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 integenomic 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 159).
The first pathogenic mutations in mtDNA were reported 1988, when
Holt and colleagues described large-scale deletions in patients
with mitochondrial myopathies,1 and Wallace and
colleagues described a point mutation in the gene encoding subunit
4 of complex I (ND4) in a family with Leber’s hereditary
optic neuropathy (LHON).2 However, these two papers
opened up a veritable Pandora’s box: the “morbidity
map” of mtDNA has gone from the one-point mutation of 1988
to over 200 pathogenic point mutations in 2008 (Fig. 158-1).3 In 1995, Bourgeron and
colleagues described the first “direct hit” mutation
in nDNA in two sisters with LS and complex II deficiency4;
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 respiratory chain [RC])5,6;
two papers, one in 1989 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)7 and with mtDNA
depletion in two infants with myopathic or hepatocerebral presentations.8 Multiple
specific nuclear genes have since been associated with defects of
Morbidity map of the human genome. Differently shaded
areas in the 15.5 kb mtDNA map represent the protein-coding genes
for the seven subunits of complex I ...
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