You are on page 1of 24

European Journal of Neurology 2004, 11: 163–186

RESEARCH ARTICLE

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

Keywords: Mitochondriopathies (MCPs) are either due to sporadic or inherited mutations in


genetics, hereditary nuclear or mitochondrial DNA located genes (primary MCPs), or due to exogenous
disease, multisystem, factors (secondary MCPs). MCPs usually show a chronic, slowly progressive course
mutations, neuromuscular and present with multiorgan involvement with varying onset between birth and late
disease, skeletal muscle adulthood. Although several proteins with signalling, assembling, transport, enzy-
matic function can be impaired in MCP, most frequently the activity of the respiratory
Received 1 June 2003 chain (RC) protein complexes is primarily or secondarily affected, leading to impaired
Accepted 28 August 2003 oxygen utilization and reduced energy production. MCPs represent a diagnostic
challenge because of their wide variation in presentation and course. Systems fre-
quently affected in MCP are the peripheral nervous system (myopathy, polyneurop-
athy, lactacidosis), brain (leucencephalopathy, calcifications, stroke-like episodes,
atrophy with dementia, epilepsy, upper motor neuron signs, ataxia, extrapyramidal
manifestations, fatigue), endocrinium (short stature, hyperhidrosis, diabetes, hyperli-
pidaemia, 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.

present with different clinical manifestations (pheno-


Introduction
copy) whilst the same clinical phenotype may be caused
Mitochondriopathies (MCPs) are either due to sporadic by different mutations (genetic heterogeneity) (DiMa-
or spontaneous mitochondrial DNA (mtDNA) or uro, 1996). This review aims to summarize the actual
nuclear DNA (nDNA) mutations in genes encoding for knowledge about the genetic background, pathomech-
enzymes, structural, signalling, carrier/shuttle, channel, anisms, clinical manifestations, diagnostic approaches
receptor, heat shock or assembling proteins, tRNAs or and therapeutic strategies concerning MCPs.
rRNAs of the mitochondrion or due to exogenous
noxes like drugs, toxins or infections (Morgan-Hughes,
Historical remarks
1994; Schapira and DiMauro, 1994; DiMauro, 1996).
Proteins most frequently affected by mutations are MCPs were initially described by Kearns and Sayre
those of the respiratory chain (RC) and the oxidative 1 (1958) and later by Ernster (1959) and Luft (1962)
phosphorylation (OXPHOS). That is why MCPs are (Luft’s disease). In 1963 the mtDNA was detected. In
often synonymously termed RC disorders (RCDs). 1974 it turned out that mtDNA genes encode for
However, MCPs may be also due to defects in pathways components of the RC. In 1980 it became clear that
and components of the mitochondrion other than the transmission of the mtDNA followed a maternal trait.
RC or OXPHOS. MCPs present with a wide spectrum Anderson et al. (1981) revealed the wild-type mtDNA
of disease and their clinical features overlap (Leonard sequence. In 1984 it turned out that non-mtDNA
and Schapira, 2000a). Concerning mtDNA, a single encoded components of the RC are nuclearly encoded.
mutation or different mutations in the same gene may In 1986 all 13 mtDNA translation products were ana-
lysed in detail. First mtDNA mutations were reported
Correspondence: Dr Josef Finsterer, Postfach 348, 1180 Vienna, in 1988 (Holt et al., 1988; Wallace et al., 1988). In 1992
Austria (fax: +43-1-4781711; e-mail: duarte@aonmail.at). the first nuclear mutation leading to MCP was detected

Ó 2004 EFNS 163


164 J. Finsterer

(Bourgeois et al., 1992). Today more than 100 point (ATP-synthase), ubiquinone, and the carnitine-palmi-
mutations in the mtDNA and >20 nDNA mutations, toyl-transferase-II (Stryer, 1996; McFarland et al.,
causing primary or secondary MCP, are known 2002). Substrate transport via the inner membrane is
(Finsterer, 1997; Servidei, 2003). selective. The inner membrane is permeable only for
unloaded molecules like O2, CO2 and H2O. There are
carriers for anions, redox equivalents and kations
Structure of mitochondria
(Stryer, 1996). Altogether, 14 carriers are known so far.
Mitochondria are intracellular spheroid or ovoid Among these are those for aspartate/glutamate, phos-
organelles with a transverse diameter of 0.1–0.5 lm and phate, pyruvate, glutamate, branched-fatty-acid, long-
a variable length (Stryer, 1996). According to the chain-fatty-acid, ketoglutarate/malate, dicarboxylate/
endosymbiont hypothesis mitochondria derive from phosphate, citrate/malate, a-glycero-phosphate/dihyd-
prokaryotes, which were integrated in nucleus con- roxyaceton-phosphate, ornitine, carnitine, glutamine,
taining cells (DiMauro, 1996; Stryer, 1996). The malate/aspartate (shuttles NADH into the matrix), and
number of mitochondria per cell ranges from none the adenine-nucleotide translocator (ANT1, responsible
(erythrocytes) to 10 000 (striated muscle cell). The for the exchange of ADP and ATP across the inner
average number is 500–2000/cell. The number of membrane) (Stryer, 1996).
mitochondria within a cell increases with the amount
of substrate and oxygen utilization a particular cell
Intermembrane space
requires (Stryer, 1996). In the muscle cell they reside
between the myofibrils, subsarcolemmally, near the Within the intermembrane space reside the adenylat-
nucleus or near the motor endplate. Mitochondria are kinase, the mitochondrial creatine-phosphokinase,
build up of four compartments: (i) the outer membrane, the deafness dystonia protein (DDP1/TIM8A), and
(ii) the inner membrane, (iii) the intermembrane space, cytochrome-c, which initiates apoptosis if released to
and (iv) the matrix. the cytosol.

Outer membrane Matrix

The outer bilayer lipid membrane is permeable to Within the matrix a large number of enzymes and
molecules <10 000 Da. For correctly folded proteins other proteins and peptides, including RC complexes,
the inner membrane is impermeable (Stryer, 1996). In DNA-polymerases, chaperones (heat shock proteins),
association with the inner membrane, unfolded pro- mRNAs, tRNAs, and the mtDNA are located.
teins, encoded as precursors by the nuclear genome, are
imported through the outer membrane via the TOM/
Function of mitochondria
TIM protein complex (Stryer, 1996). This complex
import system includes for most proteins a targeting Mitochondria serve four fundamental biological roles:
sequence at the N-terminus, which interacts with the (i) provision of ATP, (ii) mediation of cell death by
membrane receptors before being cleaved (Schapira, apoptosis (Schapira, 2002), (iii) heat production, and
2002). The protein is then folded and sorted to its (iv) contribution to human genetics. In addition mito-
correct intramitochondrial location (Schapira, 2002). chondria harbour the b-oxidation, citrate cycle (tri-
Within the outer membrane or closely associated with it carboxic cycle, Krebs cycle), degradation of amino
reside proteins like porine (voltage-dependent ion acids, parts of the haem-biosynthesis, parts of the
channel), NADH cytochrome-b5-reductase, palmitoyl- steroid metabolism, parts of the uric acid cycle,
CoA-synthetase, carnitine-palmitoyl-transferase, and mitochondrial protein synthesis, and the pyruvate
mono-amino-oxidase. dehydrogenase complex (PDC), responsible for the
decarboxylation of pyruvate.
Inner membrane
ATP production
The inner bilayer lipid membrane is folded and imper-
meable to most molecules and protons. It is built up of The principle function of the mitochondrion is to pro-
70% proteins. Cholesterol is absent, whereas cardioli- duce energy in the form of ATP, which is achieved via
pin is present (Stryer, 1996). Phosphatidyl-cholin, the PDC, citrate cycle, b-oxidation, RC, and OXPHOS
phosphatidyl-ethanol-amin and cardiolipin occur in a (Leonard and Schapira, 2000a). Fatty acids, pyruvate
relation of 4:3:2 (Stryer, 1996). Embedded in the inner and amino acids are transferred from the cytosol into
membrane are the four RC complexes, complex V the mitochondrion where they are metabolized to

