Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment

Abstract

Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (oxphos). Primary mitochondrial disease (PMD) is diagnosed clinically and ideally, but not always, confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation. The PMD genes either encode oxphos proteins directly or they affect oxphos function by impacting production of the complex machinery needed to run the oxphos process. However, many disorders have the ‘mitochondrial' phenotype without an identifiable mtDNA or nDNA mutation or they have a variant of unknown clinical significance. Secondary mitochondrial dysfunction (SMD) can be caused by genes encoding neither function nor production of the oxphos proteins and accompanies many hereditary non-mitochondrial diseases. SMD may also be due to nongenetic causes such as environmental factors. In our practice, we see many patients with clinical signs of mitochondrial dysfunction based on phenotype, biomarkers, imaging, muscle biopsy, or negative/equivocal mtDNA or nDNA test results. In these cases, it is often tempting to assign a patient's phenotype to ‘mitochondrial disease', but SMD is often challenging to distinguish from PMD. Fortunately, rapid advances in molecular testing, made possible by next generation sequencing, have been effective at least in some cases in establishing accurate diagnoses to distinguish between PMD and SMD. This is important, since their treatments and prognoses can be quite different. However, even in the absence of the ability to distinguish between PMD and SMD, treating SMD with standard treatments for PMD can be effective. We review the latest findings regarding mitochondrial disease/dysfunction and give representative examples in which differentiation between PMD and SMD has been crucial for diagnosis and treatment.

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

“…Interestingly mitochondrial dysfunction does not appear to have a clear genetic basis in ASD [46]. Folate is essential for mitochondrial function [25,65], raising the possibility that insufficiency of folate could account for mitochondrial abnormalities. Others have recently suggested that folate abnormalities and ASD may be connected through other metabolic pathways that are commonly abnormal to both such as serine, lysine and/or purine metabolism [66].…”

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

“…Approximately 15% (DiMauro and Schon 2003) of mitochondrial disorders are caused by inherited germline mutations in the mtDNA. Mitochondrial disorders can also be caused by mutations in over 250 nDNA genes and dysfunction can be acquired due to adverse environmental effects of drugs and infections (Niyazov 2016 Marked variability remains in the diagnostic approaches, treatment, and management of mitochondrial diseases (Parikh et al 2015). Conducting large-scale clinical trials for patients with mitochondrial diseases is difficult, given their extreme clinical variability, biochemical and genetic heterogeneity, and the rarity of each etiology or subtype.…”

WAYS AND MECHANISMS OF TRANSMEMBRANE EXCHANGE OF Ca2 + IN MITOCHONDRIA

“…У свою чергу Са 2+ -перевантаження мітохондрій та гіперпродукція АФК органелами лежать в основі розвитку таких патологічних станів, як серцево-судинні [52][53][54][55], нейродегенеративні [56][57][58], запальні захворювання [59,60], рак [61][62][63]. Саме тому перспективним напрям-ком у лікуванні вищезазначених патологій є мітохондріально-спрямована антиоксидантна терапія із використанням пластохінону, коензиму Q10, його аналога мітохінону, L-кар нітину -сполук, які здатні відносно спе цифічно акумулюватися мітохондріями і чини ти в цих компартментах антиоксидантну дію [56].…”

“…По-рушення транспорту Са 2+ мітохондріями та надмірне утворення в них АФК має вирішальне значення при ішемії-реперфузії та при кардіоміопатіях. Мітохондріальні кардіоміопатії можуть мати важкі прояви, включаючи серцеву недостатність, аритмію і раптову зупинку серця [52,53,56].…”