European Journal of Neurology 2004, 11: 163–186

RESEARCH ARTICLE

Mitochondriopathies
J. Finsterer
Neurological Department, Krankenanstalt Rudolfstiftung, Vienna, Austria

Keywords:

genetics, hereditary disease, multisystem, mutations, neuromuscular disease, skeletal muscle
Received 1 June 2003 Accepted 28 August 2003

Mitochondriopathies (MCPs) are either due to sporadic or inherited mutations in nuclear or mitochondrial DNA located genes (primary MCPs), or due to exogenous factors (secondary MCPs). MCPs usually show a chronic, slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. Although several proteins with signalling, assembling, transport, enzymatic function can be impaired in MCP, most frequently the activity of the respiratory chain (RC) protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. MCPs represent a diagnostic challenge because of their wide variation in presentation and course. Systems frequently affected in MCP are the peripheral nervous system (myopathy, polyneuropathy, lactacidosis), brain (leucencephalopathy, calcifications, stroke-like episodes, atrophy with dementia, epilepsy, upper motor neuron signs, ataxia, extrapyramidal manifestations, fatigue), endocrinium (short stature, hyperhidrosis, diabetes, hyperlipidaemia, hypogonadism, amenorrhoea, delayed puberty), heart (impulse generation or conduction defects, cardiomyopathy, left ventricular non-compaction heart failure), eyes (cataract, glaucoma, pigmentary retinopathy, optic atrophy), ears (deafness, tinnitus, peripheral vertigo), guts (dysphagia, vomiting, diarrhoea, hepatopathy, pseudo-obstruction, pancreatitis, pancreas insufficiency), kidney (renal failure, cysts) and bone marrow (sideroblastic anaemia). Apart from well-recognized syndromes, MCP should be considered in any patient with unexplained progressive multisystem disorder. Although there is actually no specific therapy and cure for MCP, many secondary problems require specific treatment. The rapidly increasing understanding of the pathophysiological background of MCPs may further facilitate the diagnostic approach and open perspectives to future, possibly causative therapies.

Introduction
Mitochondriopathies (MCPs) are either due to sporadic or spontaneous mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations in genes encoding for enzymes, structural, signalling, carrier/shuttle, channel, receptor, heat shock or assembling proteins, tRNAs or rRNAs of the mitochondrion or due to exogenous noxes like drugs, toxins or infections (Morgan-Hughes, 1994; Schapira and DiMauro, 1994; DiMauro, 1996). Proteins most frequently affected by mutations are those of the respiratory chain (RC) and the oxidative phosphorylation (OXPHOS). That is why MCPs are often synonymously termed RC disorders (RCDs). However, MCPs may be also due to defects in pathways and components of the mitochondrion other than the RC or OXPHOS. MCPs present with a wide spectrum of disease and their clinical features overlap (Leonard and Schapira, 2000a). Concerning mtDNA, a single mutation or different mutations in the same gene may
Correspondence: Dr Josef Finsterer, Postfach 348, 1180 Vienna, Austria (fax: +43-1-4781711; e-mail: duarte@aonmail.at).

present with different clinical manifestations (phenocopy) whilst the same clinical phenotype may be caused by different mutations (genetic heterogeneity) (DiMauro, 1996). This review aims to summarize the actual knowledge about the genetic background, pathomechanisms, clinical manifestations, diagnostic approaches and therapeutic strategies concerning MCPs.

Historical remarks
MCPs were initially described by Kearns and Sayre 1 (1958) and later by Ernster (1959) and Luft (1962) (Luft’s disease). In 1963 the mtDNA was detected. In 1974 it turned out that mtDNA genes encode for components of the RC. In 1980 it became clear that transmission of the mtDNA followed a maternal trait. Anderson et al. (1981) revealed the wild-type mtDNA sequence. In 1984 it turned out that non-mtDNA encoded components of the RC are nuclearly encoded. In 1986 all 13 mtDNA translation products were analysed in detail. First mtDNA mutations were reported in 1988 (Holt et al., 1988; Wallace et al., 1988). In 1992 the first nuclear mutation leading to MCP was detected

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(Bourgeois et al., 1992). Today more than 100 point mutations in the mtDNA and >20 nDNA mutations, causing primary or secondary MCP, are known (Finsterer, 1997; Servidei, 2003).

Structure of mitochondria
Mitochondria are intracellular spheroid or ovoid organelles with a transverse diameter of 0.1–0.5 lm and a variable length (Stryer, 1996). According to the endosymbiont hypothesis mitochondria derive from prokaryotes, which were integrated in nucleus containing cells (DiMauro, 1996; Stryer, 1996). The number of mitochondria per cell ranges from none (erythrocytes) to 10 000 (striated muscle cell). The average number is 500–2000/cell. The number of mitochondria within a cell increases with the amount of substrate and oxygen utilization a particular cell requires (Stryer, 1996). In the muscle cell they reside between the myofibrils, subsarcolemmally, near the nucleus or near the motor endplate. Mitochondria are build up of four compartments: (i) the outer membrane, (ii) the inner membrane, (iii) the intermembrane space, and (iv) the matrix.
Outer membrane

(ATP-synthase), ubiquinone, and the carnitine-palmitoyl-transferase-II (Stryer, 1996; McFarland et al., 2002). Substrate transport via the inner membrane is selective. The inner membrane is permeable only for unloaded molecules like O2, CO2 and H2O. There are carriers for anions, redox equivalents and kations (Stryer, 1996). Altogether, 14 carriers are known so far. Among these are those for aspartate/glutamate, phosphate, pyruvate, glutamate, branched-fatty-acid, longchain-fatty-acid, ketoglutarate/malate, dicarboxylate/ phosphate, citrate/malate, a-glycero-phosphate/dihydroxyaceton-phosphate, ornitine, carnitine, glutamine, malate/aspartate (shuttles NADH into the matrix), and the adenine-nucleotide translocator (ANT1, responsible for the exchange of ADP and ATP across the inner membrane) (Stryer, 1996).
Intermembrane space

Within the intermembrane space reside the adenylatkinase, the mitochondrial creatine-phosphokinase, the deafness dystonia protein (DDP1/TIM8A), and cytochrome-c, which initiates apoptosis if released to the cytosol.
Matrix

The outer bilayer lipid membrane is permeable to molecules <10 000 Da. For correctly folded proteins the inner membrane is impermeable (Stryer, 1996). In association with the inner membrane, unfolded proteins, encoded as precursors by the nuclear genome, are imported through the outer membrane via the TOM/ TIM protein complex (Stryer, 1996). This complex import system includes for most proteins a targeting sequence at the N-terminus, which interacts with the membrane receptors before being cleaved (Schapira, 2002). The protein is then folded and sorted to its correct intramitochondrial location (Schapira, 2002). Within the outer membrane or closely associated with it reside proteins like porine (voltage-dependent ion channel), NADH cytochrome-b5-reductase, palmitoylCoA-synthetase, carnitine-palmitoyl-transferase, and mono-amino-oxidase.
Inner membrane

Within the matrix a large number of enzymes and other proteins and peptides, including RC complexes, DNA-polymerases, chaperones (heat shock proteins), mRNAs, tRNAs, and the mtDNA are located.

Function of mitochondria
Mitochondria serve four fundamental biological roles: (i) provision of ATP, (ii) mediation of cell death by apoptosis (Schapira, 2002), (iii) heat production, and (iv) contribution to human genetics. In addition mitochondria harbour the b-oxidation, citrate cycle (tricarboxic cycle, Krebs cycle), degradation of amino acids, parts of the haem-biosynthesis, parts of the steroid metabolism, parts of the uric acid cycle, mitochondrial protein synthesis, and the pyruvate dehydrogenase complex (PDC), responsible for the decarboxylation of pyruvate.
ATP production

The inner bilayer lipid membrane is folded and impermeable to most molecules and protons. It is built up of 70% proteins. Cholesterol is absent, whereas cardiolipin is present (Stryer, 1996). Phosphatidyl-cholin, phosphatidyl-ethanol-amin and cardiolipin occur in a relation of 4:3:2 (Stryer, 1996). Embedded in the inner membrane are the four RC complexes, complex V

The principle function of the mitochondrion is to produce energy in the form of ATP, which is achieved via the PDC, citrate cycle, b-oxidation, RC, and OXPHOS (Leonard and Schapira, 2000a). Fatty acids, pyruvate and amino acids are transferred from the cytosol into the mitochondrion where they are metabolized to

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Table 1 Characteristics of respiratory chain and oxidative phosphorylation complexes

Complex I II III IV V

Term NADH dehydrogenase Succinate dehydrogenase Ubiquinone cytochrome-c oxidoreductase Cytochrome oxidase ATP synthase

Subunits 41 4 11 13 14

NSEN 34 4 10 10 12

NSEM 7 (ND1-6, ND4L) 0 1 (cytochrome-b) 3 (COX I, II, III) 2 (ATPase 6 and 8)

NPTI 4 0 2 2 0

NSEN, number of subunits encoded by nDNA; NSEM, number of subunits encoded by mtDNA; NPTI, number of protons transferred to the intermembrane space.

acetyl-CoA, which is further metabolized through the citrate cycle. Electrons from the citrate cycle then enter the RC. The core of the RC and OXPHOS pathway are the five multi-subunit complexes I–V (Table 1) (Leonard and Schapira, 2000a). RC and OXPHOS are built up of 83 polypeptides of which 70 are encoded by nDNA and 13 by mtDNA (Table 1). The 13 mtDNAencoded proteins comprise <5% of the mitochondrial proteins. Electrons from various substrates pass along the chain, providing energy to pump protons across the inner membrane from the matrix via complexes I, III and IV into the intermembrane space (Table 1) (Stryer, 1996; Leonard and Schapira, 2000a). Per molecule NADH 10 protons and per molecule succinate six protons are pumped to the intermembrane space (Table 1) (Stryer, 1996). The electrochemical proton gradient thus established drives the ATP generation via complex V (Leonard and Schapira, 2000a). The transfer of electrons within a complex is effected by flavones, iron/sulphur centres, cytochromes and copper centres (Stryer, 1996). The electron producing substrates glutamate, pyruvate and hydroxybutyrate enter the RC at complex I, succinate at complex II, and fatty acids at both, complex I and the electron transfer protein, coupled to ubiquinone (coenzyme Q) (Leonard and Schapira, 2000a; DiMauro and Schon, 2003). Ubiquinone shuttles electrons from complexes I and II to complex III. From complex III electrons are passed to complex IV (cytochrome oxidase, COX) by cytochrome-c, an intermembrane protein. Complex V allows protons to flow back into the matrix, using the released energy to synthesize ATP (Gillis and Kaye, 2002).
Apoptosis

kill cells by cleaving critical cell repair and homeostatic proteins as well as cytoskeletal proteins. The permeability transition pore, a megapore spanning the inner and outer membrane is built up of porine, the adenine-nucleotide-translocator, peripheral benzodiazepine receptors and cyclophilin D (Leonard and Schapira, 2000b). It is opened by Bax, Bak, reduced + transmembrane gradient, Ca+ and is closed by BcLx, protein-kinase-c and cyclosporine. Caspase-independent apoptotic cell death is mediated by the release of the apoptosis-inducing factor, a flavo-protein stored in the intermembrane space and released in response to DNA damage, oxidative stress or exocytoxic stress (Nardin and Johns, 2001; Moskowitz and Lo, 2003).
Heat production

