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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
evidence.
MtDNA mutations can lead to various syndromes
such as CPEO (Chronic progressive external
ophthalmoplegia), KSS (Kearns-Sayre Syndrome),
MERRF (Myoclonic epilepsy with ragged red fibers),
MELAS (Mitochondrial Encephalomyopathy, Lactic
Acidosis and Stroke-like episodes), NARP
(Neuropathy, Ataxia and Retinitis pigmentosa),
MNGIE (Myoneurogastrointestinal disorder and
encephalopathy), recurrent myoglobinuria due to
Coenzyme Q 10 deficiency, etc., affecting major
organs. These are associated with changes in the
skeletal muscle thus enabling diagnosis by muscle
biopsy. However conditions like Leigh's Syndrome
and LHON (Leber's hereditary optic neuropathy) are
not associated with myopathic features. Severe
neurodegenerative diseases like Parkinson's and
Alzheimer's diseases can also be caused by mtDNA
mutations, and mutations are also seen in Type II
Diabetes Mellitus. |
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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
6.
Mitochondrial diseases may also arise from
processes other than germline mutations in mtDNA.
Recent reports show somatic and homoplasmic
mutations in mtDNA causing multiple neonatal
deaths. Generally, mtDNA deletions involved in
pathogenesis are not inherited from the mother.
The disease onset may be either early or late
depending on the load of mutant mtDNA. Some mtDNA
mutations may cause disease only when the bearer
is exposed to an environmental toxin:
aminoglycoside-induced ototoxicity is one such
case. |
