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© Borgis - New Medicine 1/2003, s. 35-40
Bartłomiej Kisiel, Łukasz Małek
Mitochondrial cytopathies: genetic, biochemical and clinical features. Diagnosis and management
Student´ Scientific Association of Clinical Genetics Medical University of Warsaw, 2nd Department of Paediatrics, Section of Paediatric Diabetology and Birth Defects
Head of Department and Tutor: Lech Korniszewski MD, Ph
Mitochondrial cytopathies represent a heterogeneous group of multi-system disorders caused by either mitochondrial or nuclear mutations. These mutations lead to defects of energy metabolism. Hence, mitochondrial cytopathies preferentially affect tissues and organs highly dependent on oxidative metabolism, such as skeletal muscles and the nervous system. So far, over 200 different mutations in mtDNA causing mitochondrial disorders have been described, but it is believed that more than 90% of mitochondrial cytopathies are caused by mutations in nuclear genes, of which only a few mutations are known. Diagnostic investigations should consist of the measurement of lactate and pyruvate concentrations in serum and CSF, neuroradiological examinations (preferentially MRI), muscle biopsy (to reveal the presence of ragged-red fibres and to perform staining for cytochrome-c oxydase and succinate dehydrogenase) and genetic analysis. So far, treatments are solely symptomatic and, moreover, relatively ineffective.

Mitochondria are small, oval-shaped intracellular organelles that are present in every human cell, and play a significant role in the regulation of intracellular transport and metabolism, including the respiratory chain, fatty acid β-oxidation, and the tricarboxylic acid cycle. But the fundamental mitochondrial activity is oxidative phosphorylation (OXPHOS), the process by which energy extracted from nutritional substances gets stored as ATP molecules.
The subtle machinery for this process, the electron transport chain (ETC), embedded within the inner mitochondrial membrane, is composed of five multi-subunit enzyme complexes. Complexes I and II collect electrons derived from the oxidation of fatty acids, amino acids, and pyruvate in preparation for their transport via ubiquinone. Complex III then transfers the electrons to cytochrom c, thus allowing complex IV to transport them using oxygen particles, which will later bind protons and create molecules of water. Complexes I, II and IV use the energy derived from this electron transfer to pump protons into the intermembrane space. Complex V, or ATPase, produces ATP from an induced electrochemical gradient. The ETC consists of approximately 80 proteins, each of which is encoded by both a nuclear and mitochondrial genome.
Every human cell contains hundreds of mitochondria, with each mitochondrion containing 2 to 10 mitochondrial DNA (mtDNA) molecules, and has the structure of a double-stranded loop composed of 16569 base pairs (bp). MtDNA encodes 13 essential proteins of the respiratory chain which make up enzyme complexes I, III, IV and V; 22 tRNAs and 2 ribosomal RNAs. Of those 13 proteins, seven (genes ND1, ND2, ND3, ND4, ND4L, ND5, ND6), create the 41-subunit NADH-coenzyme Q (CoQ) reductase, or complex I; one protein, gene CYTb, together with 10 nuclear DNA subunits, forms CoQ-cytochrome-c reductase, or complex III; three proteins, genes COI, COII, COIII, make up the 13-subunit cytochrome-c oxydase, or complex IV and ATPase is formed from two mitochondrial proteins (ATP6 and ATP8) and six nuclear DNA (nDNA) encoded proteins. Out of complexes I-V, only succinate-CoQ reductase (complexII) is fully nDNA encoded (7, 14, 36). MtDNA replication is catalyzed by DNA γ polymerase and its transcription by RNA polymerase, and both are encoded by nuclear genes (7). MtDNA is maternally transmitted to the offspring via an asexual process, although recent evidence of marginal paternal transmission – even of mutated mtDNA – has been published (37).
Mitochondrial DNA is less resistant to mutation than nuclear DNA and accumulates defects at 10 times the rate. This condition has been attributed to a combination of the fact that mtDNA lacks protective histones and intrones, and has an inefficient repair mechanism within environments relatively rich in reactive oxygen species. Itis now generally assumed that at least 1 out of every 8500 individuals has a mitochondrial disease (36). Interestingly, a mixture of normal and mutant DNA copies can coexist within one cell; this condition is analogous to heterozygocity and is called heteroplasmy, which can range from 1 to 99%. Another important characteristic of mtDNA is mosaicism – where heteroplasmy can vary from cell to cell, and from tissue to tissue. Respiratory chain function will not be impaired as long as there is sufficient normal mtDNA to overcome the effects of the mutant DNA. In the event that deleterious mtDNA reaches a threshold number, the cell functions can become impaired. The threshold of mutated genome varies among persons, organs and even within individual tissues. Organs under the highest risk are the energy-demanding ones – the brain, heart, skeletal muscle, liver, gastrointestinal tract, bone marrow, kidneys and the endocrine system (11, 14, 36). Three types of molecular lesions have been identified (47): 1) point mutations of protein encoding mtDNA genes (mit-point mutations); 2) point mutations in mtDNA-tRNA or rRNA genes (syn-point mutations); 3)large-scale rearrangements of mtDNA (ρ-mutations). No correlation between the type of mutation and its phenotype has been found, and some of the described syndromes may overlap or even show progression from one to another (e.g. PS into KSS) (14, 34, 36). MtDNA is constantly replicating – even in quiescent cells. For that reason, post mitotic cells like nerves or skeletal muscle, apart from energy demands, seem to be more and more destabilized as the number of mutated DNA increases. On the other hand, cells with a fast turnover, like blood cells, show negative selection for defective mtDNA. Most of the point mutations are maternally transmitted while most of the large-scale rearrangements are sporadic events. There is also a growing number of mitochondrial disorders (MD) caused by mutations in nuclear DNA encoding some of the mitochondrial protein subunits (14, 36).
