Mitochondrial diseases: an overview of genetics, pathogenesis, clinical features and an approach to diagnosis and treatment.
N Singhal, BS Gupta, R Saigal, J Makkar, R Mathur
Department of Medicine, SMS Medical College, Jaipur, India., India
Department of Medicine, SMS Medical College, Jaipur, India.
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.
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Singhal N, Gupta B S, Saigal R, Makkar J, Mathur R. Mitochondrial diseases: an overview of genetics, pathogenesis, clinical features and an approach to diagnosis and treatment. J Postgrad Med 2000;46:224-30
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Singhal N, Gupta B S, Saigal R, Makkar J, Mathur R. Mitochondrial diseases: an overview of genetics, pathogenesis, clinical features and an approach to diagnosis and treatment. J Postgrad Med [serial online] 2000 [cited 2020 Jul 2 ];46:224-30
Available from: http://www.jpgmonline.com/text.asp?2000/46/3/224/270
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. 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. In 1988 the first disease causing mutations of mt DNA were found. Since then more than 50 different mt DNA mutations linking to human disease have been reported. Several studies have shown link between mitochondrial dysfunction & common disorders like heart failure, diabetes mellitus and neurodegeneration.,
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.
1. 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.
2. Many mitochondrial genetic codons differ from nuclear codons.
3. 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.
4. 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.
5. 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.
6. 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). Mitochondrial disease due to mutation of nuclear DNA are divided into three categories: alteration of mitochondrial protein; alteration of mitochondrial protein importation; and alteration of intergenomic communication. There are three major types of mt DNA mutations, 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).
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 cells as a compensatory mechanism.
Various mitochondrial diseases are listed in [Table:1] and [Table:2].
Review of the studies establishing role between ageing and mitochondrial dysfunction are inconclusive.
Age related accumulations of low levels of common 4977 bp deletion and A3243 G mutation in various tissues has been reported. A decline in respiratory chain capacity, particularly of complex 1-IV36 and increased oxidative damage to mt DNA with age has been demonstrated. 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%). 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).,
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. 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.,, Complex 1, III, IV defects are commonly seen.
Several studies have suggested that mt DNA mutations and dysfunction of respiratory chain may be involved in pathogenesis of DM. 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. Mutations at 3264 tRNA Leu (UUR) gives rise to DM and overlap between CPEO and MERRF. 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.
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. 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. Recent studies using cybrid cell lines suggest that sporadic Alzheimer’s disease is associated with a deficiency of cytochrome oxidase.
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. 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. Most mitochondrial abnormalities were found in schwann cells.
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.
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.
Reye’s syndrome is associated with mt DNA mutations.
Renal involvement is characterised by Fanconi like syndrome in new born and tubulointerstitial nephritis leading to uraemia in adults.
Mitochondrial diseases most commonly lead to retinal pigment defect. Diseases commonly involving retina are:
1. Kearns Sayre syndrome – salt and pepper fundus
2. CPEO – defects at the level of retinal pigment epithelium at posterior pole.
3. MELAS – Retinal pigment defect at posterior pole.
4. MERRF – Retinal pigment defect and optic neuropathy.
5. LHON - Retinal pigment defect at macula and optic neuropathy.
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.
1. 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.
2. 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.
3. 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.
4. Immuno histochemical studies detects specific respiratory chain sub units.
5. Electron Microscopy reveals abundant mitochondria with abnormal appearance with disorganized cristae or crystalline structures in the matrix..
6. Polymerase chain reaction (PCR) and Southern blot analysis:, 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.
7. Magnetic resonance imagein is a non-specific investigation.
8. Direct sequencing of mitochondrial genome from a muscle biopsy specimen can be helpful, provided more than 30% of DNA sample is mutated mt DNA.
There is, currently, no effective treatment for mitochondrial disorders. Many treatment modalities have been proposed but efficacy has not yet been proved. 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. 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. 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. 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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