probably more cases than those that are recorded in the literature and databases. This occurs because practitioners are generally unaware of the existence and/or the symptoms and signs of chaperonopathies. It is necessary to educate the medical community about these diseases and, with research, to unveil their mechanisms. The structure and functions of various chaperones in vitro have been studied, but information on the impact of mutant chaperones in humans, in vivo, is scarce. Here, we present a succinct review of the most salient abnormalities of skeletal muscle, based on our earlier report of a patient who carried a mutation in the chaperonin CCT5 subunit and suffered from a distal motor neuropathy of early onset. We discuss our results in relation to the very few other published pertinent reports we were able to find. A complex picture of multiple muscle-tissue abnormalities was evident, with signs of atrophy, apoptosis, and abnormally low levels and atypical distribution patterns of some components of muscle and the chaperone system. In-silico analysis predicts that the mutation affects CCT5 in a way that could interfere with the recognition and handling of substrate. Thus, it is possible that some of the abnormalities are the direct consequence of defective chaperoning, but others may be indirectly related to defective chaperoning or caused by other different pathogenic pathways. Biochemical, and molecular biologic and genetic analyses should now help in understanding the mechanisms underpinning the histologic abnormalities and, thus, provide clues to facilitate diagnosis and guide the development of therapeutic tools.