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 165

Table 1 Characteristics of respiratory chain


and oxidative phosphorylation complexes Complex Term Subunits NSEN NSEM NPTI

I NADH dehydrogenase 41 34 7 (ND1-6, ND4L) 4


II Succinate dehydrogenase 4 4 0 0
III Ubiquinone cytochrome-c 11 10 1 (cytochrome-b) 2
oxidoreductase
IV Cytochrome oxidase 13 10 3 (COX I, II, III) 2
V ATP synthase 14 12 2 (ATPase 6 and 8) 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 kill cells by cleaving critical cell repair and homeostatic
citrate cycle. Electrons from the citrate cycle then enter proteins as well as cytoskeletal proteins. The per-
the RC. The core of the RC and OXPHOS pathway are meability transition pore, a megapore spanning the
the five multi-subunit complexes I–V (Table 1) (Leo- inner and outer membrane is built up of porine, the
nard and Schapira, 2000a). RC and OXPHOS are built adenine-nucleotide-translocator, peripheral benzodia-
up of 83 polypeptides of which 70 are encoded by zepine receptors and cyclophilin D (Leonard and
nDNA and 13 by mtDNA (Table 1). The 13 mtDNA- Schapira, 2000b). It is opened by Bax, Bak, reduced
encoded proteins comprise <5% of the mitochondrial transmembrane gradient, Ca++ and is closed by BcLx,
proteins. Electrons from various substrates pass along protein-kinase-c and cyclosporine. Caspase-independ-
the chain, providing energy to pump protons across the ent apoptotic cell death is mediated by the release of the
inner membrane from the matrix via complexes I, III apoptosis-inducing factor, a flavo-protein stored in the
and IV into the intermembrane space (Table 1) (Stryer, intermembrane space and released in response to DNA
1996; Leonard and Schapira, 2000a). Per molecule damage, oxidative stress or exocytoxic stress (Nardin
NADH 10 protons and per molecule succinate six and Johns, 2001; Moskowitz and Lo, 2003).
protons are pumped to the intermembrane space
(Table 1) (Stryer, 1996). The electrochemical proton
Heat production
gradient thus established drives the ATP generation via
complex V (Leonard and Schapira, 2000a). The transfer Decoupling of the OXPHOS leads to the production of
of electrons within a complex is effected by flavones, heat (thermogenesis). Thermogenesis is particularly
iron/sulphur centres, cytochromes and copper centres developed in brown fat of newborns and of hibernators
(Stryer, 1996). The electron producing substrates glu- (Stryer, 1996). Hypothalamic stimulation of sympa-
tamate, pyruvate and hydroxybutyrate enter the RC at thetic nerves via b3-receptors and cAMP increases
complex I, succinate at complex II, and fatty acids at lipolysis in brown fat. cAMP increases transcription of
both, complex I and the electron transfer protein, cou- proteins important in the thermogenesis, like lipop-
pled to ubiquinone (coenzyme Q) (Leonard and Scha- roteinlipase (increases the uptake of extracellular fat)
pira, 2000a; DiMauro and Schon, 2003). Ubiquinone and thermogenin (increases the delivery of heat) (Stryer,
shuttles electrons from complexes I and II to complex 1996).
III. From complex III electrons are passed to complex
IV (cytochrome oxidase, COX) by cytochrome-c, an
Mitochondrial DNA
intermembrane protein. Complex V allows protons to
flow back into the matrix, using the released energy to Mitochondria have their own functional genome, sep-
synthesize ATP (Gillis and Kaye, 2002). arate from the nuclear one (Leonard and Schapira,
2000a). MtDNA lies within the mitochondrial matrix
and has structural and functional features different
Apoptosis
from those of nDNA (Table 2). MtDNA is a circular,
There is ample evidence that mitochondria play an double-stranded (heavy (H, rich in guanines) and light
important role in apoptosis. To initiate apoptosis the (L, rich in cytosines) strand) DNA molecule, built up of
permeability transition pore is opened, through which 16 569 base pairs. MtDNA genes encode for two
cytochrome-c is released into the cytosol. There, the rRNAs, 22 tRNAs and 13 polypeptides (28 on the
latter binds to Apaf-1, which in turn complexes with H-strand and nine on the L-strand). Unlike nDNA,
caspase-9, to initiate the caspase-cascade, terminating mtDNA coding sequences have no introns (93% are
in apoptotic cell death (Stryer, 1996; Leonard and coding compared with 5% in the nuclear genome),
Schapira, 2000b; Schapira, 2002). Activated caspases mtDNA is not interwoven with histones, has no

Ó 2004 EFNS European Journal of Neurology 11, 163–186


166 J. Finsterer

Table 2 Particularities of the mtDNA and replication is produced by the ribonucleoprotein


Circular
RNAse MRP.
Has its own apparatus for replication, transcription and translation In mammals all mitochondria are inherited from the
No coding sequences (except for D-loop, approximately 1000 bp) mother with occasional exceptions (Schwartz and
No introns (thus no splice sites) Vissing, 2002). Usually, paternally derived mtDNA is
Some genes overlap labelled with an ubiquitine tag, which invokes rapid
Single promoter site
Complete mtDNA is transcribed into two large pieces of RNA
proteolysis when it enters the oocyte (McFarland et al.,
(polycistronic transcription), which is then cleansed into mRNAs, 2002). Because of a bottleneck in early oogenesis (after
tRNAs and rRNAs meiosis the number of mitochondria per germ cell is
Mutation rate 10 times higher than that of nDNA reduced to <1000 copies), all mtDNA derives from a
Exposed to permanent oxidative stress of free radicals of the RC small number of progenitors and disproportion of cer-
No protective histones
No effective repair mechanism
tain types of mtDNA may be created (Schapira and
Maternal transmission without recombination with rare exceptions Cock, 1999; Leonard and Schapira, 2000a; Schapira,
(Williams, 2002) 2002; MITOMAP, 2003). Multiple mtDNA molecules
Frequent polymorphisms within a mitochondrion are organized in discrete pro-
Modified genetic code tein-DNA complexes, called nucleoids (Garrido et al.,
AUA methionine instead of isoleucine
UGA tryptophane instead of stop codon
2003). In these structures mtDNA co-localizes with
AGA and AGG encode for a stop codon instead of arginine twinkle-GFP fusion protein, the hmTFA, and single-
Autocatalytic RNA (RNA with enzymatic activity in the absence of stranded DNA-binding protein. Nucleoids appear to be
protein) (Williams, 2002) the mitochondrial units of inheritance (Elpeleg et al.,
RNA editing (post-translational modification of the mRNA nucleo 2002; Garrido et al., 2003).
tide sequence) (Williams, 2002)
Trans-splicing (joining of two separate primary RNA transcripts to
form a single mRNA) (Williams, 2002) Pathogenesis
Taurine-containing uridines (Suzuki et al., 2002)

