Biology of Disease

disease presents in midlife with a rapid bilateral loss of central vision due
to atrophy of the optic nerve leading to blindness. Early studies of LHON
showed a puzzling maternal pattern of inheritance, with more males than
females affected. In 1988 it was demonstrated that LHON was caused by
mutations in the mtDNA. Three main mutations are present in at least 90%
of families with the disease and all cause substitutions of highly conserved
amino acid residues in the affected mitochondrial proteins. Thus the mtDNA
mutations explain the maternal transmission of LHON although the reason
why a higher proportion of males than females are affected is not known. It
has been suggested that the expression of the disease could also require the
coinheritance of an X-linked recessive mutation; the development of LHON
could be hormonally influenced by androgens or by environmental factors,
such as heavy tobacco smoking, may also contribute to the progression of the
condition.

More than 100 pathogenic point mutations and innumerable rearrangements
of mtDNA are known that lead to general, multisystem disorders (Table 16.3),
which, like LHON, are often neuromuscular in nature. Perhaps not surpris-
ingly, most mitochondrial disorders tend to affect the most energy demand-
ing tissues, such as the central nervous system, heart and skeletal muscles,
kidneys and secretory tissues, although this is not always the case since
mutant proteins may interfere with mitochondrial functions in addition to
ATP formation. The diseases also vary in severity in patients with the same
mtDNA mutation. The term homoplasmy refers to the condition in which
every mtDNA molecule has the same causative mutation. In contrast, hetero-
plasmy occurs when the cell has a mixed population of normal and mutant
mitochondria. If heteroplasmy occurs, the severity and symptoms of the dis-
ease may depend on the proportion of abnormal mtDNA in some critical tis-
sue. The proportion can also differ between mother and child because of the
random segregation of mtDNA molecules at cell division.

Mitochondrial disorders are far more common than was previously thought
and a substantial increase in the number of genetic defects have been

MITOCHONDRIAL DISORDERS

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY )*.

Male

Female

Unaffected

Affected

Figure 16.9 An outline of the mode of inheritance associated with many mitochondrial diseases.Redrawn from Wallis, C. (1999)The
Genetic Basis of Human Disease,Portland Press, UK.

Margin Note 16.1 Acquired

mitochondrial DNA defects

The most common cause of acquired

mitochondrial DNA defects occurs in

HIV-1 sufferers treated with highly

active antiretroviral therapy (HAART).

Highly active antiretroviral therapy

for HIV-1 is a combination therapy

(Chapter 3) which uses inhibitors

of the viral reverse transcriptase

and the HIV protease. The first

inhibitor of reverse transcriptase to

be used clinically was the nucleoside

analog Zidovudine or AZT (Figure

3.32). An unwanted effect of this

drug is to inhibit the replication

of mtDNA and this depletes the

amount of mtDNA and leads to side

effects that mimic the symptoms of

inherited mitochondrial disorders.

Unfortunately such effects are

common to most nucleoside analog

inhibitors of reverse transcriptase. It

is now routine practice to monitor

mitochondrial functions in patients

treated with HAART.

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