Myopathology of Adult and Paediatric Mitochondrial Diseases

Abstract

Mitochondria are dynamic organelles ubiquitously present in nucleated eukaryotic cells, subserving multiple metabolic functions, including cellular ATP generation by oxidative phosphorylation (OXPHOS). The OXPHOS machinery comprises five transmembrane respiratory chain enzyme complexes (RC). Defective OXPHOS gives rise to mitochondrial diseases (mtD). The incredible phenotypic and genetic diversity of mtD can be attributed at least in part to the RC dual genetic control (nuclear DNA (nDNA) and mitochondrial DNA (mtDNA)) and the complex interaction between the two genomes. Despite the increasing use of next-generation-sequencing (NGS) and various omics platforms in unravelling novel mtD genes and pathomechanisms, current clinical practice for investigating mtD essentially involves a multipronged approach including clinical assessment, metabolic screening, imaging, pathological, biochemical and functional testing to guide molecular genetic analysis. This review addresses the broad muscle pathology landscape including genotype–phenotype correlations in adult and paediatric mtD, the role of immunodiagnostics in understanding some of the pathomechanisms underpinning the canonical features of mtD, and recent diagnostic advances in the field.

Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice

“…Now, based on high serum FGF-21 values, we are able to identify those adult patients that would benefit from genetic investigations without prior muscle biopsy. The availability of this assay has thus modified our diagnostic pathway in adults, whereas muscle biopsy remains more important in children [ 43 ].…”

Effectiveness of whole exome sequencing in unsolved patients with a clinical suspicion of a mitochondrial disorder in Estonia

“…A less invasive procedure to study respiratory chain enzyme activity is the analysis of cultured fibroblast cells derived from a skin biopsy. However, there might be cases with decreased activity in muscle, but not in fibroblasts [ 34 ], as was the case in two of our patients, 1 and 30.…”

“…Indeed, muscle cryosection analysis was quite indicative in our cohort, with all five MD patients in whom a muscle biopsy was performed showed RRF, marked mitochondrial subsarcolemmal aggregates, and/or pathological mitochondrial ultrastructure, whereas the other patients did not. However, this is not always the case; according to the literature, children with MDs may not always present with RRF or abnormally structured mitochondria [ 33 , 34 ]. On the other hand, a finding of mitochondriopathy in muscle could mislead us, as there are many reports of genetically confirmed neuromuscular disorders with secondary mitochondriopathy [ 35 ].…”

“…Also, because muscle biopsy is an invasive and quite traumatizing procedure for the child and the muscle, treating physicians, as well as parents would like to postpone it whenever possible. There is currently a scientific debate on whether WES analysis should precede muscle biopsy [ 34 , [37] , [38] , [39] ]. Based on our current study, we suggest that WES is performed prior to the muscle biopsy; however, muscle analysis might be needed afterwards for confirmation of the variants found, or to obtain additional information about the patient's phenotype.…”

“…However, we should bear in mind that with this technique we analyze blood lymphocytes, which may not contain the mtDNA variants, especially in patients with mitochondrial myopathy. Another bottleneck is mitochondrial heteroplasmy – a low level of the variant may not be detected [ 34 ]. In addition, mtDNA deletions and mtDNA depletion may be missed.…”