Decoupling of the OXPHOS leads to the production of heat (thermogenesis). Thermogenesis is particularly developed in brown fat of newborns and of hibernators (Stryer, 1996). Hypothalamic stimulation of sympathetic nerves via b3-receptors and cAMP increases lipolysis in brown fat. cAMP increases transcription of proteins important in the thermogenesis, like lipoproteinlipase (increases the uptake of extracellular fat) and thermogenin (increases the delivery of heat) (Stryer, 1996).
Mitochondrial DNA

There is ample evidence that mitochondria play an important role in apoptosis. To initiate apoptosis the permeability transition pore is opened, through which cytochrome-c is released into the cytosol. There, the latter binds to Apaf-1, which in turn complexes with caspase-9, to initiate the caspase-cascade, terminating in apoptotic cell death (Stryer, 1996; Leonard and Schapira, 2000b; Schapira, 2002). Activated caspases

Mitochondria have their own functional genome, separate from the nuclear one (Leonard and Schapira, 2000a). MtDNA lies within the mitochondrial matrix and has structural and functional features different from those of nDNA (Table 2). MtDNA is a circular, double-stranded (heavy (H, rich in guanines) and light (L, rich in cytosines) strand) DNA molecule, built up of 16 569 base pairs. MtDNA genes encode for two rRNAs, 22 tRNAs and 13 polypeptides (28 on the H-strand and nine on the L-strand). Unlike nDNA, mtDNA coding sequences have no introns (93% are coding compared with 5% in the nuclear genome), mtDNA is not interwoven with histones, has no

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Table 2 Particularities of the mtDNA Circular Has its own apparatus for replication, transcription and translation No coding sequences (except for D-loop, approximately 1000 bp) No introns (thus no splice sites) Some genes overlap Single promoter site Complete mtDNA is transcribed into two large pieces of RNA (polycistronic transcription), which is then cleansed into mRNAs, tRNAs and rRNAs Mutation rate 10 times higher than that of nDNA Exposed to permanent oxidative stress of free radicals of the RC No protective histones No effective repair mechanism Maternal transmission without recombination with rare exceptions (Williams, 2002) Frequent polymorphisms Modified genetic code AUA methionine instead of isoleucine UGA tryptophane instead of stop codon AGA and AGG encode for a stop codon instead of arginine Autocatalytic RNA (RNA with enzymatic activity in the absence of protein) (Williams, 2002) RNA editing (post-translational modification of the mRNA nucleo tide sequence) (Williams, 2002) Trans-splicing (joining of two separate primary RNA transcripts to form a single mRNA) (Williams, 2002) Taurine-containing uridines (Suzuki et al., 2002)

and replication is produced by the ribonucleoprotein RNAse MRP. In mammals all mitochondria are inherited from the mother with occasional exceptions (Schwartz and Vissing, 2002). Usually, paternally derived mtDNA is labelled with an ubiquitine tag, which invokes rapid proteolysis when it enters the oocyte (McFarland et al., 2002). Because of a bottleneck in early oogenesis (after meiosis the number of mitochondria per germ cell is reduced to <1000 copies), all mtDNA derives from a small number of progenitors and disproportion of certain types of mtDNA may be created (Schapira and Cock, 1999; Leonard and Schapira, 2000a; Schapira, 2002; MITOMAP, 2003). Multiple mtDNA molecules within a mitochondrion are organized in discrete protein-DNA complexes, called nucleoids (Garrido et al., 2003). In these structures mtDNA co-localizes with twinkle-GFP fusion protein, the hmTFA, and singlestranded DNA-binding protein. Nucleoids appear to be the mitochondrial units of inheritance (Elpeleg et al., 2002; Garrido et al., 2003).

Pathogenesis
Mitochondrial DNA mutations

effective repair system and uses a variant genetic code (Table 2). Since each mitochondrion contains 2–10 mtDNA copies and since a cell has up to 10 000 mitochondria, a cell contains thousands of mtDNA copies (polyplasmy) (Leonard and Schapira, 2000a; MITOMAP, 2003). Because mtDNA contains only 37 genes, of which 24 are needed for mtDNA translation, most of the approximately 1000 mitochondrial gene products are encoded by nDNA and imported from the cytosol (DiMauro and Schon, 2003). MtDNA depends on nDNA for its enzymes of replication, transcription, translation and repair. Additionally, mitochondria rely upon the nucleus for most proteins necessary for the mitochondrial function. During their development mitochondria divide and proliferate under nuclear control. MtDNA replication of the H-strand starts from OH and of the L-strand from OL. Polycistronic transcription of the total H- and L-strand is initiated from two different sites within the D-loop (triple stranded) (Schapira and Cock, 1999). An additional transcription initiation site for the H-strand is located adjacent to the 12S rRNA (Schapira and Cock, 1999). For initiation of transcription, binding of the human mitochondrial transcription-factor-A (hmTFA) to the H- and L-strand promoter is required. The transcribed RNA is cleaved into mRNAs, tRNAs and rRNAs. The transfer between mtDNA transcription

Changes in mtDNA sequence can be inherited or somatic (created in situ). MtDNA has a mutation rate of 10–20 times that of nDNA, probably due to a failure of proof-reading by mtDNA polymerases. Normally, all mtDNA of an individual is identical (homoplasmy). Occasionally, a sequence variation generates a dual population of wild type and mutant mtDNA (heteroplasmy). The heteroplasmy rate is the product of the apparently random segregation of wild type to mutant mtDNA during embryogenesis (ratio wild-type to mutant DNA). In some MCPs the Ômutant loadÕ of an affected tissue is directly related to the severity of the phenotype. However, for most MCPs the phenotype is independent of the abundance of mutant mtDNA. Factors other than the heteroplasmy rate within a cell or a mitochondrion, which contribute to the pathogenesis, are the threshold effect [percentage of mutation needed to manifest clinically (dependent on the energy need of a particular tissue)], the nuclear background, age, sex, and environment, resulting in a wide range of phenotypes (McFarland et al., 2002). The threshold for biochemical expression of an mtDNA mutation is believed to be around 60% mutant for mtDNA deletions and >90% mutant for tRNA mutations (Schapira and Cock, 1999; McFarland et al., 2002). MtDNA mutations are usually heteroplasmic [except Leber’s hereditary optic neuropathy (LHON)] and comprise point mutations, deletions and insertions (Schapira and

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Cock, 1999). As there are no introns, no splice site mutations are found. Point mutations are frequently inherited whilst deletions and insertions are usually sporadic. Why mtDNA mutations acquired during life are not transmitted to the next generation is explained by the bottleneck effect. It is speculated that mainly germ cells, which contain wild-type mtDNA survive and are transformed to oocytes. Heteroplasmic germcells are excluded from the differentiation to oocytes. Although mtDNA mutations are well-documented causes of MCP, it is believed that >95% of the MCPs are caused by nDNA mutations (Gillis and Kaye, 2002). Proper assembly and function of RC complexes require approximately 60 ancillary nDNA-encoded proteins (DiMauro and Schon, 2003). Complex-I deficiency accounts for 30% of the RCDs (Benit et al., 2001). Criteria for a pathologically relevant mtDNA mutation are: (i) heteroplasmy, (ii) amount of mutated mtDNA above threshold, (iii) relation to a particular phenotype in >1 unrelated individuals, (iv) absence of the mutation in healthy individuals, except asymptomatic relatives, (v) transferability of the metabolic defect by means of mtDNA in cybrid studies, (vi) the mutation alters an evolutionary and functionally conserved base pair or amino acid (Walker et al., 1996), and (vii) the mutation is correlated with a biochemical defect (McFarland et al., 2002). The pathogenetic role of non-modification of taurin-containing uridines in mutant mitochondrial tRNAs for leucine and lysine in the development of MCPs is under debate (Suzuki et al., 2002).
nDNA mutations

Exogenous factors

Drugs Drugs that were reported to impair mitochondrial functions are acetylsalicylic acid, alcohol, valproic acid (sequesters carnitine, precipitates seizures in MELAS), barbiturates (block complex I), tetracyclines, chloramphenicol (reduces synthesis of mitochondrial proteins and number and size of mitochondria), doxorubicin, germanium and zidovudin (causes mtDNA depletion) (Walker, 2002). There is also increasing evidence that corticosteroid myopathy is due to mitochondrial dysfunction (Mitsui et al., 2002). Oxidative stress Oxidative stress is defined as impairment of cellular functions by free oxygen radicals like OÀ , H2O2, 2 ONOO), OH). Normally the RC generates few free oxygen radicals by the OXPHOS. However, in case of RC dysfunction, the level of free oxygen radicals markedly increases. Free radicals damage DNA, proteins and phospholipids by oxidizing them. Free oxygen radicals are metabolized by SOD1, catalase and glutathion-peroxidase. Vitamin C and a-tocopherol (vitamin E) have also a protective effect. Detoxification of free radicals is a vital function of each cell. This is particularly the case for cells with high-energy consumption, which in turn augments the oxidative stress. Oxidative stress increases with age. As free radicals are particularly prevalent in the brain, its mitochondria are particularly exposed to oxidative stress. Mutations in genes, which encode for detoxifying enzymes, have deleterious effects, like in familial amyotrophic lateral sclerosis (Valentine, 2002).

Mitochondriopathies caused by nDNA mutations follow a Mendelian (autosomal recessive, autosomal dominant or X-linked) pattern of inheritance. In addition to the 70 RC proteins, nDNA located genes encode for approximately 1000 mitochondrial proteins not involved in the RC. Nuclearly encoded peptides involved in the RC are the complex II and the Fe-S Protein 4. nDNA mutations causing MCP are frequently found in highly conserved RC subunits. General features of nuclearly encoded mitochondrial proteins are that they are synthesized in the cytoplasm and that they are imported into the mitochondrion via specific import systems.

