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INTRODUCTION

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This chapter provides a general overview of mitochondrial disorders presenting in the pediatric age group. Although there are a variety of disorders in which mitochondrial dysfunction is a secondary phenomenon (eg, Rett syndrome, Friedreich ataxia), we focus predominately on the disorders that result from germline (although acquired mutations can cause disease as well) mutations to mitochondrial DNA (mtDNA), those that alter mtDNA content and quality (depletion and deletions, respectively), and those that (directly or indirectly) alter the composition and assembly of the oxidative phosphorylation (OXPHOS) complexes. Although the pyruvate dehydrogenase (PDH) complex disorders and the citric acid cycle disorders are often considered within the mitochondrial disease framework, these are covered separately in Chapter 8. Given the complexities of the OXPHOS system, the uniqueness of the mitochondrial genome and mitochondrial transcription, a background on the normal physiology and general principles of mtDNA replication and general mitochondrial biology is essential to understand the phenotypic and biochemical consequences of mitochondrial dysfunction and to rationally plan diagnostic and therapeutic strategies. Although the focus is on pediatric mitochondrial disorders, there is a wide clinical spectrum and a number of the disorders discussed in this chapter can also present in adulthood, particularly the disorders caused by mtDNA point mutations and mtDNA maintenance that result in mtDNA depletion or replication infidelity.

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MITOCHONDRIAL PHYSIOLOGY AND PATHOPHYSIOLOGY

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Normal Physiology

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Mitochondria are dynamic organelles that house the cascade of enzymes referred to as the OXPHOS system,1 which can generate up to 38 ATP molecules for each molecule of glucose that is completely oxidized. Classically, the mitochondrion has been portrayed as a discrete and isolated ovoid-shaped organelle, which is a conclusion based primarily on electron micrographic representations of fixed tissues. However, the advent of fluorescence technology along with the development of microscopes which impart low photon damage have resulted in a dramatic change in the way mitochondria are visualized in vivo. Imaging a live cell shows that the mitochondria form highly reticulated structures that are continuously fusing and breaking apart. Such dynamic motions are an essential component of normal physiology.2

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Production of mitochondrial energy requires a system of regulatory and signaling mechanisms whose complexity has only begun to be appreciated over the past few decades. Not surprisingly, a number of diseases have been identified where the cause is a defect in the signaling pathways or structural elements within the functional framework of this complex organelle. Mitochondrial disorders result because of a decreased energy supply but also from macromolecular damage incurred from increased production of reactive oxygen species (ROS). The clinical challenge in diagnosing and treating mitochondrial dysfunction is complicated by the broad presentation of the symptoms (phenotypic heterogeneity).3 Any alteration in the ATP output of the mitochondria has the potential to impact all cellular pathways that are dependent upon ATP. It is therefore important to gain a basic understanding of the elements involved in OXPHOS ...

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