1.Leber´s hereditary optic neuropathy (LHON)
LHON is the commonest cause of blindness in otherwise healthy young men, with an incidence of approximately 1 in 50000.
Genetics. The three most frequent mutations in LHON patients are G11778A (in subunit 4 of complex I – ND4), G3460A (in ND1) and T14484C (in ND6). These are called primary mutations and every LHON patient harbours one of them. The primary mutations aren´t found in non-LHON individuals. The G11778A mutation is found in 69% of all LHON families whilst the other two primary mutations are in 27% (9). The primary mutations can be homoplasmic or heteroplasmic with a varied mutant load in the blood of LHON families. The relationship between mutant load and the risk of developing LHON isn´t clear, and both symptomatic and asymptomatic family members may carry identical mutant loads. The penetrance of LHON, even in individuals carrying a homoplasmic mutation, is below 100%. These facts suggest that additional factors such as secondary mutations (mtDNA mutations which are found more frequently in LHON families than in non-LHON individuals), nuclear background and environmental factors may play a role.
Male predominance and age at onset. Males are in the majority among LHON patients (80% for G11778A mutation). According to this fact Bu and Rotter (8) suggested the presence of a visual loss susceptibility locus on the X chromosome (VLSL). But this hypothesis has not yet been confirmed. The majority of patients develop visual loss in the 2nd and 3rd decades of life and 95% of patients are affected by the age of 50, but the age at onset may range between the 1st and 7th decades (5, 33).
Clinical features. The first sign of the disease is peripapillary teleangiectatic microangiopathy, which is visible ophthalmoscopically. This is the presym-ptomatic stage (26, 27). Along with the beginning of the acute stage increased hyperaemia, swelling of the optic disc, and arteriolar dilatation occur (17). The visual disturbance takes place in this stage. Typically it is sequential with a median inter-eye delay of 8 weeks. A monocular affection is extremely rare. Visual acuity declines over a period of 4-6 weeks to 6/60 or less and a centrocecal scotoma develops (18, 19, 25, 28, 33,). At the end stage microangiopathy disappears. Simultaneously the whole retinal nerve fibre layer becomes atrophic. At this stage centrocecal scotoma is large and absolute (17). Final visual acuities are 1/60 for G11778A mutation, 3/60 for G3460A mutation, and 6/9 for T14484C mutation. In typical LHON, visual loss is permanent. But the disease can also manifest in three atypical forms: subclinical disease, a slowly progressive disease, and a disease with a classic acute stage but with spontaneous recovery (29). The last form occurs mainly in patients with T14484C mutation.
Additional symptoms. In some cases additional symptoms such as epilepsy, polyneuropathy, tremor, multiple sclerosis-like disorder, or thoracic kyphosis occur (30).
a)Electrodiagnostic studies – usually electro-retinograms and electro-oculograms are normal. However in some cases the b wave of the flash ERG may be attenuated or curtailed. At the acute stage we observe abnormalities of VEPs such as decreased amplitude and increased latency (33). At the end stage (atrophic stage) VEPs usually completely disappear.
b)Perimetry – at the early stages perimetry reveals an increased blind spot. At the final stage there is the presence of a centrocecal scotoma.
Biochemistry. Histochemically, there are no ragged-red fibres (RRF). Biochemically there is marked deficiency of complex I activity.
2.Neuropathy, ataxia and retinitis pigmentosa (NARP) and Leigh syndrome (LS)
Genetics. The major mutations causing NARP and maternally inherited LS are T8993G/C (subunit 6 of ATPase). If the mutation level is above 90% the patients develop LS; patients with mutant load between 70% and 90% suffer from NARP (42). Individuals with less than 70% of the mutation can be asymptomatic. The X-linked and autosomal recessive forms of LS are also known (2, 23, 41, 43, 44) but rarer than the mtDNA transmitted form.