Mitochondrial DNA mutations

effective repair system and uses a variant genetic code Changes in mtDNA sequence can be inherited or
(Table 2). Since each mitochondrion contains 2–10 somatic (created in situ). MtDNA has a mutation rate
mtDNA copies and since a cell has up to 10 000 of 10–20 times that of nDNA, probably due to a failure
mitochondria, a cell contains thousands of mtDNA of proof-reading by mtDNA polymerases. Normally,
copies (polyplasmy) (Leonard and Schapira, 2000a; all mtDNA of an individual is identical (homoplasmy).
MITOMAP, 2003). Occasionally, a sequence variation generates a dual
Because mtDNA contains only 37 genes, of which population of wild type and mutant mtDNA (hetero-
24 are needed for mtDNA translation, most of the plasmy). The heteroplasmy rate is the product of the
approximately 1000 mitochondrial gene products are apparently random segregation of wild type to mutant
encoded by nDNA and imported from the cytosol mtDNA during embryogenesis (ratio wild-type to
(DiMauro and Schon, 2003). MtDNA depends on mutant DNA). In some MCPs the Ômutant loadÕ of an
nDNA for its enzymes of replication, transcription, affected tissue is directly related to the severity of the
translation and repair. Additionally, mitochondria phenotype. However, for most MCPs the phenotype is
rely upon the nucleus for most proteins necessary for independent of the abundance of mutant mtDNA.
the mitochondrial function. During their development Factors other than the heteroplasmy rate within a cell
mitochondria divide and proliferate under nuclear or a mitochondrion, which contribute to the patho-
control. MtDNA replication of the H-strand starts genesis, are the threshold effect [percentage of mutation
from OH and of the L-strand from OL. Polycistronic needed to manifest clinically (dependent on the energy
transcription of the total H- and L-strand is initiated need of a particular tissue)], the nuclear background,
from two different sites within the D-loop (triple age, sex, and environment, resulting in a wide range of
stranded) (Schapira and Cock, 1999). An additional phenotypes (McFarland et al., 2002). The threshold for
transcription initiation site for the H-strand is located biochemical expression of an mtDNA mutation is
adjacent to the 12S rRNA (Schapira and Cock, believed to be around 60% mutant for mtDNA dele-
1999). For initiation of transcription, binding of the tions and >90% mutant for tRNA mutations (Scha-
human mitochondrial transcription-factor-A (hmTFA) pira and Cock, 1999; McFarland et al., 2002). MtDNA
to the H- and L-strand promoter is required. The mutations are usually heteroplasmic [except Leber’s
transcribed RNA is cleaved into mRNAs, tRNAs and hereditary optic neuropathy (LHON)] and comprise
rRNAs. The transfer between mtDNA transcription point mutations, deletions and insertions (Schapira and

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 167

Cock, 1999). As there are no introns, no splice site


Exogenous factors
mutations are found. Point mutations are frequently
inherited whilst deletions and insertions are usually Drugs
sporadic. Why mtDNA mutations acquired during life Drugs that were reported to impair mitochondrial
are not transmitted to the next generation is explained functions are acetylsalicylic acid, alcohol, valproic acid
by the bottleneck effect. It is speculated that mainly (sequesters carnitine, precipitates seizures in MELAS),
germ cells, which contain wild-type mtDNA survive barbiturates (block complex I), tetracyclines, chloram-
and are transformed to oocytes. Heteroplasmic germ- phenicol (reduces synthesis of mitochondrial proteins
cells are excluded from the differentiation to oocytes. and number and size of mitochondria), doxorubicin,
Although mtDNA mutations are well-documented germanium and zidovudin (causes mtDNA depletion)
causes of MCP, it is believed that >95% of the MCPs (Walker, 2002). There is also increasing evidence that
are caused by nDNA mutations (Gillis and Kaye, corticosteroid myopathy is due to mitochondrial dys-
2002). Proper assembly and function of RC complexes function (Mitsui et al., 2002).
require approximately 60 ancillary nDNA-encoded
proteins (DiMauro and Schon, 2003). Complex-I defi- Oxidative stress
ciency accounts for 30% of the RCDs (Benit et al., Oxidative stress is defined as impairment of cellular
2001). Criteria for a pathologically relevant mtDNA functions by free oxygen radicals like O2 , H2O2,
mutation are: (i) heteroplasmy, (ii) amount of mutated ONOO), OH). Normally the RC generates few free
mtDNA above threshold, (iii) relation to a particular oxygen radicals by the OXPHOS. However, in case of
phenotype in >1 unrelated individuals, (iv) absence of RC dysfunction, the level of free oxygen radicals
the mutation in healthy individuals, except asympto- markedly increases. Free radicals damage DNA, pro-
matic relatives, (v) transferability of the metabolic teins and phospholipids by oxidizing them. Free oxygen
defect by means of mtDNA in cybrid studies, (vi) the radicals are metabolized by SOD1, catalase and glu-
mutation alters an evolutionary and functionally con- tathion-peroxidase. Vitamin C and a-tocopherol (vita-
served base pair or amino acid (Walker et al., 1996), min E) have also a protective effect. Detoxification of
and (vii) the mutation is correlated with a biochemical free radicals is a vital function of each cell. This is
defect (McFarland et al., 2002). The pathogenetic role particularly the case for cells with high-energy con-
of non-modification of taurin-containing uridines in sumption, which in turn augments the oxidative stress.
mutant mitochondrial tRNAs for leucine and lysine in Oxidative stress increases with age. As free radicals are
the development of MCPs is under debate (Suzuki particularly prevalent in the brain, its mitochondria are
et al., 2002). particularly exposed to oxidative stress. Mutations in
genes, which encode for detoxifying enzymes, have
deleterious effects, like in familial amyotrophic lateral
nDNA mutations
sclerosis (Valentine, 2002).
Mitochondriopathies caused by nDNA mutations fol-
low a Mendelian (autosomal recessive, autosomal
Classification of MCPs
dominant or X-linked) pattern of inheritance. In addi-
tion to the 70 RC proteins, nDNA located genes encode In addition to the separation into primary and secon-
for approximately 1000 mitochondrial proteins not dary MCPs, MCPs are classified according to genetic,
involved in the RC. Nuclearly encoded peptides involved biochemical or clinical criteria (Tables 3–5). According
in the RC are the complex II and the Fe-S Protein 4. to genetic criteria a causative mutation resides either in
nDNA mutations causing MCP are frequently found in the nDNA or mtDNA and affects RC complex genes or
highly conserved RC subunits. General features of nu- non-RC mitochondrial proteins (Table 3). According
clearly encoded mitochondrial proteins are that they are to biochemical criteria defects of the inter- and intra-
synthesized in the cytoplasm and that they are imported mitochondrial transport, defects of substrate utiliza-
into the mitochondrion via specific import systems. tion, 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

Ó 2004 EFNS European Journal of Neurology 11, 163–186


168 J. Finsterer

Table 4 Biochemical classification of mitochondrial diseases defects of the RC are differentiated (Table 4). Accord-
Defects of substrate transport
ing to clinical criteria MCPs are classified as single
Carnitine-palmitoyl-transferase deficiency organ diseases or multisystem disorders (Table 5).
Primary systemic or muscle carnitine deficiency Single organ MCPs are rare and tend to proceed into
Secondary carnitine deficiency multisystem disorders over time. Whether each affected
Defects of substrate utilization individual should be regarded as a unique phenotype or
PDC deficiency (E1, E2, E3, protein X)
Pyruvate-decarboxylase deficiency
if there are typical distinct phenotypes is still under
Pyruvate-carboxylase deficiency debate, also known as the conflict between splitters and
Defects of the b-oxidation lumpers (Fadic and Johns, 1996; Walker et al., 1996).
Defects of the Krebs cycle According to the splitters, MCPs are made up of a
Fumarase deficiency number of syndromes (actually >40), of which most
Ketoglutarate dehydrogenase deficiency
Aconitase deficiency
have become well known because of their widely
Defects of the oxidation-phosphorylation coupling propagated acronyms (Table 5). As most of these syn-
Luft’s syndrome (loose coupling and hypermetabolism) dromes exhibit individual manifestations, depending on
Defects of the RC age, some authors recommend individualization of the
Complex I, II, III, IV or V defect phenotype description. A valid classification of MCPs
Combined defects of the RC components
Combined defects of the PDC and the RC
will be established not before all genes involved in the
biogenesis of mitochondrial molecules are known and
RC, respiratory chain; PDC, pyruvate-dehydrogenase when the mechanisms of secondary RC involvement
complex. have been fully elucidated (Schapira and Cock, 1999;
Wolf and Smeitink, 2002).

