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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859 EISSN: 0972-2823
Vol. 46, Num. 3, 2000, pp. 224-230
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Journal of Postgraduate Medicine, Vol. 46, No. 3, July-September, 2000,
pp. 224-230
Review Article
Mitochondrial Diseases: An Overview of Genetics,
Pathogenesis, Clinical Features and an Approach to Diagnosis
and Treatment
Singhal N, Gupta BS, Saigal R, Makkar J, Mathur R
Department of Medicine, SMS Medical College, Jaipur, India.
Address for correspondence: B.S. Gupta, MD, 28,
Gangwal Park, Jaipur - 302 004, India.
Code Number: jp00078
Abstract:
Defects in structures or functions of mitochondria, mainly involving the oxidative
phosphorylation, mitochondrial biogenesis and other metabolic pathways have
been shown to be associated with a wide spectrum of clinical phenotypes. The
ubiquitous nature of mitochondria and their unique genetic features contribute
to the clinical, biochemical and genetic heterogenecity of mitochondrial diseases.
This article focuses on the recent advances in the field of mitochondrial disorders
with respect to the consequences for an advanced clinical and genetic diagnostics.
In addition, an overview on recently identified genetic defects and their pathogenic
molecular mechanisms are given. (J Postgrad Med 2000; 46:224-230)
Key Words: Mitochondria, mt DNA, Myopathy, Encephalopathy.
The term "mitochondrial disease" encompasses a heterogenous group
of disorders in which a primary mitochondrial dysfunction is suspected or proven
by morphologic, genetic or biochemical criteria.1 Nass & Nass
were first to discover that mitochondria contain their own DNA - mitochondrial
DNA (mt DNA). Complete sequence of mt DNA in human and mouse were reported in
1981.2 In 1988 the first disease causing mutations of mt DNA were
found.3 Since then more than 50 different mt DNA mutations linking
to human disease have been reported.4 Several studies have shown
link between mitochondrial dysfunction & common disorders like heart failure,
diabetes mellitus and neurodegeneration.5,6
Mitochondrial DNA & Genetics
Human mitochondrial genome is a double stranded 16569 bp molecule which is
replicted and transcribed with in the mitochondrial matrix. Each mitochondria
contains between 2-10 copies of mt DNA and there are typically 103-104
copies of mt DNA per cell. mt DNA contains 37 genes out of which 22 encode tRNA
and 2 encode rRNA for protein synthesis. Remaining 13 gene encode proteins for
respiratory chain. mt DNA encode sub units for complex 1 (7 sub units), complex
III (1 sub unit), complex IV (3 sub unit) & complex V (2 sub unit). Complex
II and rest of the proteins are nuclear coded. Nuclear DNA also encodes several
factors that control mt DNA replication, transcription and translocation.10
Unique features of mt DNA
- mt DNA does not contain introns and both strands of circular mt DNA are
transcribed as long primary transcripts corresponding to several genes. These
primary transcripts are processed to release the individual tRNA, rRNA &
mRNA.
- Many mitochondrial genetic codons differ from nuclear codons.
- mt DNA is exclusively maternally inherited. Mothers with a higher concentration
of mutated mt DNA are more likely to have clinically affected children. Deleted
molecules are rarely, if ever, transmitted from clinically affected woman
to her children while a woman with a point mutations duplications may transmit
a variable amount of mutated DNA to her children.
- Fixation of mtDNA mutations is more than 10 times higher in comparison with
the nuclear DNA mutations. This is because of lack of histones and absence
of effective DNA repair system. mt DNA is also subjected to reactive oxygen
spices (ROS) produced as a by-product of oxidative phosphorylation.
- An individual may carry several allelic forms of mt DNA, known as heteroplasmy.
Individuals with mt DNA disease often harbour a mixture of mutated and wild
(normal) mt DNA. Heteroplasmy contributes to disease process only when a certain
threshold of abnormal mitochondria is crossed. Post mitotic tissues as neurons,
cardiac muscles, skeletal muscles, liver, kidney and endocrine organs have
high energy demands and are therefore highly sensitive. These organs accumulate
high levels of mutated mt DNA and are often clinically involved. In contrast
rapidly dividing tissues such as bone marrow are only rarely affected as they
may loose deleted mt DNA by clonal selection.
- New mt DNA alleles can arise only from spontaneous mutations.
Mitochondrial disease can result from either nuclear DNA mutation (Mendelian
inheritance) or mt DNA mutations (maternal inheritance).10 Mitochondrial
disease due to mutation of nuclear DNA are divided into three categories:10
alteration of mitochondrial protein; alteration of mitochondrial protein importation;
and alteration of intergenomic communication. There are three major types of
mt DNA mutations,20 leading to mitochondrial diseases: large sporadic
rearrangements including deletions and duplications; point mutations; and maternally
inherited rearrangements (duplication).