Classification of MCPs
In addition to the separation into primary and secondary MCPs, MCPs are classified according to genetic, biochemical or clinical criteria (Tables 3–5). According to genetic criteria a causative mutation resides either in the nDNA or mtDNA and affects RC complex genes or non-RC mitochondrial proteins (Table 3). According to biochemical criteria defects of the inter- and intramitochondrial transport, defects of substrate utilization, defects of the citrate cycle, OXPHOS defects, and

Table 3 Genetic classification of MCPs Disorders due to mutations in mtDNA genes encoding for RC proteins, tRNAs or rRNAs Disorders due to mutations in nDNA genes encoding for RC proteins Disorders due to mutations in nDNA genes encoding for non-RC mitochondrial proteins (Friedreich ataxia, COX-deficient Leigh syndrome, hereditary spastic paraplegia, Table 9) Disorders associated with RC defects due to mutations in nDNA genes encoding for non-mitochondrial proteins

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Table 4 Biochemical classification of mitochondrial diseases Defects of substrate transport Carnitine-palmitoyl-transferase deficiency Primary systemic or muscle carnitine deficiency Secondary carnitine deficiency Defects of substrate utilization PDC deficiency (E1, E2, E3, protein X) Pyruvate-decarboxylase deficiency Pyruvate-carboxylase deficiency Defects of the b-oxidation Defects of the Krebs cycle Fumarase deficiency Ketoglutarate dehydrogenase deficiency Aconitase deficiency Defects of the oxidation-phosphorylation coupling Luft’s syndrome (loose coupling and hypermetabolism) Defects of the RC Complex I, II, III, IV or V defect Combined defects of the RC components Combined defects of the PDC and the RC RC, respiratory chain; PDC, pyruvate-dehydrogenase complex.

defects of the RC are differentiated (Table 4). According to clinical criteria MCPs are classified as single organ diseases or multisystem disorders (Table 5). Single organ MCPs are rare and tend to proceed into multisystem disorders over time. Whether each affected individual should be regarded as a unique phenotype or if there are typical distinct phenotypes is still under debate, also known as the conflict between splitters and lumpers (Fadic and Johns, 1996; Walker et al., 1996). According to the splitters, MCPs are made up of a number of syndromes (actually >40), of which most have become well known because of their widely propagated acronyms (Table 5). As most of these syndromes exhibit individual manifestations, depending on age, some authors recommend individualization of the phenotype description. A valid classification of MCPs will be established not before all genes involved in the biogenesis of mitochondrial molecules are known and when the mechanisms of secondary RC involvement have been fully elucidated (Schapira and Cock, 1999; Wolf and Smeitink, 2002).

Table 5 Clinical classification Acronym/syndrome CPEO KSS Pearson syndrome MELAS MERRF LHON Leigh syndrome MNGIE NARP Wolfram syndrome (DIDMOAD) MIMYCA NIDDM Alpers syndrome CoQ deficiency May–White syndrome Fanconi–Debre–DeToni syndrome Luft syndrome Menkes syndrome Canavan syndrome Ketoazidotic coma Familial MSL PDC deficiency ARCO Clinical manifestations Ophthalmoparesis or ophthalmoplegia, ptosis CPEO, retinitis pigmentosa, elevated CSF protein, cardiac conduction defects, ataxia, deafness, endocrine dysfunction, anaemia Sideroblastic anaemia with variable degree of thrombopenia and neutropenia, hepatic failure, exogenous pancreas insufficiency Stroke-like episodes, diabetes, epilepsy, dementia, ataxia, cortical blindness, optic atrophy, deafness, migraine, cardiomyopathy, vomiting Myopathy, ataxia, dementia, CPEO, deafness, epilepsy Impaired visual acuity, blindness Developmental delay, seizures, upper motor neurone signs, ataxia, optic atrophy, retinitis pigmentosa, CPEO, lactic acidosis, hypotonia Myopathy, neuropathy, gastrointestinal disorder or encephalopathy Sensori-motor polyneuropathy, ataxia, retinitis pigmentosa, mental retardation, dementia, epilepsy Diabetes insipidus, diabetes mellitus, optic atrophy, deafness, neurogenic bladder, intestinal dysmotility Mitochondrial myopathy with cardiomyopathy Maternally inherited non-insulin-dependent diabetes Infantile poliodystrophy, developmental delay, hypotonia, vomiting, failure to thrive, hepatopathy, gliosis, spongiosis with neuronal loss (Chow and Thorburn, 2000) Mental retardation, myopathy Myocloni, ataxia, deafness Mental retardation, renal insufficiency due to tubular dysfunction with aminoacidura, glucosuria, phosphaturia, hyperuricaemia Hyperhidrosis, polyphagia, polydipsia, weakness, fatigue exercise intolerance Epilepsy, developmental delay, hair abnormalities, fragile bones, hypopigmentation, temperature instability Mental retardation, subcortical lesions in the N. dentatus, basal ganglia or brain stem Short stature, ataxia, deafness, episodic daze Symmetric multiple lipoma Absent corpus callosum, absent pyramids, ectopic inferior olives, rarefication of neutrophils Sensory neuropathy, dysarthria and ophthalmoparesis

CPEO, chronic progressive external ophthalmoplegia; KSS, Kearns–Sayre syndrome; MELAS, myopathy, encephalopathy, lactic acidosis and stroke-like-episodes; MERRF, myoclonic epilepsy and ragged-red fibres; LHON, Leber’s hereditary optic neuropathy; MNGIE, myoneurogastrointestinal encephalopathy; NARP, neuropathy, ataxia, retinitis pigmentosa; CoQ, coenzyme Q.

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Frequency
At the beginning of their recognition, MCPs were regarded rare disorders. Meanwhile it turned out, that they are more frequent than previously thought. In children, approximately one-third of the inherited metabolic disorders are attributable to MCPs (Sperl, 1997). The prevalence of mtDNA mutations in adults is estimated to be 1:50 000 (Chinnery and Turnbull, 1997). In a recent report the incidence of MCPs was estimated to be 4–5/100 000 life births, but may be as high as 1 in 5000–10 000 life births (Gillis and Kaye, 2002; McFarland et al., 2002). Based upon our own data we calculated a prevalence of 1:25 000 (unpublished data). Most likely, the prevalence of MCPs is even higher.

Clinical presentation
Onset

The onset of MCPs ranges from early embryogenesis to late adulthood. Accordingly, MCPs can present at any age (Wolf and Smeitink, 2002).
General features

varying thresholds of biochemical expression for both the mutation and the tissue involved, and the modulating effect of nuclear and other mitochondrial genes (Leonard and Schapira, 2000b). There is no single identifying feature of MCP. In the majority of the cases patients have combinations of problems with varying onset (Table 6). Tissues or organs with high oxygen and energy demand and substrate utilization, like muscle, brain, heart, liver and epithelium (retina, ear, guts, renal tubules), are predominantly affected (Sperl, 1997; Wolf and Smeitink, 2002). Thus, MCPs most commonly present with neuromuscular symptoms. As a rule of thumb one should think of MCP if a common disease has atypical features that set it apart from the back, if several organ systems are involved, or if there are recurrent setbacks or flare-ups in a chronic disease (The Mitochondrial Disease Foundation, 2003). MCPs should be particularly considered if features listed in Table 6 remain unexplained and occur alone or in combination. In rare cases MCP manifest during general anaesthesia with malignant hyperthermia-like features or weaning problems after general anaesthesia (Finsterer et al., 1998).
Specific MCP phenotypes and syndromes

A striking feature of MCPs is their clinical heterogeneity, ranging from single organ involvement to severe multisystem disease (Leonard and Schapira, 2000a). This variability may be due to the rate of heteroplasmy,

Chronic progressive external ophthalmoplegia Chronic progressive external ophthalmoplegia (CPEO) is the commonest manifestation of an mtDNA mutation and is, at onset (birth to sixth decade),

Table 6 Frequent manifestations of MCPs (Fadic and Johns, 1996; Walker et al., 1996; Finsterer, 1997; Sperl, 1997; Leonard and Schapira, 2000a) PNS Myopathy [weakness (ptosis, ophthalmoparesis, limbs, masticatory muscles), wasting, fasciculations, myokymia, hypotonia, stiffness, myotonia, reduced or absent reflexes, fatigue, exercise intolerance, cramps, muscle aching, myoglobinuria, lactic acidosis], polyneuropathy [weakness, wasting, reduced or absent tendon reflexes, fasciculations, cramps, neuropathic pain (dysaesthesia, paraesthesia), restless legs, gastro-oesophageal reflux, delayed gastric emptying, sicca syndrome, absent or excessive sweating] Developmental delay, mental retardation or regression, early and late-onset dementia, fatigue, epilepsy, myocloni, migraine, stroke-like episodes, dystonia, dyskinesia, atypical cerebral palsy, leucencephalopathy, extrapyramidal signs, upper motor neurone signs, cerebellar signs, basal ganglia calcifications, weakness, psychosis, central fatigue, myelopathy, coma Short stature, polyphagia, failure to gain weight, diabetes mellitus and insipidus, hypoglycaemia, thyroid and parathyroid dysfunction, amenorrhoea, hypogonadism, delayed puberty, gynaecomastia, osteoporosis, hyperlipidaemia, hypopituitarism, hypoparathyroidism, hyperaldosteronism, adrenocorticotropin deficiency Impulse generation and conduction defects, myocardial thickening, left ventricular hypertrabeculation/non-compaction, heart failure (exertional dyspnoea, leg oedema, rales) Hypacusis, sensorineural deafness, tinnitus, peripheral vertigo Cataract, glaucoma, pigmentary retinopathy, optic atrophy, uveitis, acquired strabism Paradontosis, impaired swallowing, dysphagia, chronic vomiting, inability to produce digestive enzymes, hepatopathy with liver failure and hyperammonaemia, recurrent diarrhoea (due to exogenous pancreas insufficiency), low production of digestive enzymes, villous atrophy, pancreatitis, constipation, sicca syndrome, failure to thrive, anorexia, underweight or difficulties in maintaining or gaining weight despite adequate calorie intake, malabsorption, intestinal pseudo-obstruction Renal tubular insufficiency, Fanconi syndrome, renal cysts Sideroblastic anaemia, leucopenia, thrombopenia, pancytopenia

CNS

Endocrinium

Heart Ears Eyes Intestines

Kidney Bone marrow

PNS, peripheral nervous system; CNS, central nervous system.

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characterized by ophthalmoplegia and ptosis (Holt et al., 1989). Later on cataracts, retinitis pigmentosa, deafness, fatigue, ataxia, limb weakness, neuropathy, cardiomyopathy and renal insufficiency may develop (Schapira and Cock, 1999; McFarland et al., 2002). The particular susceptibility of the extra-ocular muscles is explained by the three to four times greater mitochondrial volume fraction compared with limb muscles (Schapira and Cock, 1999). The clinical course is usually benign in that additional tissue or organ failure is rare with low risk of serious disability (Table 5). CPEO is due to mtDNA deletions (40% of the cases), nDNA mutations, and point mutations in mtDNA encoded tRNAs (Tables 7–9) (Zeviani et al., 1989). Kearns–Sayre syndrome Kearns–Sayre syndrome (KSS) is a subtype of CPEO with pigmentary retinopathy, cardiac conduction defects, cerebellar ataxia, raised CSF protein and onset <20 years (Kearns and Sayre, 1958). A proximal myopathy develops as the disease progresses. Additional features may be mental retardation, deafness, bulbar symptoms, stroke-like episodes, endocrine dysfunction, sideroblastic anaemia (Pearson syndrome) and lactic acidosis (Schapira and Cock, 1999). Dysphagia in KSS may be due to cricopharyngeal achalasia (Kornblum et al., 2001). The prognosis of KSS is worse than that of CPEO and patients rarely survive beyond the age of 30. KSS is due to sporadic, single large deletions ranging from 1.3 to 8.8 kb (90% of the cases) or duplications (Table 8). The origins of replication and transcription within the mtDNA are usually spared (Schapira and Cock, 1999). Pearson syndrome Pearson syndrome, first described in 1979 (Pearson et al., 1979), is a childhood disorder, characterized by refractory sideroblastic anaemia, and exocrine pancreatic dysfunction. Patients present at early infancy with a refractory, transfusion-dependent, macrocytic anaemia, neutropenia, and thrombocytopenia. Bone marrow biopsy is characterized by normal cellularity, but vacuolization of the precursor cells (Schapira and Cock, 1999). Additional features are failure to thrive, and chronic diarrhoea with villous atrophy. With disease progression, hepatomegaly, raised transaminases, hyperbilirubinaemia, coagulopathy and tubular dysfunction with aminoaciduria and glucosuria (Fanconi’s syndrome) may occur (Schapira and Cock, 1999). In single patients hepatic failure is the predominant manifestation (Gillis and Kaye, 2002). In patients who survive beyond infancy the syndrome evolves into KSS. Pearson syndrome is usually due to heteroplasmic mtDNA deletions with a heteroplasmy