Table 5 Clinical classification

Acronym/syndrome Clinical manifestations

CPEO Ophthalmoparesis or ophthalmoplegia, ptosis


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

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 169

varying thresholds of biochemical expression for both


Frequency
the mutation and the tissue involved, and the modula-
At the beginning of their recognition, MCPs were ting effect of nuclear and other mitochondrial genes
regarded rare disorders. Meanwhile it turned out, that (Leonard and Schapira, 2000b). There is no single
they are more frequent than previously thought. In identifying feature of MCP. In the majority of the cases
children, approximately one-third of the inherited patients have combinations of problems with varying
metabolic disorders are attributable to MCPs (Sperl, onset (Table 6). Tissues or organs with high oxygen and
1997). The prevalence of mtDNA mutations in adults is energy demand and substrate utilization, like muscle,
estimated to be 1:50 000 (Chinnery and Turnbull, 1997). brain, heart, liver and epithelium (retina, ear, guts,
In a recent report the incidence of MCPs was estima- renal tubules), are predominantly affected (Sperl, 1997;
ted to be 4–5/100 000 life births, but may be as high as Wolf and Smeitink, 2002). Thus, MCPs most com-
1 in 5000–10 000 life births (Gillis and Kaye, 2002; monly present with neuromuscular symptoms. As a rule
McFarland et al., 2002). Based upon our own data we of thumb one should think of MCP if a common dis-
calculated a prevalence of 1:25 000 (unpublished data). ease has atypical features that set it apart from the
Most likely, the prevalence of MCPs is even higher. 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
Clinical presentation
should be particularly considered if features listed in
Table 6 remain unexplained and occur alone or in
Onset
combination. In rare cases MCP manifest during gen-
The onset of MCPs ranges from early embryogenesis to eral anaesthesia with malignant hyperthermia-like fea-
late adulthood. Accordingly, MCPs can present at any tures or weaning problems after general anaesthesia
age (Wolf and Smeitink, 2002). (Finsterer et al., 1998).

General features Specific MCP phenotypes and syndromes

A striking feature of MCPs is their clinical heterogen- Chronic progressive external ophthalmoplegia
eity, ranging from single organ involvement to severe Chronic progressive external ophthalmoplegia (CPEO)
multisystem disease (Leonard and Schapira, 2000a). is the commonest manifestation of an mtDNA
This variability may be due to the rate of heteroplasmy, 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]
CNS 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
Endocrinium 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
Heart Impulse generation and conduction defects, myocardial thickening, left ventricular hypertrabeculation/non-compaction,
heart failure (exertional dyspnoea, leg oedema, rales)
Ears Hypacusis, sensorineural deafness, tinnitus, peripheral vertigo
Eyes Cataract, glaucoma, pigmentary retinopathy, optic atrophy, uveitis, acquired strabism
Intestines 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
Kidney Renal tubular insufficiency, Fanconi syndrome, renal cysts
Bone marrow Sideroblastic anaemia, leucopenia, thrombopenia, pancytopenia

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

Ó 2004 EFNS European Journal of Neurology 11, 163–186


170 J. Finsterer

characterized by ophthalmoplegia and ptosis (Holt rate of up to 90% in blood (Table 8) (McFarland
et al., 1989). Later on cataracts, retinitis pigmentosa, et al., 2002).
deafness, fatigue, ataxia, limb weakness, neuropathy,
cardiomyopathy and renal insufficiency may develop Myopathy, encephalopathy, lactacidosis
(Schapira and Cock, 1999; McFarland et al., 2002). The and stroke-like episodes
particular susceptibility of the extra-ocular muscles is The commonest of the encephalomyopathies is myop-
explained by the three to four times greater mitoch- athy, encephalopathy, lactacidosis and stroke-like epi-
ondrial volume fraction compared with limb muscles sodes (MELAS), of which the key features were first
(Schapira and Cock, 1999). The clinical course is usu- described in 1984 (Pavlakis et al., 1984). Onset is usu-
ally benign in that additional tissue or organ failure is ally between childhood and adolescence. Typical fea-
rare with low risk of serious disability (Table 5). CPEO tures comprise stroke-like episodes with hemiparesis,
is due to mtDNA deletions (40% of the cases), nDNA hemianopsia, migraine, nausea and vomiting. Addi-
mutations, and point mutations in mtDNA encoded tional features are deafness, diabetes, seizures, demen-
tRNAs (Tables 7–9) (Zeviani et al., 1989). tia, ataxia, cortical blindness, optic atrophy,
pigmentary retinopathy, deafness, dilative cardiomyo-
Kearns–Sayre syndrome pathy, myopathy (87% of the cases), exercise intoler-
Kearns–Sayre syndrome (KSS) is a subtype of CPEO ance, lactic acidosis and short stature (55% of the cases)
with pigmentary retinopathy, cardiac conduction (Schapira and Cock, 1999; McFarland et al., 2002).
defects, cerebellar ataxia, raised CSF protein and onset Many ÔoverlapÕ cases have been described with addi-
<20 years (Kearns and Sayre, 1958). A proximal tional features like CPEO, cardiomyopathy, myocloni
myopathy develops as the disease progresses. Addi- and ataxia. Frequently, stroke-like episodes are located
tional features may be mental retardation, deafness, parieto-occipitally, but the remainder of the cortex may
bulbar symptoms, stroke-like episodes, endocrine dys- be also affected (Leonard and Schapira, 2000a). The
function, sideroblastic anaemia (Pearson syndrome) strokes do not conform to vascular territories and are
and lactic acidosis (Schapira and Cock, 1999). Dys- assumed due to metabolic derangements, spreading
phagia in KSS may be due to cricopharyngeal achalasia beyond an ischaemic focus, possibly precipitated by
(Kornblum et al., 2001). The prognosis of KSS is worse aberrant arterial tone due to defective mitochondria in
than that of CPEO and patients rarely survive beyond the smooth muscle of the vasculature or stenosis of
the age of 30. KSS is due to sporadic, single large arterioles due to enlarged endothelial mitochondria
deletions ranging from 1.3 to 8.8 kb (90% of the cases) (Hasegawa et al., 1991; DiMauro, 1996; McFarland
or duplications (Table 8). The origins of replication and et al., 2002). The metabolic hypothesis envisions groups
transcription within the mtDNA are usually spared of neurons in the cortex harbouring very high levels of
(Schapira and Cock, 1999). mutant mtDNA, just below the threshold level. A
sudden increase in energy demand imposed on these
Pearson syndrome cells, like in a seizure, could cause their decompensation
Pearson syndrome, first described in 1979 (Pearson (DiMauro, 1996). Stroke-like episodes invariably occur
et al., 1979), is a childhood disorder, characterized by before age 40, why MELAS enters into the differential
refractory sideroblastic anaemia, and exocrine pan- diagnosis of stroke in the young (Leonard and Scha-
creatic dysfunction. Patients present at early infancy pira, 2000a). Typically, these recurrent episodes are
with a refractory, transfusion-dependent, macrocytic non-disabling. Computed tomography (CT) and mag-
anaemia, neutropenia, and thrombocytopenia. Bone netic resonance imaging (MRI) show multiple white
marrow biopsy is characterized by normal cellularity, matter lesions in >80% of the cases (Schapira and
but vacuolization of the precursor cells (Schapira and Cock, 1999). Basal ganglia calcification is common. The
Cock, 1999). Additional features are failure to thrive, course is slowly progressive. MELAS is not only due to
and chronic diarrhoea with villous atrophy. With mtDNA point mutations in tRNA and mRNA genes
disease progression, hepatomegaly, raised transamin- but also due to small-scale mtDNA deletions (Tables 7
ases, hyperbilirubinaemia, coagulopathy and tubular and 8).
dysfunction with aminoaciduria and glucosuria
(Fanconi’s syndrome) may occur (Schapira and Cock, Myoclonic epilepsy and ragged-red fibres
1999). In single patients hepatic failure is the pre- Myoclonic epilepsy and ragged-red fibres (MERRF),
dominant manifestation (Gillis and Kaye, 2002). In first described in 1973 (Tsaris et al., 1973), usually
patients who survive beyond infancy the syndrome presents between childhood and early adulthood. Typ-
evolves into KSS. Pearson syndrome is usually due to ical features include myoclonic epilepsy with photo-
heteroplasmic mtDNA deletions with a heteroplasmy sensitive general tonic–clonic seizures, myopathy with