Mutations can occur spontaneously in germline allowing maternal inheritance
(commonly point mutation) or in somatic cells causing sporadic cases (large
sporadic rearrangements).21
mt DNA is not replicated in absolute synchrony with cell division thus leading
to unequal distribution of mutated DNA. This leads to a variable levels of mutated
DNA between various tissues and also among cells of the same tissue. Germline
random distribution leads to different levels of mt DNA from one generation
to next and siblings often inherit widely varying levels of mutated mt DNA.
Clinical phenotypes associated with a particular mutation may vary, for example,
A 3243 mutation is associated with PEO, maternally inherited DM and deafness
and MELAS. Mutations of mt DNA leads to assembly of bionergitically incompetant
mitochondria leading to various manifestations depending on tissue involved.
Cells containing such mutation are 3-4 fold larger than control cells22
as a compensatory mechanism.
Various mitochondrial diseases are listed in table 1
and 2 a, 2b.
Ageing
Review of the studies establishing role between ageing and mitochondrial dysfunction
are inconclusive.34
Age related accumulations of low levels of common 4977 bp deletion and A3243
G mutation in various tissues has been reported.35 A decline in respiratory
chain capacity, particularly of complex 1-IV36 and increased oxidative
damage to mt DNA with age has been demonstrated.37 The levels of
accumulated mutations observed in older individuals vary between 0.1-12% in
comparison with the levels that are required for causing respiratory chain dysfunction
in, for instance, Kearns Sayre syndrome (> 60%).38 Reactive oxygen
species (ROS) generated as a by-product of respiratory chain, reacts with and
mutate mt DNA, which leads to impaired function of respiratory chain which in
turn further promotes generation of free radicals. The reduced availability
of ATP decreases the transmembrane potential and may induce apoptosis by release
of cytochrome C, which is a apoptosis inducing factor.
The free radical hypothesis of ageing has been corrobrated by animal studies
of superoxide dismutases (SODs).39,40
Heart
Heart is a highly ATP dependent organ. It has long been speculated that inadequate
energy production may be an important contributing factor to heart failure.41
Patients with mt DNA mutations often develop AV blocks (1 - III) especially
KSS patients. Left ventricular hypertrophy is characteristic of mitochondrial
encephalomyopathy. Idiopathic DCM is reported in number of studies.42-44
Complex 1, III, IV defects are commonly seen.
Diabetes Mellitus
Several studies have suggested that mt DNA mutations and dysfunction of respiratory
chain may be involved in pathogenesis of DM.45 First, pathogenic
mt DNA mutations associated with mitochondrial encephalopathies (KSS, MELAS)
have also been identified in patients with DM. A3243 G tRNA leu (UUR) gene is
present in both.46 Mutations at 3264 tRNA Leu (UUR) gives rise to
DM and overlap between CPEO and MERRF.47 Secondly, direct evidence
for mtDNA involvement in DM has been found in pedigrees with maternally transmitted
DM and deafness. Last, it is more common to inherit DM from mother than from
affected father.
It has been demonstrated that mt DNA mutations and other causes of respiratory
chain function may lead to decreased insulin secretion and subsequent development
of DM.
Neurodegenerative Disorders
Studies have provided evidence that there is an involvement of deficient oxidative
phosphorylation and increased oxidative damage in the pathogenesis of Parkinson's
disease and possibly in Alzheimer's disease.
Both a deficiency of complex 1 and increased oxidative damage have been reported
in substantia nigra of Parkinson's patients.48 Neurotoxin MPTP which
causes Parkinsonism is metabolised to MPP+ which selectively inhibits the function
of Complex 1 and also causes a decrease in mt DNA copy number.
However no families with maternally inherited Parkinson's decrease has yet
been identified.
Familial ALS is associated with point mutation in human SOD 1 which leads to
increased generation of free radicals and thereby contribute to mitochondrial
dysfunction.49 Recent studies using cybrid cell lines suggest that
sporadic Alzheimer's disease is associated with a deficiency of cytochrome oxidase.49
Recently, Friedrich's ataxia, Wilson disease and autosomal recessive spastic
paraplegia were suggested to be mitochondrial disorders. Friedrich's ataxia
is caused by mutation in gene frataxin.49 Frataxin is a mitochondrial
protein involved in regulation of mitochondrial iron transport. The iron overload
in mitochondrial matrix leads to increased production of reactive O2
species which in turn damages the Fe-S dependent respiratory chain complexes
(1, II & III) and aconitase. Mutations of paraplegin gene causes autosomal
recessive Hereditary spastic paraplegia. Paraplegin has high similarity to known
mitochondrial metalloproteins and contains a mitochondrial import signal. Muscle
biopsies of these patients contained COX-negative fibres as well as ragged red
fibres indicating that loss of paraplegin leads to respiratory chain dysfunction.
Mitochondrial neuropathies are sensory motor neuropathies. Peripheral neuropathy
was present in all cases of mitochondrial myopathies in a study.50
Most mitochondrial abnormalities were found in schwann cells.
