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The respiratory chain (RC) is the terminal pathway of mitochondrial metabolism, where most energy is produced as adenosine triphosphate (ATP). It is also the only metabolic pathway under dual genetic control: Of the approximately 80 subunits of the RC, 13 are encoded by mitochondrial DNA (mtDNA) and the rest by nuclear DNA (nDNA). Defects of the RC cause an extremely heterogeneous group of disorders that affect both children and adults, often involving multiple tissues and resulting in characteristic syndromes but sometimes affecting single tissues. Disorders due to mutations in mtDNA are especially challenging for the clinician because the rules of mitochondrial genetics make for intrafamilial variability, including often elusive maternal inheritance, syndromic or nonsyndromic multisystem involvement, and variably severe laboratory abnormalities. Disorders due to mutations in nDNA are inherited as Mendelian traits and include “direct hits,” or mutations directly affecting subunits of the RC; “indirect hits,” or mutations in proteins needed for the proper assembly of individual RC complexes; and defects of intergenomic signaling, such as mutations in proteins needed for the maintenance of mtDNA (translation, replication, repair). The central disorder of pediatric interest is Leigh syndrome (LS), which reflects the consequences of impaired energy metabolism on the developing brain and is characterized clinically by psychomotor regression and signs of brain stem dysfunction; radiologically, it is characterized by bilateral, symmetrical lesions in the basal ganglia and the brain stem. LS is associated with both mtDNA- and nDNA-related disorders and with defects of pyruvate metabolism (see Chapter 154).


The first pathogenic mutations in mtDNA were reported 1988, when Holt and colleagues described large-scale deletions in patients with mitochondrial myopathies and Wallace and colleagues described a point mutation in the gene encoding subunit 4 of complex I (ND4) in a family with Leber hereditary optic neuropathy (LHON). However, these 2 papers opened up a veritable Pandora’s box: the “morbidity map” of mtDNA has gone from the 1-point mutation of 1988 to over 200 pathogenic point mutations in 2008 (Fig. 153-1). In 1995, Bourgeron and colleagues described the first “direct hit” mutation in nDNA in 2 sisters with LS and complex II deficiency; the first “indirect hit” also caused LS and was due to mutations in SURF1, a protein needed to assemble cytochrome c oxidase (COX, complex IV of the RC); 2 papers, 1 published in 1989 and the other in 1991, suggested that mutations in nDNA-encoded maintenance proteins were responsible for multiple mtDNA deletions in patients with autosomal dominant progressive external ophthalmoplegia (PEO) and for mtDNA depletion in 2 infants with myopathic or hepatocerebral presentations. Multiple specific nuclear genes have since been associated with defects of intergenomic communication.

Figure 153-1

Morbidity map of the human genome. Differently shaded areas in the 15.5-kb mtDNA map represent the protein-coding genes for the 7 subunits of complex I (ND), 3 subunits of complex IV (COX), cytochrome b (Cyt b), 2 subunits of ...

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