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 171

Table 7 MtDNA mutations published until January 2004 (Servidei, 2004)

Transitions Transversions

A>G G>A C>T T>C T>G T>A G>T C>G A>T

tRNA genes
MELAS 3243, 3252 1642 3271
3260, 5814 583 3291
MERRF 8344 8363 8356
MERRF/MELAS 8356, 7512
CPEO 3243 4309, 5703 4274, 4285
5692 12 315 12 311
CPEO/multiple sclerosis 4298
CPEO/myoclonus 8342
CPEO/myopathy/sudden death 3251
CPEO/multisystem 3256
CPEO/diabetes/ataxia 3264
Myopathy 3288, 3302 5521 15 990 618,3250
12 320 4409
Myopathy/CMP (MIMYCA) 3260 3303 3254
Myopathy/painful stiffness 3243
Myopathy/dystonia 3243
Hypertrophic CMP 4300, 4295 9997
1555, 8296
Multisystem/CMP 4269 8363 4320
Dementia/chorea 5549
EMP/Diabetes 14 709
Diabetes/deafness 3243, 8296
Sensori-neural deafness 7445 7511
Congenital multisystem 15 923
EMP 3243 15 915, 1606 3243
5540, 8328
7543
Sudden death/multisystem disorder 10 044
Exercise intolerance/myoglobinuria 606
Intestinal dysfunction/EMP 8313 1644
MILS (adult onset) 8344
Idiopathic sideroblastic anaemia 12 301
mRNA genes
LHON 4917 3460, 5244 3394, 4160
7444, 9438 4216, 9101
9804, 11 778 14 484
13 708, 15 257
15 812
LHON/dystonia 11 696 14 459 14 596
MILS 8993 8993
NARP 8993
NARP/MILS 8993, 9176 8993
MELAS 13 513 9957
MELAS/bilateral striatal necrosis 3308
Bilateral striatal necrosis 8851, 9176
Exercise intolerance/myoglobinuria 15 615, 11 832
14 846, 15 059
15 084, 15 168
15 723, 15 498
EMP 9952, 6930
Myopathy 15 762
Hypertrophic CMP 15 243
LHON/MELAS 13 513
Idiopathic sideroblastic anaemia 6721, 6742
rRNA genes
Aminoglykosid-induced deafness 1555

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

Ó 2004 EFNS European Journal of Neurology 11, 163–186


172 J. Finsterer

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, the SURF1, NDUFS or SDHA genes (Table 9) (Leo-
dementia and deafness. Myocloni occur alone or in nard and Schapira, 2000b). These genes encode for
association with generalized seizures. Seizures respond mitochondrial proteins involved in the maintenance of
well to valproic acid (should be avoided), clonazepam, complex-IV activity by guaranteeing the correct holo-
piracetam or levetirazetam. Other features include pes enzyme assembly (Table 8).
cavus, polyneuropathy, optic atrophy, dorsal column
loss, lipomatosis, cardiomyopathy, heart block and Leber’s hereditary optic neuropathy
heart failure (Schapira and Cock, 1999; McFarland Leber’s hereditary optic neuropathy is the commonest
et al., 2002). Central nervous system (CNS) pathology cause of maternally inherited blindness in otherwise
comprises gliosis in the dentate nuclei, globus pallidus, healthy young men. The clinical condition was first
red nuclei, substantia nigra, inferior olives, optic nerves described in 1871 and the first mtDNA mutation
and cerebellar cortex and demyelination in the spino- detected in 1988 (Wallace et al., 1988). LHON is due to
thalamic tracts, posterior columns, and corticospinal homoplasmic mtDNA mutations affecting mRNA
tracts. Disease severity ranges from minor, non-disab- genes (Table 7). Three primary LHON mutations
ling symptoms to progressive, ultimately fatal disease. [A3460G (13% of the cases), A11778G (70%),
MERRF is caused by tRNALys point mutations in the T14484C (13%)] account for >95% of the cases (Man
mtDNA (Table 7). MERRF is the exception to the rule et al., 2002; McFarland et al., 2002). Mutations at
that a particular phenotype is caused by various muta- nt14459 (LHON with dystonia) and nt4160 (LHON
tions in different genes (DiMauro and Schon, 2003). with CNS disease) may be also classified as primary,
although atypical clinically. Only 50% of males and
Leigh syndrome 10% of females, harbouring a primary LHON muta-
Leigh syndrome, also known as subacute necrotizing tion, actually develop LHON (Man et al., 2002). The
encephalomyopathy and first described in 1977 incomplete penetrance and the predominance of males
(Willems et al., 1977), is a neuropathologically defined suggest factors other than mtDNA mutations (secon-
multisystem disorder of infancy. The clinical picture is dary LHON mutations, nDNA) to play a pathogenic
dominated by weakness, hypotonia, seizures, develop- role. However, the exact pathogenic role of secondary
mental delay and lactic acidosis. Additional features LHON mutations is under debate. Onset is the late
may be pyramidal signs, dystonia, optic atrophy, adolescence or early adulthood with subacute, painless,
nystagmus, retinitis pigmentosa, ataxia deafness, neur- bilateral visual loss. By age 50 all patients carrying the
opathy, CPEO, recurrent vomiting and respiratory mutation are clinically affected. Funduscopy at onset
failure. Typical CT or MRI abnormalities include reveals peripapillary teleangiectasia (disappears with
bilateral, symmetric signal alterations in the spinal disease progression), disc pseudo-oedema and tortuous
cord, upper brainstem, cerebellum, midbrain, thalamus, retinal arteries. Later on, optic atrophy develops. In
and basal ganglia, with or without cortical changes, and single cases, other tissues, like skeletal muscle, heart,
basal ganglia calcifications in MELAS. Leigh syndrome cerebrum (dystonia), are additionally affected. Some
is caused by mutations in mtDNA or nDNA genes female LHON patients present with a multiple scler-
encoding for the PDC or RC components. A small osis-like phenotype (Harding and Hammans, 1992).
proportion is due to maternally inherited mtDNA White matter lesions were also reported in a male
mRNA mutations (MILS) (Table 7). Complex-IV with the A3460G mutation (Lev et al., 2002). Some
(COX)-deficient Leigh syndrome is due to mutations in mutations are associated with early onset dystonia