rate of up to 90% in blood (Table 8) (McFarland et al., 2002). Myopathy, encephalopathy, lactacidosis and stroke-like episodes The commonest of the encephalomyopathies is myopathy, encephalopathy, lactacidosis and stroke-like episodes (MELAS), of which the key features were first described in 1984 (Pavlakis et al., 1984). Onset is usually between childhood and adolescence. Typical features comprise stroke-like episodes with hemiparesis, hemianopsia, migraine, nausea and vomiting. Additional features are deafness, diabetes, seizures, dementia, ataxia, cortical blindness, optic atrophy, pigmentary retinopathy, deafness, dilative cardiomyopathy, myopathy (87% of the cases), exercise intolerance, lactic acidosis and short stature (55% of the cases) (Schapira and Cock, 1999; McFarland et al., 2002). Many ÔoverlapÕ cases have been described with additional features like CPEO, cardiomyopathy, myocloni and ataxia. Frequently, stroke-like episodes are located parieto-occipitally, but the remainder of the cortex may be also affected (Leonard and Schapira, 2000a). The strokes do not conform to vascular territories and are assumed due to metabolic derangements, spreading beyond an ischaemic focus, possibly precipitated by aberrant arterial tone due to defective mitochondria in the smooth muscle of the vasculature or stenosis of arterioles due to enlarged endothelial mitochondria (Hasegawa et al., 1991; DiMauro, 1996; McFarland et al., 2002). The metabolic hypothesis envisions groups of neurons in the cortex harbouring very high levels of mutant mtDNA, just below the threshold level. A sudden increase in energy demand imposed on these cells, like in a seizure, could cause their decompensation (DiMauro, 1996). Stroke-like episodes invariably occur before age 40, why MELAS enters into the differential diagnosis of stroke in the young (Leonard and Schapira, 2000a). Typically, these recurrent episodes are non-disabling. Computed tomography (CT) and magnetic resonance imaging (MRI) show multiple white matter lesions in >80% of the cases (Schapira and Cock, 1999). Basal ganglia calcification is common. The course is slowly progressive. MELAS is not only due to mtDNA point mutations in tRNA and mRNA genes but also due to small-scale mtDNA deletions (Tables 7 and 8). Myoclonic epilepsy and ragged-red fibres Myoclonic epilepsy and ragged-red fibres (MERRF), first described in 1973 (Tsaris et al., 1973), usually presents between childhood and early adulthood. Typical features include myoclonic epilepsy with photosensitive general tonic–clonic seizures, myopathy with

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Table 7 MtDNA mutations published until January 2004 (Servidei, 2004) Transitions A>G tRNA genes MELAS MERRF MERRF/MELAS CPEO CPEO/multiple sclerosis CPEO/myoclonus CPEO/myopathy/sudden death CPEO/multisystem CPEO/diabetes/ataxia Myopathy Myopathy/CMP (MIMYCA) Myopathy/painful stiffness Myopathy/dystonia Hypertrophic CMP Multisystem/CMP Dementia/chorea EMP/Diabetes Diabetes/deafness Sensori-neural deafness Congenital multisystem EMP G>A C>T T>C Transversions T>G T>A G>T C>G A>T

3243, 3252 3260, 5814 8344 3243 5692

1642 583 8363 4309, 5703 12 315 4298 8342 3256

3271 3291 8356 8356, 7512 4274, 4285 12 311

3251 3264 618,3250 4409 3254

3288, 3302 12 320 3260 3243 3243 4300, 4295 1555, 8296 4269

5521

15 990 3303

9997 8363 5549 4320 14 709

3243, 8296 7445 15 923 3243

7511 15 915, 1606 5540, 8328 7543 3243

Sudden death/multisystem disorder Exercise intolerance/myoglobinuria Intestinal dysfunction/EMP MILS (adult onset) Idiopathic sideroblastic anaemia mRNA genes LHON

10 044 606 8313 8344 12 301 4917 3460, 5244 7444, 9438 9804, 11 778 13 708, 15 257 15 812 14 459 3394, 4160 4216, 9101 14 484 1644

LHON/dystonia MILS NARP NARP/MILS MELAS MELAS/bilateral striatal necrosis Bilateral striatal necrosis Exercise intolerance/myoglobinuria

11 696

14 596 8993 8993, 9176 9957 3308 8851, 9176 8993 8993 8993

13 513

EMP Myopathy Hypertrophic CMP LHON/MELAS Idiopathic sideroblastic anaemia rRNA genes Aminoglykosid-induced deafness

15 615, 11 832 14 846, 15 059 15 084, 15 168 15 723, 15 498 9952, 6930 15 762 15 243 13 513 6721, 6742 1555

KSS, Kearns–Sayre syndrome; CPEO, chronic progressive external ophthalmoplegia; CMP, cardiomyopathy; EMP, encephalomyopathy. Numbers given represent the mutated nucleotide.

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Table 8 MCPs due to mtDNA deletions or insertions (Servidei, 2004) Deletions 1 KSS, Pearson syndrome/KSS, diabetes/deafness/maculopathy, diabetes/deafness/optic atrophy, CPEO, MELAS, myopathy/neuropathy, Wolfram syndrome (DIDMOAD), ataxia/leucodystrophy, mitochondrial encephalomyopathy (T-deletion at nt 3271), exercise intolerance/ recurrent myoglobinuria (15 and 24 bp microdeletion), motor neuron disease-like (5 bp microdeletion), MELAS/Parkinsonism (4 bp microdeletion at nt 14 787) 2 Deletion and duplication Diabetes/deafness, diarrhoea/villous atrophy/multisystem disorder, Pearson/multisystem Insertions 1 Single insertions Deafness/ataxia/myocloni (C-insertion at nt 7472), mitochondrial encephalomyopathy (T-insertion at nt 5537) 2 Tandem duplications KSS, myopathy (209 tandem insertion), diabetes/deafness, tubulopathy/diabetes/ataxia, Pearson syndrome/multisystem disorder, chronic diarrhoea/villous atrophy, multisystem

ptosis and ophthalmoparesis, cerebellar ataxia, dementia and deafness. Myocloni occur alone or in association with generalized seizures. Seizures respond well to valproic acid (should be avoided), clonazepam, piracetam or levetirazetam. Other features include pes cavus, polyneuropathy, optic atrophy, dorsal column loss, lipomatosis, cardiomyopathy, heart block and heart failure (Schapira and Cock, 1999; McFarland et al., 2002). Central nervous system (CNS) pathology comprises gliosis in the dentate nuclei, globus pallidus, red nuclei, substantia nigra, inferior olives, optic nerves and cerebellar cortex and demyelination in the spinothalamic tracts, posterior columns, and corticospinal tracts. Disease severity ranges from minor, non-disabling symptoms to progressive, ultimately fatal disease. MERRF is caused by tRNALys point mutations in the mtDNA (Table 7). MERRF is the exception to the rule that a particular phenotype is caused by various mutations in different genes (DiMauro and Schon, 2003). Leigh syndrome Leigh syndrome, also known as subacute necrotizing encephalomyopathy and first described in 1977 (Willems et al., 1977), is a neuropathologically defined multisystem disorder of infancy. The clinical picture is dominated by weakness, hypotonia, seizures, developmental delay and lactic acidosis. Additional features may be pyramidal signs, dystonia, optic atrophy, nystagmus, retinitis pigmentosa, ataxia deafness, neuropathy, CPEO, recurrent vomiting and respiratory failure. Typical CT or MRI abnormalities include bilateral, symmetric signal alterations in the spinal cord, upper brainstem, cerebellum, midbrain, thalamus, and basal ganglia, with or without cortical changes, and basal ganglia calcifications in MELAS. Leigh syndrome is caused by mutations in mtDNA or nDNA genes encoding for the PDC or RC components. A small proportion is due to maternally inherited mtDNA mRNA mutations (MILS) (Table 7). Complex-IV (COX)-deficient Leigh syndrome is due to mutations in

the SURF1, NDUFS or SDHA genes (Table 9) (Leonard and Schapira, 2000b). These genes encode for mitochondrial proteins involved in the maintenance of complex-IV activity by guaranteeing the correct holoenzyme assembly (Table 8). Leber’s hereditary optic neuropathy Leber’s hereditary optic neuropathy is the commonest cause of maternally inherited blindness in otherwise healthy young men. The clinical condition was first described in 1871 and the first mtDNA mutation detected in 1988 (Wallace et al., 1988). LHON is due to homoplasmic mtDNA mutations affecting mRNA genes (Table 7). Three primary LHON mutations [A3460G (13% of the cases), A11778G (70%), T14484C (13%)] account for >95% of the cases (Man et al., 2002; McFarland et al., 2002). Mutations at nt14459 (LHON with dystonia) and nt4160 (LHON with CNS disease) may be also classified as primary, although atypical clinically. Only 50% of males and 10% of females, harbouring a primary LHON mutation, actually develop LHON (Man et al., 2002). The incomplete penetrance and the predominance of males suggest factors other than mtDNA mutations (secondary LHON mutations, nDNA) to play a pathogenic role. However, the exact pathogenic role of secondary LHON mutations is under debate. Onset is the late adolescence or early adulthood with subacute, painless, bilateral visual loss. By age 50 all patients carrying the mutation are clinically affected. Funduscopy at onset reveals peripapillary teleangiectasia (disappears with disease progression), disc pseudo-oedema and tortuous retinal arteries. Later on, optic atrophy develops. In single cases, other tissues, like skeletal muscle, heart, cerebrum (dystonia), are additionally affected. Some female LHON patients present with a multiple sclerosis-like phenotype (Harding and Hammans, 1992). White matter lesions were also reported in a male with the A3460G mutation (Lev et al., 2002). Some mutations are associated with early onset dystonia

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Table 9 Known or suspected nDNA mutations leading to MCP (DiMauro, 1996; Sue and Schon, 2000; Zeviani et al., 2000; DiMauro and Schon, 2003; Pestronk, 2003; Servidei, 2003) Gene Location TR EMD Clinical features

