section 14.6

Mitochondrial Diseases

269

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

26,

273

(1994).]

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

disease.

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

and

ragged red

fiber

(MERRF)

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