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 173

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 ar CI Childhood encephalopathy (Pestronk, 2003)
NDUFS2 1q23 ar CI CMP, encephalopathy (Pestronk, 2003)
NDUFS4 5q11.1 ar CI Multisystem complex I deficiency (Van den Heuvel et al.,
11 1998; Benit et al., 2003)
NDUFS7 19p13 ar CI Leigh syndrome (Triepels et al., 1999, 2001)
NDUFS8 11q13 ar CI Leigh syndrome (Loeffen et al., 1998, 2001)
NDUFV1 11q13 ar CI Leucodystrophy/myoclonic epilepsy (Schuelke et al., 1999;
Benit et al., 2001)
SDHA 5p15 ar, ad CII Leigh syndrome (Bourgeron et al., 1995)
SDHB 1p36.1-p35 ad CII Hereditary paraganglioma (Ackrell, 2002; Niemann et al., 2003)
12 SDHC 1q21 ad CII Benign vascularized head and neck tumours (Pestronk, 2003)
SDHD 11q23 ad CII Hereditary paraganglioma (Ackrell, 2002; Niemann et al., 2003)
BCS1L 2q33–37 ar CIII Gracile syndrome (de Lonlay et al., 2001; Fellman, 2002;
Visapaa et al., 2002)
SURF1 9q34 ar CIV Leigh syndrome (Tiranti et al., 1998)
SCO1 17p13.1 ar CIV Hepatopathy, ketoacidotic coma (Shoubridge, 2001)
13 SCO2 22q13 ar CIV Infantile cardioencephalomyopathy (Walker et al., 1996;
Papadopoulou et al., 1999)
COX10 17p13.1-q11.1 ar CIV Encephalopathy/renal tubulopathy (Sacconi et al., 2003)
COX15 UK UK CIV Defect haem-biosynthesis (Antonicka et al., 2003;
Sacconi et al., 2003)
LRPPRC 2p16 ar CIV Leigh syndrome (Pestronk, 2003)
Taffazin Xq28 X UK Barth syndrome (Pestronk, 2003)
Paraplegin 16q24.3 ar UK Hereditary spastic paraplegia
14 Ubiquinone UK UK UK Familial cerebellar ataxia (Musumeci et al., 2001)

Genes encoding for non-RC mitochondrial proteins


Pyruvate dehydrogenase Xp22.2-p22.1 ar UK Episodic ataxia, epilepsy, encephalopathy (Pestronk, 2003)
Pyruvate carboxylase 11q13.4-q13.5 ar UK Developmental delay, encephalopathy (Pestronk, 2003)
15 HSP60 2q24–34 UK UK Multisystem (Huckriede and Agsteribbe, 1994;
Hansen et al., 2003)
DDP1/TIMM8A Xq22 X UK Mohr-Tranebjaerg syndrome (deafness/dystonia) (Bauer et al.,
16 1999; Paschen et al., 2000; Bauer and Neupert, 2001;
17 Hofmann et al., 2002; Roesch et al., 2002)
ANT1 (SCL25A4) 4q34–35 ad MD Myopathy, CPEO, psychosis (Chen, 2002; Siciliano et al., 2003)
SCL25A19 17q25.3 ar UK Microcephaly (Pestronk, 2003)
Thymidin-phosphokinase 22q13.32qter ar MD MNGIE (Hirano et al., 1994, 2001; Nishino et al., 1999, 2001)
Thymidine kinase 16q22 ar DEPL MtDNA depletion (SMA-like) (Pestronk, 2003)
19 Twinkle 10q23.3-24.3 ad MD CPEO (Suomalainen et al., 1995; Elpeleg et al., 2002; Lewis et al.,
18 2002; Agostino et al., 2003)
FRDA (frataxin) 9q13 ar RNAproc Friedreich ataxia (Lodi et al., 2001, 2002a)
HADHA and B 2p23 ar b-Oxidation CMP, myopathy, hepatomegaly, retinopathy (Pestronk, 2003)
Ornithine transporter 13q14 ar UK HHH syndrome (Pestronk, 2003)
POLG1 (polymerase c) 15q25 ad,ar MPG Neuropathy, dysarthria, CPEO (SANDO) (Fadic et al., 1997;
20 Van Goethem et al., 2003)
OPA1 3q28 ad UK Optic atrophy (Pestronk, 2003)
OPA2 18q12.2-q12.3 ad UK Optic atrophy (Pestronk, 2003)
HMGCS2 1p13-p12 ar UK Seizures, encephalopathy (Pestronk, 2003)
DGUOK 2p13 ar UK Hepatopathy, hypotonia, failure to thrive (Pestronk, 2003)
HMC-CoA-lyase 1pter-p33 ar UK Encephalopathy, hepatomegaly
UK 3p14.1-21.2) ad MD CPEO (Kaukonen et al., 1996)
UK 4p34-q35 ad MD CPEO (Kaukonen et al., 1999)
UK 4p16, 4q22-q24 ar SD, MD Wolfram syndrome (DIDMOAD) (Barrientos et al., 1996a,b)
Fumarate hydrolase 1q42.1 ar UK Developmental delay (Pestronk, 2003)
DCAR 8q21.3 ar UK Hypocarnitineaemia, hypolysineaemia (Pestronk, 2003)
ATPase Xq12 X UK Menkes disease, occipital horn syndrome (Pestronk, 2003)
Lipoamide dehydrogenase 7q31-q32 ar UK Recurrent vomiting (Pestronk, 2003)
Deoxyguanosine kinase 2p13 ar UK MtDNA depletion (hepathopathy, hyperreflexia) (Pestronk, 2003)

Ó 2004 EFNS European Journal of Neurology 11, 163–186


174 J. Finsterer

Table 9 (Continued)