Genes encoding for RC proteins NDUFS1 2q33-q34 NDUFS2 1q23 NDUFS4 5q11.1 11 NDUFS7 NDUFS8 NDUFV1 SDHA SDHB 12 SDHC SDHD BCS1L SURF1 SCO1 13 SCO2 COX10 COX15 LRPPRC Taffazin Paraplegin 14 Ubiquinone 19p13 11q13 11q13 5p15 1p36.1-p35 1q21 11q23 2q33–37 9q34 17p13.1 22q13 17p13.1-q11.1 UK 2p16 Xq28 16q24.3 UK

ar ar ar ar ar ar ar, ad ad ad ad ar ar ar ar ar UK ar X ar UK

CI CI CI CI CI CI CII CII CII CII CIII CIV CIV CIV CIV CIV CIV UK UK UK UK UK UK UK

Childhood encephalopathy (Pestronk, 2003) CMP, encephalopathy (Pestronk, 2003) Multisystem complex I deficiency (Van den Heuvel et al., 1998; Benit et al., 2003) Leigh syndrome (Triepels et al., 1999, 2001) Leigh syndrome (Loeffen et al., 1998, 2001) Leucodystrophy/myoclonic epilepsy (Schuelke et al., 1999; Benit et al., 2001) Leigh syndrome (Bourgeron et al., 1995) Hereditary paraganglioma (Ackrell, 2002; Niemann et al., 2003) Benign vascularized head and neck tumours (Pestronk, 2003) Hereditary paraganglioma (Ackrell, 2002; Niemann et al., 2003) Gracile syndrome (de Lonlay et al., 2001; Fellman, 2002; Visapaa et al., 2002) Leigh syndrome (Tiranti et al., 1998) Hepatopathy, ketoacidotic coma (Shoubridge, 2001) Infantile cardioencephalomyopathy (Walker et al., 1996; Papadopoulou et al., 1999) Encephalopathy/renal tubulopathy (Sacconi et al., 2003) Defect haem-biosynthesis (Antonicka et al., 2003; Sacconi et al., 2003) Leigh syndrome (Pestronk, 2003) Barth syndrome (Pestronk, 2003) Hereditary spastic paraplegia Familial cerebellar ataxia (Musumeci et al., 2001) Episodic ataxia, epilepsy, encephalopathy (Pestronk, 2003) Developmental delay, encephalopathy (Pestronk, 2003) Multisystem (Huckriede and Agsteribbe, 1994; Hansen et al., 2003) Mohr-Tranebjaerg syndrome (deafness/dystonia) (Bauer et al., 1999; Paschen et al., 2000; Bauer and Neupert, 2001; Hofmann et al., 2002; Roesch et al., 2002) Myopathy, CPEO, psychosis (Chen, 2002; Siciliano et al., 2003) Microcephaly (Pestronk, 2003) MNGIE (Hirano et al., 1994, 2001; Nishino et al., 1999, 2001) MtDNA depletion (SMA-like) (Pestronk, 2003) CPEO (Suomalainen et al., 1995; Elpeleg et al., 2002; Lewis et al., 2002; Agostino et al., 2003) Friedreich ataxia (Lodi et al., 2001, 2002a) CMP, myopathy, hepatomegaly, retinopathy (Pestronk, 2003) HHH syndrome (Pestronk, 2003) Neuropathy, dysarthria, CPEO (SANDO) (Fadic et al., 1997; Van Goethem et al., 2003) Optic atrophy (Pestronk, 2003) Optic atrophy (Pestronk, 2003) Seizures, encephalopathy (Pestronk, 2003) Hepatopathy, hypotonia, failure to thrive (Pestronk, 2003) Encephalopathy, hepatomegaly CPEO (Kaukonen et al., 1996) CPEO (Kaukonen et al., 1999) Wolfram syndrome (DIDMOAD) (Barrientos et al., 1996a,b) Developmental delay (Pestronk, 2003) Hypocarnitineaemia, hypolysineaemia (Pestronk, 2003) Menkes disease, occipital horn syndrome (Pestronk, 2003) Recurrent vomiting (Pestronk, 2003) MtDNA depletion (hepathopathy, hyperreflexia) (Pestronk, 2003)

Genes encoding for non-RC mitochondrial proteins Pyruvate dehydrogenase Xp22.2-p22.1 ar Pyruvate carboxylase 11q13.4-q13.5 ar 15 HSP60 2q24–34 UK DDP1/TIMM8A 16 17 ANT1 (SCL25A4) SCL25A19 Thymidin-phosphokinase Thymidine kinase 19 Twinkle 18 FRDA (frataxin) HADHA and B Ornithine transporter POLG1 (polymerase c) 20 OPA1 OPA2 HMGCS2 DGUOK HMC-CoA-lyase UK UK UK Fumarate hydrolase DCAR ATPase Lipoamide dehydrogenase Deoxyguanosine kinase 4q34–35 17q25.3 22q13.32qter 16q22 10q23.3-24.3 9q13 2p23 13q14 15q25 3q28 18q12.2-q12.3 1p13-p12 2p13 1pter-p33 3p14.1-21.2) 4p34-q35 4p16, 4q22-q24 1q42.1 8q21.3 Xq12 7q31-q32 2p13 ad ar ar ar ad ar ar ar ad,ar ad ad ar ar ar ad ad ar ar ar X ar ar Xq22 X

MD UK MD DEPL MD RNAproc b-Oxidation UK MPG UK UK UK UK UK MD MD SD, MD UK UK UK UK UK

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Table 9 (Continued) Gene Location TR EMD Clinical features

Genes encoding for non-mitochondrial proteins ATP7B 13q14.3 ar Huntingtin 4p16.3 ad ALC7A3, 9 2p16 ar

UK CII-IV CI-IV

Wilson’s disease (Leonard and Schapira, 2000b) Huntington’s disease Cystinuria, seizures, somatic/developmental delay (Parvari et al., 2001)

No locus; Luft’s disease (Luft et al., 1962); autosomal recessive CMP and ophthalmoplegia (ARCO) (Carrozzo et al., 1998); CPEO/CMP (MD) 21 (Bohlega et al., 1996); hmTFA depletion (DEPL) (Poulton et al., 1994); myopathy (MD) (Yuzaki et al., 1989); sideroblastic anaemia/myopathy (MD) (Casademont et al., 1994); progressive encephalomyopathy (MD) (Cormier et al., 1991); recurrent myoglobinuria (MD) (Ohno et al., 1991); familial CMP (MD) (Suomalainen et al., 1992); MERRF (MD) (Blumenthal et al., 1998); infantile myopathy (DEPL) (Moraes et al., 1991); myopathy in childhood (DEPL) (Tritschler et al., 1992); infantile hepatopathy (DEPL) (Mazziotta et al., 1992); encephalomyopathy (DEPL) (Kirches et al., 1998); encephalomyopathy/hepatopathy (DEPL) (Naviaux et al., 1999); Parkinson disease (Leonard and Schapira, 2000b); Alzheimer’s disease (Leonard and Schapira, 2000b); pyruvate-decarboxylase deficiency (Pestronk, 2003); Stuve-Wiedemann syndrome (Pestronk, 2003); triose-phosphate isomerase (Pestronk, 2003). TR, transmission; EMD, effect on mitochondrial DNA; SDHA, succinate-dehydrogenase 2; UK, unknown; MP, myopathy; Thymphos, thymidine-phosphorylase; MD, multiple deletions; SD, single deletion; DEPL, mtDNA depletion; CMP, cardiomyopathy; SANDO, sensory ataxic neuropathy; dysarthria and ophthalmoparesis; ANT1, adenine nucleotide translocator 1; MPG, mitochondrial DNA polymerase-c; hmTFA, human mitochondrial transcription-factor-A; HADHA, B, hydroxyacyl-CoA-dehydrogenase a, b-subunit; HMG, 3-hydroxy-3-methyl-glutaryl; DCAR, 2.4-dienoyl-CoA-reductase.

accompanied by bilateral basal ganglia degeneration (McFarland et al., 2002). Neuropathy, ataxia, retinitis pigmentosa The neuropathy, ataxia, retinitis pigmentosa (NARP) syndrome, first described in 1990 (Holt et al., 1990), is characterized by weakness due to motor neuropathy, sensory disturbances, cerebellar ataxia and retinitis pigmentosa. Additional features may be developmental delay, mental retardation, dementia, ataxia, cardiomyopathy and epilepsy. There is no clinical or histological evidence of myopathy in NARP. NARP is due to mtDNA mutations encoding for mRNA genes (ATPase6) (Table 7) (McFarland et al., 2002). Myoneurogastrointestinal encephalopathy Myoneurogastrointestinal encephalopathy (MNGIE), also termed polyneuropathy, ophthalmoplegia, leucencephalopathy, intestinal pseudo-obstruction (POLIP), is a multisystem disorder, first described in 1983 (Ionasescu, 1983). MNGIE is characterized by gastrointestinal dysmotility, manifesting before age 20 years as episodic nausea, vomiting, gastroparesis, progressive intestinal pseudo-obstruction, abdominal pain, dilation and dysmotility of oesophagus, stomach and small intestine, diarrhoea, and malabsorption with progressive malnutrition, leading to death around 40 years of age. Additional features include generalized myopathy with CPEO, cognitive decline due to leucencephalopathy, retinitis pigmentosa, deafness, hoarseness, dysarthria and polyneuropathy. Post-mortem changes include visceral neuropathy (loss of neurons and fibrosis in the coeliac, mesenteric and Auerbach plexuses) and scleroderma-like changes (Schapira and

Cock, 1999). Recently, MNGIE has been shown to result from mutations in the nDNA-encoded gene for the thymidine-phosphorylase (Table 9) (Nishino et al., 1999, 2001; DiMauro and Schon, 2003). Thymidinephosphorylase is likely to have an important role in nucleoside metabolism by regulating the availability of thymidine for DNA synthesis. Additional functions of the enzyme include the angiogenesis and cell trophism (Gillis and Kaye, 2002). MtDNA depletion MtDNA depletion of various degrees leads to a fatal multisystem infantile disorder, first described in 1991 (Moraes et al., 1991). The clinical picture is characterized by weakness, hypotonia, CPEO and severe lactic acidosis. Additional features may be hepatopathy, Fanconi syndrome, encephalopathy, seizures, cardiomyopathy and cataract (Moraes et al., 1991; McFarland et al., 2002). Total DNA levels in these patients are below 35% of those in controls. No mtDNA mutations are found in these patients. The underlying defect is an impaired replication or maintenance of mtDNA due to nDNA mutations (Table 9).
Other MCPs

In addition to the syndromes mentioned above, other MCPs have been described (Tables 5 and 9). They may be due to mtDNA or nDNA mutations and may primarily or secondarily impair the RC or mitochondrial pathways other than the RC. MCPs due to mutations in nuclear genes affecting the RC include: hereditary paragangliomas caused by mutations in genes encoding for the subunits SDHB,

