section 14.6
Mitochondrial Diseases
FIGURE 14-23
Human mitochondrial genome showing locations of disease-causing mutations. [Reproduced with permission from
M.D. Brown and D.C. Wallace: Molecular basis of mitochondrial DNA disease,
J. Bioenerg. Biom em branes
families. In one, the mutation leads to neurogenic muscle
weakness, ataxia, and retinitis pigmentosa (NAPP) while
in most individuals the presentation is described as
Leigh ’s
These mutations cause replacement of a highly
conserved leucine residue resulting in loss of ATP pro-
duction. The differences in the clinical phenotypes of the
various mtDNA substitution mutations (LHON, LHON
and dystonia, and NARP/Leigh’s disease) illustrate the
clinical variability of mtDNA diseases.
The LHON group of diseases demonstrates that mildly
deleterious mtDNA point mutations can accumulate on a
mitochondrial chromosome during evolution, thus creat-
ing a “predisposing” mtDNA genotype. Such mutations
are relatively benign and require other factors such as
age-related decline in oxidative phosphorylation to re-
duce energy output sufficiently to cause disease. Conse-
quently, these mtDNA mutations are generally associated
with late-onset disease and also may predispose individu-
als to Alzheimer’s and Parkinson’s disease. Figure 14-23
presents a map of the human mitochondrial genome show-
ing positions of point mutations and deletions.
Transfer RNA (tRNA) Mutations
Fourteen mtDNA tRNA mutations have been associated
with maternally inherited disease. Such mutations are typ-
ically associated with severe mitochondrial myopathies,
characterized by “ragged red” skeletal muscle fibers
upon Gomori trichrome staining and the accumulation
of structurally abnormal mitochondria in muscle. Muta-
tions in tRNAs exemplify the threshold effect whereby
(due to replicative segragation) individuals may not ex-
hibit clinical signs until the proportion of mutant mtDNA
exceeds 80-90%.
Myoclonic epilepsy
ragged red
disease, mitochondrial encephalomyo-
pathy lactic acidosis (MELAS),
as well as maternally in-
herited myopathy and cardiomyopathy (MMC) are well-
characterized mitochondrial diseases.
Because oxidative phosphorylation capacity declines
with age, individuals with identical mtDNA genotypes
may express different clinical signs if they are of different
ages. Individuals under the age of 20 with 80% mutant
mtDNAs can be asymptomatic; individuals with the same
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