Liver Diseases
mt DNA depletion syndromes leads to liver failure and neurologic abnormalities.
Primary mitochondrial hepatopathies include Pearson's marrow pancreas syndrome,
Alper's disease, MNGIE and Navago neuropathy.51
Secondary mitochondrial hepathopathies are conditions in which mitochondria
are major targets during liver injury from other causes as metal overload, drugs,
toxins, alcoholic liver injury and oxidant stress.
The common 4977 base pair deletion is frequent in the hepatic DNA of alcoholic
patients with microvesicular steatosis.52
Reye's syndrome is associated with mt DNA mutations.
Renal Disease53
Renal involvement is characterised by Fanconi like syndrome in new born and
tubulointerstitial nephritis leading to uraemia in adults.
Retinal Manifestations54
Mitochondrial diseases most commonly lead to retinal pigment defect. Diseases
commonly involving retina are:
- Kearns Sayre syndrome - salt and pepper fundus
- CPEO - defects at the level of retinal pigment epithelium at posterior
pole.
- MELAS - Retinal pigment defect at posterior pole.
- MERRF - Retinal pigment defect and optic neuropathy.
- LHON - Retinal pigment defect at macula and optic neuropathy.
Investigations
The diagnosis of mitochondrial diseases involves the careful assimilation of
clinical and laboratory data. The laboratory diagnosis rests on combination
of biochemical and morphological methods to evaluate respiratory chain function
and molecular genetics to detect underlying mt DNA and or nuclear mutation.
Various laboratory procedures in use are enumerated below.
- Polarographic (oxygraphic) method: It directly measures the respiratory
chain function in freshly isolated mitochondria. Different substrates that
enter the respiratory chain at different points are added and the O2
consumption is monitored.
- Enzyme histochemical staining - useful for estimation of complex II, IV,
V. Activity of complex 1 is difficult to assess by this method. Only marked
deficiencies will give positive results.
- Gomori trichome stain for mitochondrial accumulation in muscle fibres totally
lacking cytochrome C oxidase gives red colour, known as ragged red fibres
(RRF). Double staining for SDH II and cytochrome oxidase IV is also possible
where RRF appears blue and normal muscle as brown.
- Immuno histochemical studies detects specific respiratory chain sub units.
- Electron Microscopy reveals abundant mitochondria with abnormal appearance
with disorganized cristae or crystalline structures in the matrix..
- Polymerase chain reaction (PCR) and Southern blot analysis:55,56
Point mutations are detected by PCR, while southern blot and long PCR detects
mt DNA rearrangements. Heteroplasmic deletions and point mutations may not
be present in blood despite high levels in muscle.
- Magnetic resonance imagein is a non-specific investigation.57
- Direct sequencing of mitochondrial genome from a muscle biopsy specimen
can be helpful, provided more than 30% of DNA sample is mutated mt DNA.
Management
There is, currently, no effective treatment for mitochondrial disorders. Many
treatment modalities have been proposed but efficacy has not yet been proved.59
A variety of experimental therapies are being tested.
Genetic counselling may be appropriate for certain diseases so. Appropriate
clinical monitoring is must to prevent the known complications of mitochondrial
diseases. Interventions at appropriate time such as cardiac pacing, surgical
correction of ptosis, cataract surgery, mechanical aids can be taken.
Antioxidants may be beneficial to patients as free radical are proposed to
be important in pathogenesis of mitochondrial disorder. Coenzyme Q works as
an electron transporter and free radical scavanger and has been reported to
be beneficial in KSS and MELAS. Standard doses of vitamin C, E, K, riboflavin,
thiamine, succinate, nicotinamide have been used to bypass blocks in respiratory
chain.59 Peptide nucleic acid (PNA) are synthetic polyamide nucleic
acids and it is possible to design PNA molecule so that they are complementary
to a short mt DNA sequence harbouring a point mutation or a deletion breakpoint.60
The aim is to use PNA as antisense probe, which selectively inhibits the replication
of the mutated mt DNA.
Some patients with heteroplasmic tRNA mutations have high levels of mutated
mt DNA in differentiated muscle and low levels in the surrounding satellite
cells, which are responsible for muscle regeneration. Activation of satellite
cells after inducing localised necrosis leads to muscle segment with completely
reversed genotype and low levels of mutated mt DNA.
An inhibitor of mitochondrial oxidation has been used in cultured cells to
alter the ratio of mutant mt DNA to wild type mt DNA.
Gene therapy would be final answer by replacing or repairing the defective
gene. In addition to many difficulties related to nuclear gene therapy, there
is problem of introducing gene into mitochondria of in vitro cultured cells.
Also the cells contain multiple copies of mt DNA and many mitochondrial mutations
are heteroplasmic. Two approaches are being currently explored.62
A self-replicating copy of a normal gene sequence has been successfully delivered
into mitochondria in vitro and an approach for heteroplasmic mt DNA disorders
is to specifically inhibit replication of mutant mt DNA.
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