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SDHC and SDHD of complex-II (Table 9) (Ackrell, 2002; Niemann et al., 2003); MCPs manifesting as hepatopathy, cardiomyopathy, encephalopathy, or tubulopathy due to mutations in genes encoding for enzymes involved in the COX assembly, like SCO1 and SCO2 (Table 9) (Schapira, 2002); hereditary spastic paraplegia with lower limb paraspasticity, polyneuropathy with distal sensory disturbances, amyotrophy and urinary dysfunction due to mutations in the paraplegin gene. Muscle biopsy from these patients shows ragged-red fibres (Schapira, 2002); Gracile syndrome (Fellman, 2002); Barth syndrome due to taffazin mutations, most likely affecting the cardiolipin synthesis (cardiolipin is markedly decreased in skeletal muscle, myocardium and platelets in these patients) (DiMauro and Schon, 2003; Pestronk, 2003) and a number of other disorders (Table 9). MCPs due to mutations in nuclear genes encoding for non-RC mitochondrial proteins include: lethal multisystem disease due to HSP60 gene mutations (Huck2 riede and Agsteribbe, 1994). HSP60 is a chaperone needed for the folding of proteins imported into the mitochondrion (DiMauro and Schon, 2003); X-linked Mohr-Tranebjaerg syndrome, characterized by deafness, cataract, blindness, dystonia, dysphagia and paranoia, due to mutations in the gene encoding for the deafness-dystonia protein (DDP1/TIM8A) (Hofmann et al., 2002); Friedreich ataxia due to a GAA triplet expansion in intron 1 of the frataxin gene, affecting the mitochondria because of its involvement in RNA processing and the intramitochondrial iron handling, leading to iron accumulation, increased sensitivity to oxidative stress and deficient RC activity (Lodi et al., 2002a; Schapira, 2002). There are indications that the mutation results in a defect of iron/sulphur protein construction (Schapira, 2002). Iron is a pro-oxidant and the defect in Friedreich ataxia is identical to that seen in the mouse model of oxidative stress; Wolfram syndrome (Barrientos et al., 1996a); Menkes disease (Pestronk, 2003) and a number of other disorders (Table 9). MCPs due to mutations in nuclear genes encoding for non-mitochondrial proteins include: Wilson’s disease due to mutations in the ATPase gene (Table 9); Huntington’s disease, due to a CAG-repeat expansion in the Huntingtin gene, affecting complex II, III and IV (Table 9); and a syndrome characterized by cystinuria, seizures and developmental delay (Table 9). In a number of disorders a genetic background is evident but no candidate gene has been identified yet, like in Parkinson’s disease due to aconitin deficiency, or in Alzheimer’s disease, frequently associated with COX defects (Table 9) (DiMauro and Schon, 2003). Secondary RC involvement occurs particularly in other inborn errors of metabolism, such as fatty-acidoxidation disorders, thiamine-responsive megaloblastic

anaemia and various neurodegenerative disorders of childhood (Wolf and Smeitink, 2002). Whether corticosteroid-responsive idiopathic myelofibrosis is a MCP, remains speculative.

Diagnosis
Diagnosing MCP is a challenge because of the genetic heterogeneity, phenocopy and the lacking golden standard. The diagnostic approach to a patient with suspected MCP has to be individualized and requires an integral approach, incorporating clinical, electrophysiological, imaging, histological, biochemical and genetic investigations (Table 10) (Fadic and Johns, 1996; Chinnery and Turnbull, 1997). Because of the diagnostic difficulties and because most of the cases follow a slowly progressive course, patients have to be regularly and vigilantly pursued, preferentially always by the 3 same doctor. Many MCPs are sporadic and do not fit into one of the described particular categories (Chinnery and Turnbull, 1997). However, certain clinical features, particularly when in combination, are strongly suggestive of MCP. MCP should be also considered when dealing with an unexplained association of manifestations with progressive course, involving seemingly unrelated organs (Gillis and Kaye, 2002). Myopathy with or without lactic acidosis is the most common presenting feature (Finsterer et al., 2001). Combinations of clinical features like deafness, cardiomyopathy and diabetes together with encephalopathy and myopathy are highly susceptible of MCP and should be regarded as red flags (Leonard and Schapira, 2000a). The combination of myopathy and deafness is also highly suggestive of MCP. MCP patients often have short stature, deafness and ptosis (Chinnery and Turnbull, 1997). Mitochondrial stroke is often associated with migraine. MCP should also be suspected if there is leucencephalopathy of undetermined cause, particularly if multiple sclerosis and leucodystrophy have been ruled out (Nardin and Johns, 2001). If a patient has a classical phenotype for maternally inherited MCP (MELAS, MERRF, LHON), appropriate mtDNA studies should be carried out first (Fig. 1). If the phenotype is typical for an nDNAinherited MCP (MNGIE), the clinician should proceed with genetic studies (Gillis and Kaye, 2002). If the phenotype is non-specific, but highly suggestive of MCP, one should start with blood, urine and CSF studies, and if negative, proceed with electrophysiological and neuroimaging studies and investigations of potentially affected organs other than the nervous system (Fig. 1). If negative a muscle biopsy and biochemical investigations should be carried out (Fig. 1) (Gillis and Kaye, 2002; McFarland et al., 2002).

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Table 10 Diagnostic work-up for suspected MCPs P Blood Glucose, HbA1c, glucose tolerance test Creatine-kinase, aspartate, alanine transferase, lactate dehydrogenase, aldolase Trijodthyronine, thyroxine, thyroidea-stimulating hormone Blood-urea-nitrogen, creatinin, creatinin clearance, uric acid, electrolytes Blood cell counts Liver function parameters, including ammonia Lactate and pyruvate at rest and under standardized stress [lactate/pyruvate ratio >20 (RCD, Krebs cycle defect), <10 (PDC defect)] Ketones (b-hydroxybutyric acid/acetic acid ratio >2 (RCD), <1 (Krebs cycle or PDC defect) Amino acids Organic acids (3-methyl-glutaconic-acid, ethylmalonic-acid, dicarboxylic-acid, tiglylglycine, butyrylglycine, 2-ethyl-hydracryl, 2-methyl-succinate, isovalerylglycine) Venous oxygen concentration under stress Free carnitine, total carnitine, acetyl carnitine Free fatty acids Coenzyme Q10 Urine Amino acids, organic acids, ketones, free carnitine, total carnitine, acetyl-carnitine, lactate/24 h CSF Lactate, pyruvate, ketones, amino acids, organic acids, protein, glucose, cells, oligoclonal bands Neuroelectrophysiology Electromyography, nerve conduction, electroencephalography, repetitive nerve stimulation, transcranial magnetic stimulation, visually evoked potentials Cardiac investigations ECG, 24hAECG, echocardiography, chest X-ray, cMRI, coronary angiography Ophthalomologic investigations Visual acuity, fields, slit lamp, funduscopy, retinogram, intraocular pressure Otologic investigation Neuroimaging Cerebral CT/MRI, SPECT Magnetic resonance spectroscopy Proton spectroscopy (in-vivo lactate determination) Phosphorus spectroscopy (in-vivo ATP determination) Biopsy of muscle, nerve, liver, kidney, skin (histology, immunehistology, electron microscopy, spectrophotometry, polarography, immunoblot) DNA nDNA and mtDNA analysis in blood, muscle or other tissues if a patient fits into a specific, well described MCP phenotype S T

x x x x x x x x x x x

x x x x

x x x x x x x x

x x x x

x x x x x x x

x

x

x

P, initial laboratory investigation; S, secondary laboratory investigation; T, tertiary laboratory investigation; ECG, electrocardiogram; 24 h AECG: 24 h ambulatory ECG.

History

developmental delay, should be particularly addressed (McFarland et al., 2002).
Clinical neurologic investigation

The most frequent symptoms patients complain about at diagnosis are myalgia, fatigue, weakness, muscle cramps, muscle stiffness, double vision, sensory disturbances, deafness, wasting and ptosis (Finsterer et al., 2001). With disease progression, the history may become positive for additional features listed in Table 6. In single cases, ischaemic stroke may be the only manifestation of MCP (Jackson et al., 1995; Martinez-Fernandez et al., 2001). When taking the history issues such as maternal health, obstetric history, family history of neonatal or childhood deaths, deafness, diabetes, cardiac disease, visual impairment, and

On clinical neurologic investigation there may be short stature, facial dysmorphism, mental retardation, dementia, impaired consciousness, impaired visual acuity, double vision, visual field defect, nystagmus, hypacusis, deafness, dysarthria, dry mouth, reduced gag reflex, exaggerated masseter reflex, weakness [limb, lid (ptosis), gaze paresis, eye muscles (ophthalmoparesis), chewing], wasting, hypotonia, reduced deep tendon reflexes, long tract signs (upper motor neurone signs,

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Clinical presentation

Specific, recognizable MCP phenotype (single or multiple manifestations)

Non-specific phenotype, suggestive of MCP

Classic for mtDNA inherited MCP

Classic for nDNA inherited MCP

Investigations of blood, urine or CSF

Electromyography

Neuroimaging

abnormal mtDNA mutations causing MELAS, MERRF, LHON nDNA mutations causing MNGIE, Leigh-syndrome

abnormal

abnormal

Muscle biopsy, biochemical investigations

MRS

DNA-analysis

Endocrinologic, cardiac, ophthalmologic otologic, nephrologic, gastrointestinal investigations

Figure 1 Proposed diagnostic work-up if MCP is suspected.

exaggerated deep tendon reflexes, spasticity), fasciculations, myocloni, cogwheel rigidity, rigor, dystonia, ataxia, brady/dysdiadochokinesia, sensory disturbances, and gait disturbance (Jackson et al., 1995; Finsterer et al., 2001).
Blood chemistry at rest

Laboratory testing is the usual method to go about evaluating patients for MCP. Recommended initial laboratory evaluations are listed in Table 10. Not all laboratory tests are required for all patients. There is no substitute for good clinical judgement. The most important parameters are lactate and pyruvate. Serum lactate and pyruvate are frequently increased at rest. The lactate/pyruvate ratio, a measure of the cytoplasmatic redox state, is increased >20 in RCDs and citrate cycle defects, but <10 in PDC defects (Sperl, 1997; Gillis and Kaye, 2002). The b-hydroxybutyric acid/acetic acid ratio, a measure of the intramitochondrial redox state, is >2 in RCDs, but <1 in citrate cycle and PDC defects (Gillis and Kaye,

2002). Creatine-kinase (CK) levels are either normal or slightly elevated. The highest values were found in mtDNA depletion syndromes (Table 9). Normal CK does not rule out MCP. Other muscle enzymes that may be raised are the alanine-transaminase, aspartatetransaminase, lactate-dehydrogenase or aldolase. If there is diabetes, serum glucose and glycosilized haemoglobin may be elevated. Renal insufficiency may manifest as increased blood urea nitrogen, creatinine and creatinine clearance. In case of pancreatitis amylase and lipase may be elevated. If there is hepatopathyelevated liver enzymes, hyperbilirubinaemia and hyperammonaemia can be found. In Pearson’s syndrome there may be sideroblastic anaemia or pancytopenia (Table 10).
Blood chemistry during exercise

A clinical hallmark of RCD is exercise intolerance with a maximal oxygen uptake during exercise of one-third to one-half of normal (Finsterer et al., 2001; Vissing et al., 2001; Jensen et al., 2002). Because of the