Clinical features. LS is a progressive neurodegenerative disease, which usually starts in early childhood. At first it manifests with failure to thrive, developmental delay and loss of developmental milestones. Other symptoms include ataxia, dystonia, muscle weakness, respiratory dysfunction and lactic acidosis (36). Frequently, death occurs in the 1st decade of life. However, milder forms of LS, with an age of onset in adulthood and without shortening of life, are also known.
NARP generally starts in the 2nd decade of life and progresses much more slowly than LS. Major symptoms are axonal neuropathy, ataxia and retinitis pigmentosa. In some cases additional symptoms such as dementia and seizures occur (36).
Investigations. In LS and NARP lactic acid level is elevated in either blood or cerebrospinal fluid. RRF are usually absent in LS, but generally occur in NARP. MRI in LS shows bilateral symmetric lesions involving the medulla oblongata, mesencephalon, cerebellum and the basal ganglia. In NARP we can usually find only cerebellar and olivopontocerebellar atrophy.
Biochemistry. The biochemical basis of both syndromes is deficiency of respiratory chain activity (involving complex I or cytochrome-c oxidase) or a defect of one of the other enzymes involved in energy production such as pyruvate dehydrogenase or pyruvate decarboxylase.
1.Myoclonus epilepsy with raggedred fibres (MERRF)
Genetics. The typical mtDNA mutation in MERRF is A8344G in the tRNALys gene (approximately 80% of affected individuals carry the A8344G mutation in heteroplasmic form) (38), but two other mutations in the same gene (T8356C and G8363A) have also been described (31, 40).
Clinical features. MERRF usually starts in the 2nd or 3rd decade of life. Typical features are myoclonic epilepsy and the presence of RRF in skeletal muscles. Other symptoms such as myoclonus and cerebellar ataxia are very common. Less common signs include dementia, hearing loss, peripheral neuropathy, multiple lipomas, optic nerve atrophy and cardiomyopathy.
Investigations. Pyruvate and lactate concentrations in blood and CSF are increased in most cases, and RRF are present in all patients. Neuroradiological examinations (CT, MRI) usually reveal a general cerebral atrophy. On EEG epileptic features may be present, and EMG may show a myopathic pattern.
Biochemistry. The defect in tRNALys results in a disturbance in the translation of all mtDNA-encoded genes. It leads to a deficiency of the respiratory chain function, concerning mostly complexes I and IV (4,45).
2.Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS)
Genetics. The most frequent mutation in MELAS families is A3243G mutation in the mitochondrial gene for tRNALeu (80% of all MELAS families), but other mutations in this gene (at positions 3250 and 3252) have also been described (36). The disease may occur even in patients with a very low level of mutant mtDNA – a MELAS patient with a level of 4% mutant mtDNA in blood cells, 38% in skeletal muscles and 41% in cultured skin fibroblasts has been described (13) – but in severe cases the mutation load is usually high (above 80%). It is worth mentioning that A3243G mutation has been found in a small percentage of patients with CPEOplus or KSS not associated with mtDNA deletions (47).
Clinical features. The disease usually starts in childhood. The first symptoms are stroke-like episodes, vomiting and lactic acidosis. Stroke-like episodes primarily affect occipital and temporal regions, leading to hemianopia and hemiparesis. Other symptoms are myopathy with excessive fatigue, ophthalmoparesis, ataxia, cardiomyopathy, short stature and hearing loss. Endocrine dysfunction concerning the hypothalamic-pituitary axis, the thyroid and the pancreas is very common. In the end stage dementia develops and patients usually die in the 2nd decade of life.
Investigations. Lactic acidosis occurs in all cases. Histochemistry reveals the presence of RRF. EMG shows a myopathic pattern in affected muscles. On neuroradiological examinations bilateral basal ganglia calcifications, cerebellar and cerebral atrophy may be found.
Biochemistry. In MELAS patients activities of complex I and cytochrome-c oxidase are reduced.
3.Familial aminoglycoside-induced progressive sensorineuronal deafness
This syndrome is caused by A1555G mutation in 12S rRNA gene. In patients with a homoplasmic mutation, deafness may develop rapidly during aminoglycosides administration. However, hearing deterioration (or deafness) may occur in individuals harbouring this mutation even without treatment with aminoglycosides (12).
Mitochondrial rearrangements consist of deletions and duplications. We include depletion, which is a decrease in the number of mtDNA copies per mitochondrion. MtDNA rearrangements can also be a secondary event due to lack of communication between the nucleus and mitochondrion (11, 14, 36). This condition is called ”murder by proxy” and the number of nuclear mutations responsible has been continuously growing since the decodification of the human genome (11). We have divided rearrangements with onset in premature age into several groups:
1.Primary mtDNA deletions

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New Medicine 1/2003
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