Gene Location TR EMD Clinical features

Genes encoding for non-mitochondrial proteins


ATP7B 13q14.3 ar UK Wilson’s disease (Leonard and Schapira, 2000b)
Huntingtin 4p16.3 ad CII-IV Huntington’s disease
ALC7A3, 9 2p16 ar CI-IV 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 Cock, 1999). Recently, MNGIE has been shown to
(McFarland et al., 2002). result from mutations in the nDNA-encoded gene for
the thymidine-phosphorylase (Table 9) (Nishino et al.,
Neuropathy, ataxia, retinitis pigmentosa 1999, 2001; DiMauro and Schon, 2003). Thymidine-
The neuropathy, ataxia, retinitis pigmentosa (NARP) phosphorylase is likely to have an important role in
syndrome, first described in 1990 (Holt et al., 1990), is nucleoside metabolism by regulating the availability of
characterized by weakness due to motor neuropathy, thymidine for DNA synthesis. Additional functions of
sensory disturbances, cerebellar ataxia and retinitis the enzyme include the angiogenesis and cell trophism
pigmentosa. Additional features may be developmental (Gillis and Kaye, 2002).
delay, mental retardation, dementia, ataxia, cardiomy-
opathy and epilepsy. There is no clinical or histological MtDNA depletion
evidence of myopathy in NARP. NARP is due MtDNA depletion of various degrees leads to a fatal
to mtDNA mutations encoding for mRNA genes multisystem infantile disorder, first described in 1991
(ATPase6) (Table 7) (McFarland et al., 2002). (Moraes et al., 1991). The clinical picture is character-
ized by weakness, hypotonia, CPEO and severe lactic
Myoneurogastrointestinal encephalopathy acidosis. Additional features may be hepatopathy,
Myoneurogastrointestinal encephalopathy (MNGIE), Fanconi syndrome, encephalopathy, seizures,
also termed polyneuropathy, ophthalmoplegia, leucen- cardiomyopathy and cataract (Moraes et al., 1991;
cephalopathy, intestinal pseudo-obstruction (POLIP), McFarland et al., 2002). Total DNA levels in these
is a multisystem disorder, first described in 1983 (Ion- patients are below 35% of those in controls. No
asescu, 1983). MNGIE is characterized by gastrointes- mtDNA mutations are found in these patients. The
tinal dysmotility, manifesting before age 20 years as underlying defect is an impaired replication or main-
episodic nausea, vomiting, gastroparesis, progressive tenance of mtDNA due to nDNA mutations (Table 9).
intestinal pseudo-obstruction, abdominal pain, dilation
and dysmotility of oesophagus, stomach and small
Other MCPs
intestine, diarrhoea, and malabsorption with progres-
sive malnutrition, leading to death around 40 years of In addition to the syndromes mentioned above, other
age. Additional features include generalized myopathy MCPs have been described (Tables 5 and 9). They may
with CPEO, cognitive decline due to leucencephalopa- be due to mtDNA or nDNA mutations and may pri-
thy, retinitis pigmentosa, deafness, hoarseness, dys- marily or secondarily impair the RC or mitochondrial
arthria and polyneuropathy. Post-mortem changes pathways other than the RC.
include visceral neuropathy (loss of neurons and MCPs due to mutations in nuclear genes affecting the
fibrosis in the coeliac, mesenteric and Auerbach plex- RC include: hereditary paragangliomas caused by
uses) and scleroderma-like changes (Schapira and mutations in genes encoding for the subunits SDHB,

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 175

SDHC and SDHD of complex-II (Table 9) (Ackrell, anaemia and various neurodegenerative disorders of
2002; Niemann et al., 2003); MCPs manifesting as hepa- childhood (Wolf and Smeitink, 2002). Whether corti-
topathy, cardiomyopathy, encephalopathy, or tubulo- costeroid-responsive idiopathic myelofibrosis is a MCP,
pathy due to mutations in genes encoding for enzymes remains speculative.
involved in the COX assembly, like SCO1 and SCO2
(Table 9) (Schapira, 2002); hereditary spastic paraplegia
Diagnosis
with lower limb paraspasticity, polyneuropathy with
distal sensory disturbances, amyotrophy and urinary Diagnosing MCP is a challenge because of the genetic
dysfunction due to mutations in the paraplegin gene. heterogeneity, phenocopy and the lacking golden
Muscle biopsy from these patients shows ragged-red standard. The diagnostic approach to a patient with
fibres (Schapira, 2002); Gracile syndrome (Fellman, suspected MCP has to be individualized and requires an
2002); Barth syndrome due to taffazin mutations, most integral approach, incorporating clinical, electrophysi-
likely affecting the cardiolipin synthesis (cardiolipin is ological, imaging, histological, biochemical and genetic
markedly decreased in skeletal muscle, myocardium and investigations (Table 10) (Fadic and Johns, 1996;
platelets in these patients) (DiMauro and Schon, 2003; Chinnery and Turnbull, 1997). Because of the diag-
Pestronk, 2003) and a number of other disorders (Table 9). nostic difficulties and because most of the cases follow a
MCPs due to mutations in nuclear genes encoding for slowly progressive course, patients have to be regularly
non-RC mitochondrial proteins include: lethal multi- and vigilantly pursued, preferentially always by the
system disease due to HSP60 gene mutations (Huck- 3 same doctor. Many MCPs are sporadic and do not fit
2 riede and Agsteribbe, 1994). HSP60 is a chaperone into one of the described particular categories (Chin-
needed for the folding of proteins imported into the nery and Turnbull, 1997). However, certain clinical
mitochondrion (DiMauro and Schon, 2003); X-linked features, particularly when in combination, are strongly
Mohr-Tranebjaerg syndrome, characterized by deaf- suggestive of MCP. MCP should be also considered
ness, cataract, blindness, dystonia, dysphagia and when dealing with an unexplained association of man-
paranoia, due to mutations in the gene encoding for the ifestations with progressive course, involving seemingly
deafness-dystonia protein (DDP1/TIM8A) (Hofmann unrelated organs (Gillis and Kaye, 2002). Myopathy
et al., 2002); Friedreich ataxia due to a GAA triplet with or without lactic acidosis is the most common
expansion in intron 1 of the frataxin gene, affecting the presenting feature (Finsterer et al., 2001). Combina-
mitochondria because of its involvement in RNA pro- tions of clinical features like deafness, cardiomyopathy
cessing and the intramitochondrial iron handling, lead- and diabetes together with encephalopathy and myop-
ing to iron accumulation, increased sensitivity to athy are highly susceptible of MCP and should be
oxidative stress and deficient RC activity (Lodi et al., regarded as red flags (Leonard and Schapira, 2000a).
2002a; Schapira, 2002). There are indications that the The combination of myopathy and deafness is also
mutation results in a defect of iron/sulphur protein highly suggestive of MCP. MCP patients often have
construction (Schapira, 2002). Iron is a pro-oxidant and short stature, deafness and ptosis (Chinnery and
the defect in Friedreich ataxia is identical to that seen in Turnbull, 1997). Mitochondrial stroke is often associ-
the mouse model of oxidative stress; Wolfram syndrome ated with migraine. MCP should also be suspected if
(Barrientos et al., 1996a); Menkes disease (Pestronk, there is leucencephalopathy of undetermined cause,
2003) and a number of other disorders (Table 9). particularly if multiple sclerosis and leucodystrophy
MCPs due to mutations in nuclear genes encoding for have been ruled out (Nardin and Johns, 2001).
non-mitochondrial proteins include: Wilson’s disease If a patient has a classical phenotype for maternally
due to mutations in the ATPase gene (Table 9); Hunt- inherited MCP (MELAS, MERRF, LHON), appro-
ington’s disease, due to a CAG-repeat expansion in priate mtDNA studies should be carried out first
the Huntingtin gene, affecting complex II, III and IV (Fig. 1). If the phenotype is typical for an nDNA-
(Table 9); and a syndrome characterized by cystinuria, inherited MCP (MNGIE), the clinician should proceed
seizures and developmental delay (Table 9). In a num- with genetic studies (Gillis and Kaye, 2002). If the
ber of disorders a genetic background is evident but no phenotype is non-specific, but highly suggestive of
candidate gene has been identified yet, like in Parkin- MCP, one should start with blood, urine and CSF
son’s disease due to aconitin deficiency, or in Alzhei- studies, and if negative, proceed with electrophysio-
mer’s disease, frequently associated with COX defects logical and neuroimaging studies and investigations
(Table 9) (DiMauro and Schon, 2003). of potentially affected organs other than the nervous
Secondary RC involvement occurs particularly in system (Fig. 1). If negative a muscle biopsy and bio-
other inborn errors of metabolism, such as fatty-acid- chemical investigations should be carried out (Fig. 1)
oxidation disorders, thiamine-responsive megaloblastic (Gillis and Kaye, 2002; McFarland et al., 2002).