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disturbed OXPHOS, there is impaired systemic oxygen extraction (increased cardiac output/oxygen uptake ratio), reduced anaerobic threshold and thus an exaggerated accumulation of extracellular lactate during aerobic exercise (Siciliano et al., 1999; Finsterer et al., 2000; Vissing et al., 2001; Finsterer and Milvay, 2002; Jensen et al., 2002). Based on these findings, lactate increases already during slight exercise on a bicycle ergometer or other devices in MCP patients, but remains normal in healthy subjects (lactate stress test) (Finsterer and Milvay, 2002). Exercise tests give false-positive results in patients with heart failure, renal insufficiency, diabetes, hepatopathy, glycogenosis, malignancy or under barbiturates, biguanids, corticosteroids, contraceptives, alcohol, acetyl-salicylic acid, and valproic acid. The ischaemic-forearm test is based on decreased oxygen extraction from capillary blood, resulting in high oxygen saturation in venous effluent blood from working muscles (Jensen et al., 2002). The aerobicforearm exercise test is almost as sensitive for the diagnosis of RCD as muscle biopsy (Table 10) (Jensen et al., 2002).
CSF investigations

evoked potentials frequently show an increased P100latency, particularly in patients with clinical CNS involvement. In patients with CNS abnormalities or seizures, the electroencephalogram may show specific or non-specific focal or generalized alterations (Table 10) (Sciacco et al., 2001).
Neuroimaging

In some cases the CSF protein is elevated, like in KSS. In cases with encephalomyopathy (MELAS, MERRF, Leigh syndrome) CSF lactate may be elevated (Jackson et al., 1995; Finsterer, 2001). In single cases, oligoclonal bands are positive (Fadic and Johns, 1996). There are also single cases with aseptic pleocytosis (Table 10) (unpublished data).
Electrophysiology

Nerve conduction studies may be normal or may reveal polyneuropathy, even in the absence of established risk factors. Polyneuropathy exclusively attributable to MCP, was found in up to one-third of the cases (unpublished data). In the majority of the cases polyneuropathy is of the axonal type. As repetitive nerve stimulation may be abnormal, even in the absence of myasthenia (Finsterer et al., 2002), it should be routinely carried out. Electromyography may be normal, neurogenic or myogenic, non-specifically abnormal, showing increased rate of polyphasia, increased rate of satellite potentials but normal motor unit action potential duration. A myogenic electromyogram (EMG) can be found in only one-third of the cases (Finsterer and Fuglsang-Frederiksen, 1999). Altogether, the EMG is abnormal in only half of the cases (Finsterer and Fuglsang-Frederiksen, 1999). Visually

Cerebral CT may be normal or abnormal. Cerebral CT may be normal even if there is clinical CNS involvement. Abnormal cerebral CT may demonstrate scattered hypodensities, hyperdense white matter lesions, calcification of the basal ganglia (KSS, MELAS) and supratentorial or cerebellar atrophy. Stroke-like lesions are hypodense on CT, primarily involving the posteriortemporal and occipital regions. T1-weighted images may show hyperintese cortical signals compatible with cortical laminar necrosis. On T2-weighted MRI MELAS patients may show hyperintensities either deep in the white matter or at the grey white matter interface (Fadic and Johns, 1996; Chinnery and Turnbull, 1997). In patients with LHON or Leigh syndrome symmetrical changes in the basal ganglia (putamen, globus pallidus, caudate nucleus) and brainstem can be found on T2-weighted images. Leucencephalopathy may mimic lesions seen in multiple sclerosis (Table 10) (Sciacco et al., 2001). White matter changes may be also found in Leigh syndrome and MNGIE (Schapira and Cock, 1999). Two main types of magnetic resonance spectroscopy (MRS) are applied to MCPs, phosphorous MRS (31PMRS) and proton MRS. 31P-MRS allows to in-vivo quantify the amount of available ATP, phosphocreatine, inorganic phosphate and indirectly ADP (Lodi et al., 2002a). Common 31P-MRS findings in patients with RCD are low resting phosphocreatine/inorganic phosphate ratio in muscle and delayed phosphocreatine recovery following exercise (Fadic and Johns, 1996). In LHON patients 31P-MRS demonstrates tissue-specific distribution of the biochemical expression of primary LHON mutations (Lodi et al., 2002b). However, MRS 4 findings are non-specific (Argov et al., 1998) and have a lower sensitivity and specificity than other tests (Jensen et al., 2002). Proton MRS allows to in-vivo quantify the amount of lactate within a tissue (Table 10) (Sperl, 1997; Lin et al., 2003). Single photon emission tomography may show focal reductions of metabolism and blood flow in patients with normal MRI (Fadic and Johns, 1996). Positron emission tomography may reveal abnormal cortical metabolism with reduced oxygen or glucose consumption in the context of normal cerebral blood flow (Schapira and Cock, 1999).

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Near infrared spectroscopy (NIRS) investigations may demonstrate impaired deoxygenation in working muscle of RCD patients. However, NIRS cannot distinguish RCD from McArdle disease (Abe et al., 1997). Because of the low sensitivity and complicated technique, NIRS is not widely used for diagnosing MCP (Jensen et al., 2002).
Muscle biopsy

Muscle biopsy is the most helpful diagnostic procedure for evaluating MCP (Fadic and Johns, 1996; McFarland et al., 2002). Muscle biopsy can be diagnostic even if other tests are normal. Because muscle biopsy may be also normal and because of its invasive character, risks and costs must be weighted against the chance that biopsy will yield positive results and the benefit gained by the diagnosis (treatment decisions, family planning, prognosis, anaesthetic risk). Muscle tissue should be investigated for: (i) Routine light microscopy including modified Gomori trichrome stain (ragged-red fibres). (ii) Immunohistochemistry including COX, succinate dehydrogenase (raggedblue fibres), NADH, ATPase, PAS, lipid stain. (iii) Electron microscopy to view the mitochondrial structure (proliferation of the cristae mitochondriales (whirled cristae), paracrystalline inclusions), and evaluate for mitochondrial proliferation with accumulation of excessive, enlarged mitochondria in the subsarcolemmal region (pleoconial myopathy). (iv) Biochemical investigations by spectrophotometry, which can be performed in tissue homogenates and do not require the use of isolated mitochondria. Spectrophotometric studies include analysis of the individual or group complex activity, the b-oxidation spiral and carnitine and acyl-carnitine transport capacity. (v) Polarography studies include measurement of the oxygen consumption in isolated mitochondria through an oxygen electrode after addition of substrates [state III (plenty of O2, ADP and phosphorus are available) or state IV (absence of ADP limits oxygen consumption)]. Polarography determines the RC activity, the OXPHOS activity, the integrity of the mitochondrial membranes, and the efficiency of the substrate transport (Gillis and Kaye, 2002). (vi) Immunoblot measures the molecular weight of various proteins (Sperl, 1997; Gillis and Kaye, 2002; The Mitochondrial Disease Foundation, 2003). Patients with mtDNA mutations typically exhibit a mosaic staining pattern for COX. A uniform low level of COX staining and intense SDH staining are suggestive of a nuclear gene defect, but may be also found in cytochorme b mutations. However, normal COX staining does not rule out MCP. Mitochondrial

proliferation with ragged-red fibres is typically found in patients with deletions, depletion or point mutations in tRNA genes (MELAS, MERRF) (DiMauro, 1996). In contrast, ragged-red fibres are almost never observed in patients with mtDNA point mutations of structural genes (LHON, NARP, Leigh) (Walker et al., 1996). Instead of ragged-red fibres, COX-negative fibres may be found in Leigh syndrome (Leonard and Schapira, 2000a). Principally, ragged-red fibres, ragged-blue fibres and COX-negative fibres are a non-specific finding and may be also seen in non-RCD myopathies, including inclusion body myositis, PDC deficiency, or carnitine-palmitoyl-transferase deficiency (Walker et al., 1996). Identification of a single ragged-red fibre in a subject <30 years is suspicious of MCP and a level >2% is a major diagnostic indicator at any age (Walker et al., 1996). COX-negative muscle fibres are normal over the age of 40 years, and the proportion further increases with age. COX-negative fibres >2% under age 50 years or >5% at any age strongly suggest RC dysfunction (Walker et al., 1996). Normal findings on muscle biopsy, particularly from patients with tRNA mutations, do not rule out MCP. Some MELAS patients have unremarkable biopsy findings, but a biochemical complex-I defect (McFarland et al., 2002). The biochemical phenotype is also different in two situations: a mutation in a structural gene usually results in reduced activity of the affected enzyme, whereas mutations in genes controlling the protein synthesis result in decreased activities of all RC complexes (DiMauro, 1996). The linked spectrophotometric assay of complex I and III or complex II and III can be useful to detect ubiquinone deficiency, causing familial cerebellar ataxia and responding well to ubiquinone substitution (McFarland et al., 2002).
Genetic testing

Genetic testing should be carried out only if the clinical features are highly suggestive of one of the classical syndromes, such as MELAS, MERRF or LHON (Fig. 1). However, negative results should be interpreted with caution, because they rarely exclude MCP when the clinical suspicion is high (McFarland et al., 2002). Recent studies have shown that mtDNA mutations only account for <5% of the MCP cases. Therefore, if suspicion of MCP is sufficiently strong, patients without a mtDNA mutation should undergo long-term follow-up. If there is then still clinical, histochemical and biochemical evidence for MCP, mtDNA genes, encoding for tRNAs, should be sequenced, as most recognized pathogenic mtDNA mutations occur in these genes. MtDNA deletions are

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hardly ever detected in blood, except for deletions in Pearson syndrome (McFarland et al., 2002). MtDNA rearrangements (single deletions, duplications, multiple deletions) can be detected by Southern plot analysis or long-range PCR. In the absence of rearrangements a screen for common mtDNA point mutations by PCR or RFLP is carried out. Sequencing of the entire mtDNA should be carried out only from muscle mtDNA. Evidence for new mtDNA mutations is best provided by single-fibre PCR-RFLP analysis (McFarland et al., 2002).
Diagnostic scores

diagnostic. Ragged-red fibres or mitochondrial abnormalities on electron microscopy are also regarded diagnostic. Abnormalities found on enzymology or polarography are regarded ÔprobablyÕ diagnostic. Firstdegree relatives of an MCP patient (parents, siblings, children) have ÔprobableÕ MCP (Wolf and Smeitink, 2002).

Differential diagnoses
Neurological differential diagnoses of MCP are myasthenia (Finsterer, 2002), myasthenic syndrome, congenital myopathy, motor neuron disease (amyotrophic lateral sclerosis, spinal muscular atrophy, X-linked bulbospinal muscular atrophy Kennedy) (Finsterer, 2002), vasculitis, thyroid dysfunction, and oculopharyngeal muscular dystrophy.

