Mitochondrial diseases may arise either due to mutations in mtDNA or nuclear DNA encoding a mitochondrial protein. Mitochondrial diseases are severely debilitating, often fatal and characteristically complex in nature. Current estimates place the incidence of mitochondrial disease at about 1 in 2000 to 1 in 5000 live births in Western countries. We do not yet know exact incidence of mitochondrial diseases in India.
Mitochondria play a crucial role in energy production, mediate cell death, and perform different functions in different tissues. Because of its vicinity to electron transport chain and lack of histones, mitochondrial DNA (mtDNA) is prone to mutations at about ten times the rate of nuclear DNA. These variations cause impairment of oxidative phosphorylation and normal physiology of mitochondria leading to hundreds of mitochondrial disorder. Each disorder produces a wide spectrum of dysfunction that can be extremely perplexing to the scientist and physician.
One of the diagnostic hallmarks
of Mitochondrial myopathy on light microscopy are
the presence of 'ragged blue' fibers on Succinic
dehydrogenase (SDH) staining (irregular, increased
subsarcolemmal accumulation of reaction product)
and 'ragged red' fibers on Modified Gomoris
trichrome (MGT) stain. These fibers may be
negative on Cytochrome C oxidase (COX) staining.
This may be reflected by increased accumulation of
abnormal mitochondria (varying size, altered
cristae and paracrystalline inclusions). However,
these changes are not universally present in all
the cases of mitochondrial encephalomyopathies due
to variability and severity of muscle involvement.
With the advent of molecular genetics and
identification of mtDNA mutations, a larger number
of mitochondrial disorders have been detected.
Thus, the exact sensitivity and specificity of
muscle biopsy needs to be ascertained by
correlating molecular genetics and clinical
MtDNA mutations are not always
homogenous in all cells. The mutations are
selectively eliminated from highly proliferating
tissues, like blood, by a process of cytological
negative selection. However, the mutant level will
increase in post-mitotic tissues due to lack of
such selection. The increased mutant load will
lead to progression of the disease. The
coexistence of both the normal and mutant mtDNA is
referred to as heteroplasmy, and provides a reason
why phenotypes are so variable, even within the
families. The disease manifests when the level of
the mutant mtDNA increases beyond a certain
threshold, illustrated by NARP and MILS
(Maternally Inherited Leigh Syndrome), caused by a
single pathogenic point mutation T8993G in ATPase