Although there is a need for generally accepted criteria for the diagnosis of RCDs, clear definitions concerning the various clinical and laboratory items are still missing (Thorburn and Smeitink, 2001; Wolf and Smeitink, 2002). Consensus diagnostic criteria based on clinical, histological, biochemical and genetic items (adult criteria), were first published in 1996 (Walker et al., 1996). However, for the biochemical studies no widely used quality assessment programme is currently available and no gold standard is generally accepted (Wolf and Smeitink, 2002). In the adult criteria biochemical investigations do not include functional studies of the whole RC, such as substrate activation rates or ATP production. To allow the diagnosis of paediatric cases, modified adult criteria have been 5 proposed (Bernier et al., 2002). Wolf and Smeitink proposed a third scoring system (mitochondrial disease criteria, MDC), which relies upon symptoms, metabolic and imaging findings, skeletal muscle morphology, biochemical investigations, and genetic data. Applying the MDC, clinical presentation, metabolic investigations, imaging and histopathology each contributes a maximum of four points (Wolf and Smeitink, 2002). Clinical criteria are divided into three main groups, skeletal muscle, CNS and multisystem. Patients are allocated to one of these groups according to their predominant clinical feature. Biochemical investigations assessed by the MDC include oxidation rates of 14C-labelled substrate, ATP and phosphocreatine production rate and activity of single RC complexes. Difficulties arise from the lack of agreement on optimal biochemical assays and cut-off values and the common occurrence of secondary RC dysfunction (Wolf and Smeitink, 2002). All available information is scored and the results assigned to one of the four levels ÔunlikelyÕ, ÔpossibleÕ, ÔprobableÕ or ÔdefiniteÕ. Mutations in mtDNA or nDNA are not taken into account as a distinct item, although the diagnosis of RCD is ÔdefiniteÕ if a known pathogenic mutation is found. A novel heteroplasmic mutation in a symptomatic individual is ÔprobablyÕ

Genetic counselling
Genetic counselling in MCP is difficult because of the genetic heterogeneity, the uncertainty about heteroplasmy rates, and threshold levels. Confidently, the following statements can be given: males with mtDNA mutations will only exceptionally transmit the disease (Schwartz and Vissing, 2002; Williams, 2002); the risk of having an affected child increases with the level of heteroplasmy in the mother, but there is no degree of heteroplasmy at which the risk is low enough to be ignored. Females with single mtDNA deletions, like in KSS and CPEO have a risk of <8% to transmit the disease; with point mutations the chance that MCP is transmitted increases with the heteroplasmy rate; recurrence risks of an individual with LHON are 30% for brothers, 8% for sisters, 46% for nephews, 10% for nieces, and 31 and 6% for male and female cousins, respectively (Leonard and Schapira, 2000a); depending on the random segregation of normal and mutant mtDNA during meiosis, none, some or all children of an affected mother may have MCP. The random segregation of normal and mutant mtDNA during mitosis in early embryonic development determines the tissues which are affected. Accordingly, phenotype and severity vary within a single family; once an mtDNA mutation is identified it may be detected even in clinically unaffected individuals; most cases with mtDNA mutations are sporadic cases; 40% of the LHON patients with the commonest mutation have a negative family history; in patients with tRNA mutations the family history is either normal or reveals abnormalities like deafness or diabetes; a negative family history does not exclude familial MCP. Overall, each mutation manifests differently, making it difficult to give advice in the clinical routine.

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Because the individual mtDNA genotype is most likely determined by the relative proportions of wildtype to mutant mtDNA in the oocyte, the heteroplasmy rate of a blastomere, ought to be a random sample of the oocyte’s mtDNA complement. This could be a good predictor of the foetal mtDNA genotype. The fact that little segregation of mtDNA sequence variants occurs during foetal life suggests that sampling of any foetal tissue ought to provide a reliable indicator of the overall mtDNA mutation load.

Treatment
Treatment of patients with MCP is woefully inadequate. There is no causal but only symptomatic or supportive therapy for MCP. No treatment is able to reverse already sustained damage. Thus, goal of each treatment is to alleviate symptoms or to cure secondary problems with specific treatment. Generally, an individual therapy should be tailored to optimally meet a patient’s needs. An individualized treatment is usually more effective than Ôempirical treatmentÕ (treatment makes sense, but the benefit is not obvious or effective). This is particularly important, as many of the therapies are ineffective. In such a case therapy would be a waste of time, money and effort. In some cases, therapy even can be dangerous (corticosteroids). Supportive care forms the mainstay of patients with MCP. A team of specialists involving the neurologist, cardiologist, endocrinologist, otologist, ophthalmologist, nephrologist and gastroenterologist, nurses, physiotherapists and speech therapists should be involved (Table 11).

General measures comprise: (i) Regular physiotherapy, plenty of sleep, physical exercise below the maximal individual limit. (ii) Avoidance of mental and physical stress, cold stress, heat stress, alcohol, nicotine, infections and drugs known to induce secondary MCP. (iii) Dietary (no fasting, ketogenic dietary (65% fat) except for PDC deficiency, no glutamate, instead of fat carbohydrates). (iv) Elimination of toxic substances like lactate by dichloroacetate. Dichloracetate reduces lactate but has no effect on the clinical course. If there is severe lactacidosis, plasmapheresis is recommended (Sperl, 1997). However, there are indications that lactic acidosis, at least in part, compensates for impaired RC activity (Chinnery and Turnbull, 1997). (v) Supplementation of RC components like coenzyme Q (particularly effective in ubiquinone deficiency). (vi) Administration of artificial electron acceptors like vitamin C and K. In single cases with complex I and III defect vitamin D, vitamin K3, vitamin C proved to have some effect. (vii) Administration of metabolites and cofactors like carnitine, thiamin and riboflavin. However, substitution of carnitine is indicated only if there is secondary carnitine deficiency (Chinnery and Turnbull, 1997). In general, the benefit of vitamins and cofactors is minimal. High doses of corticosteroids have been reported beneficial in single cases, but in one case it proved fatal, why it is not recommended in MCPs (Table 11). (viii) Care should be taken with general anaesthesia and with local anaesthetics (Finsterer et al., 1998, unpublished data). MCP patients are susceptible particularly to complications from general anaesthesia. There may be increased sensitivity to etomidate and

Table 11 Treatment of MCPs General measures Tailor individual therapy to optimally meet the patient’s need Dietary measures [no fasting, ketogenic dietary (65% fat) in PDC deficiency, no glutamate, reduction of fat and simultaneous increase in carbohydrates (except PDC deficiency)] Physical exercise only below the maximal individual limit (avoidance of overexertion) Avoidance of mental and physical stress (plenty of sleep), cold and heat stress, including direct exposure to sunlight, infections, fasting, alcohol, smoking Physical therapy, orthosis, crunches, braces, wheel chair for motor problems Medication Coenzyme-Q (5–15 mg/kg/day), L-carnitine (30–100 mg/kg/day), acetyl-L-carnitine (250–1000 mg/day), vitamin C (100–1500 mg/day, increases intestinal iron resorption), vitamin D, vitamin E (200–1200 IU/day), vitamin K3 (5–30 mg/day), thiamin (50–100 mg/day), nicotinamide (50–100 mg/day), riboflavin B2 (50–200 mg/day), lipoic acid (180–300 mg/day), selenium (25–50 lg/day), b-carotin (10 000 IU/day), biotin (2.5–10 mg/day), calcium, phosphate, succinate (6 g/day), creatine-mono-hydrate (5 g/day), uridine, citrate, dichloroacetate (reduces serum lactate), idebenone (coenzyme analogue) (90–225 mg/day) Avoidance of valproic acid, barbiturates, biguanides, tetracyclines, chloramphenicol, zidovudin, doxorubicin, germanium Care with local and general anaesthesia Specific measures Therapy of seizures, dementia, migraine, spasticity, dystonia, Parkinsonism, pain, cramps, muscle stiffness, myotonia, diabetes, renal insufficiency, hepatic failure, cardiac impairment, glaucoma, osteoporosis, hyperlipidaemia, hormone replacement, prescription of a hearing device, surgical correction of ptosis, cataract, glaucoma, percutaneous enterogastrostomy

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thiopental. Hypoxia and CO2 should be avoided during anaesthesia. Generally, non-specific pharmacological treatment is of limited benefit and short lived, suggesting a strong placebo effect. The effectiveness of treatment varies from patient to patient, depending on the particular disorder and its severity. As a general rule, mild degrees tend to respond better to therapy than severe disease. In some MCPs, treatment may be noted immediately, whereas in other MCPs its benefit may take a few months to be noticed (Lodi et al., 2001). In other cases, the benefit of treatment may never be noticed, although the treatment may be effective in delaying or stopping progression of the disease (Leonard and Schapira, 2000a). There may be also patients who do not benefit from any therapy at all. Specific treatment is available in case of epilepsy, dementia, spasticity, Parkinsonism, myalgia, muscle cramps, dysaesthesias, restless legs syndrome, or endocrine dysfunction. Therapy of heart failure and rhythm abnormalities, renal failure or diabetes follows established guidelines (Table 11). Surgical therapy may be indicated for ptosis, cataract and glaucoma (Finsterer, 2002) (Table 11). In case of severe dysphagia or weight loss percutaneous gastrotomy is helpful (Fadic and Johns, 1996). Patients with cochlear defects benefit from cochlear implants (McFarland et al., 2002).

confirmed or ruled out. Longitudinal observation by a single specialist will be more effective than repeated visits by different doctors. In fact, there is considerable lack of consensus as to what is or is not an MCP. A known pathogenic mutation in a symptomatic individual is regarded diagnostic. However, if a patient presents with a ÔclassicÕ maternally inherited disorder (MELAS, MERRF, LHON) or a phenotype classic for an nDNA mutation (MNGIE), appropriate nDNA or mtDNA studies should be initiated first. If the phenotype is non-specific, the clinician should start with blood, urine or CSF investigations. If these investigations are abnormal, one should proceed with more invasive investigations, like morphological and biochemical studies. Concerning the prognosis, it is difficult to chart the future of an affected individual. Generally, those with a high degree of abnormal mtDNA heteroplasmy do worse than those with a lesser degree. Usually, it is not possible to predict the course of first-degree family members based upon the phenotype of the first family member identified. It is also not possible to predict the response to treatment before tried. The rapidly increasing understanding of the pathophysiological background of MCPs may further facilitate the diagnostic approach and open perspectives to future, possibly causative therapies.

References Conclusion
Mitochondriopathies are usually multisystem disorders, which predominantly manifest in tissues or organs with high oxygen consumption like skeletal muscle, brain, myelon, endocrinium, myocardium, eyes, ears, intestines, kidneys and bone marrow. More than 95% of the MCPs are caused by nDNA mutations, of which only a few have been identified thus far. Less than 5% of the MCPs are due to mtDNA mutations. MtDNA-derived MCPs may be due to inherited (germline) mutations or due to acquired (somatic) mutations. Concerning both their genetic background and their phenotype, MCPs are extremely heterogeneous. Although various typical syndromes have been identified, they frequently overlap and some even think that each affected individual has its unique phenotype. MCPs are more frequent than previously thought. There is no gold diagnostic standard to identify MCP. Frequently, even exhaustive evaluations are not informative. Not all MCPs develop lactic acidosis. There are several cases in which serum lactate levels decrease with age. As MCPs are progressive diseases, normal laboratory tests at a certain point do not rule out MCP. Thus, if MCP is suspected and cannot be confirmed by any investigation, patients have to be vigilantly pursued until the suspicion is either
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