Ó 2004 EFNS European Journal of Neurology 11, 163–186


176 J. Finsterer

Table 10 Diagnostic work-up for suspected MCPs

P S T

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

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

developmental delay, should be particularly addressed


History
(McFarland et al., 2002).
The most frequent symptoms patients complain about
at diagnosis are myalgia, fatigue, weakness, muscle
Clinical neurologic investigation
cramps, muscle stiffness, double vision, sensory distur-
bances, deafness, wasting and ptosis (Finsterer et al., On clinical neurologic investigation there may be short
2001). With disease progression, the history may stature, facial dysmorphism, mental retardation,
become positive for additional features listed in dementia, impaired consciousness, impaired visual
Table 6. In single cases, ischaemic stroke may be the acuity, double vision, visual field defect, nystagmus,
only manifestation of MCP (Jackson et al., 1995; hypacusis, deafness, dysarthria, dry mouth, reduced gag
Martinez-Fernandez et al., 2001). When taking the reflex, exaggerated masseter reflex, weakness [limb, lid
history issues such as maternal health, obstetric history, (ptosis), gaze paresis, eye muscles (ophthalmoparesis),
family history of neonatal or childhood deaths, deaf- chewing], wasting, hypotonia, reduced deep tendon
ness, diabetes, cardiac disease, visual impairment, and reflexes, long tract signs (upper motor neurone signs,

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 177

Clinical presentation

Specific, recognizable
MCP phenotype (single or Non-specific phenotype,
multiple manifestations) suggestive of MCP

Classic for mtDNA Classic for nDNA Investigations


Electromyo-
inherited MCP inherited MCP of blood, urine Neuroimaging
graphy
or CSF

abnormal abnormal abnormal


mtDNA mutations nDNA mutations
causing MELAS, causing MNGIE,
MERRF, LHON Leigh-syndrome
Muscle biopsy, biochemical
MRS
investigations

Endocrinologic, cardiac, ophthalmologic


DNA-analysis otologic, nephrologic, gastrointestinal
investigations

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

exaggerated deep tendon reflexes, spasticity), fascicu- 2002). Creatine-kinase (CK) levels are either normal or
lations, myocloni, cogwheel rigidity, rigor, dystonia, slightly elevated. The highest values were found in
ataxia, brady/dysdiadochokinesia, sensory distur- mtDNA depletion syndromes (Table 9). Normal CK
bances, and gait disturbance (Jackson et al., 1995; does not rule out MCP. Other muscle enzymes that may
Finsterer et al., 2001). be raised are the alanine-transaminase, aspartate-
transaminase, lactate-dehydrogenase or aldolase. If
there is diabetes, serum glucose and glycosilized hae-
Blood chemistry at rest
moglobin may be elevated. Renal insufficiency may
Laboratory testing is the usual method to go about manifest as increased blood urea nitrogen, creatinine
evaluating patients for MCP. Recommended initial and creatinine clearance. In case of pancreatitis amylase
laboratory evaluations are listed in Table 10. Not all and lipase may be elevated. If there is hepatopathy-
laboratory tests are required for all patients. There is elevated liver enzymes, hyperbilirubinaemia and
no substitute for good clinical judgement. The most hyperammonaemia can be found. In Pearson’s syn-
important parameters are lactate and pyruvate. Ser- drome there may be sideroblastic anaemia or pancy-
um lactate and pyruvate are frequently increased at topenia (Table 10).
rest. The lactate/pyruvate ratio, a measure of the
cytoplasmatic redox state, is increased >20 in RCDs
Blood chemistry during exercise
and citrate cycle defects, but <10 in PDC defects
(Sperl, 1997; Gillis and Kaye, 2002). The b-hydroxy- A clinical hallmark of RCD is exercise intolerance with
butyric acid/acetic acid ratio, a measure of the a maximal oxygen uptake during exercise of one-third
intramitochondrial redox state, is >2 in RCDs, but <1 to one-half of normal (Finsterer et al., 2001; Vissing
in citrate cycle and PDC defects (Gillis and Kaye, et al., 2001; Jensen et al., 2002). Because of the

Ó 2004 EFNS European Journal of Neurology 11, 163–186


178 J. Finsterer

disturbed OXPHOS, there is impaired systemic oxygen evoked potentials frequently show an increased P100-
extraction (increased cardiac output/oxygen uptake latency, particularly in patients with clinical CNS
ratio), reduced anaerobic threshold and thus an exag- involvement. In patients with CNS abnormalities or
gerated accumulation of extracellular lactate during seizures, the electroencephalogram may show specific or
aerobic exercise (Siciliano et al., 1999; Finsterer et al., non-specific focal or generalized alterations (Table 10)
2000; Vissing et al., 2001; Finsterer and Milvay, 2002; (Sciacco et al., 2001).
Jensen et al., 2002).
Based on these findings, lactate increases already
Neuroimaging
during slight exercise on a bicycle ergometer or other
devices in MCP patients, but remains normal in Cerebral CT may be normal or abnormal. Cerebral CT
healthy subjects (lactate stress test) (Finsterer and may be normal even if there is clinical CNS involve-
Milvay, 2002). Exercise tests give false-positive results ment. Abnormal cerebral CT may demonstrate scat-
in patients with heart failure, renal insufficiency, tered hypodensities, hyperdense white matter lesions,
diabetes, hepatopathy, glycogenosis, malignancy or calcification of the basal ganglia (KSS, MELAS) and
under barbiturates, biguanids, corticosteroids, con- supratentorial or cerebellar atrophy. Stroke-like lesions
traceptives, alcohol, acetyl-salicylic acid, and valproic are hypodense on CT, primarily involving the posterior-
acid. temporal and occipital regions.
The ischaemic-forearm test is based on decreased T1-weighted images may show hyperintese cortical
oxygen extraction from capillary blood, resulting in signals compatible with cortical laminar necrosis. On
high oxygen saturation in venous effluent blood from T2-weighted MRI MELAS patients may show hyper-
working muscles (Jensen et al., 2002). The aerobic- intensities either deep in the white matter or at the grey
forearm exercise test is almost as sensitive for the white matter interface (Fadic and Johns, 1996;
diagnosis of RCD as muscle biopsy (Table 10) (Jensen Chinnery and Turnbull, 1997). In patients with LHON
et al., 2002). or Leigh syndrome symmetrical changes in the basal
ganglia (putamen, globus pallidus, caudate nucleus)
and brainstem can be found on T2-weighted images.
CSF investigations
Leucencephalopathy may mimic lesions seen in multiple
In some cases the CSF protein is elevated, like in KSS. sclerosis (Table 10) (Sciacco et al., 2001). White matter
In cases with encephalomyopathy (MELAS, MERRF, changes may be also found in Leigh syndrome and
Leigh syndrome) CSF lactate may be elevated (Jackson MNGIE (Schapira and Cock, 1999).
et al., 1995; Finsterer, 2001). In single cases, oligoclonal Two main types of magnetic resonance spectroscopy
bands are positive (Fadic and Johns, 1996). There are (MRS) are applied to MCPs, phosphorous MRS (31P-
also single cases with aseptic pleocytosis (Table 10) MRS) and proton MRS. 31P-MRS allows to in-vivo
(unpublished data). quantify the amount of available ATP, phosphocrea-
tine, inorganic phosphate and indirectly ADP (Lodi
et al., 2002a). Common 31P-MRS findings in patients
Electrophysiology
with RCD are low resting phosphocreatine/inorganic
Nerve conduction studies may be normal or may reveal phosphate ratio in muscle and delayed phosphocreatine
polyneuropathy, even in the absence of established risk recovery following exercise (Fadic and Johns, 1996). In
factors. Polyneuropathy exclusively attributable to LHON patients 31P-MRS demonstrates tissue-specific
MCP, was found in up to one-third of the cases distribution of the biochemical expression of primary
(unpublished data). In the majority of the cases poly- LHON mutations (Lodi et al., 2002b). However, MRS
neuropathy is of the axonal type. As repetitive nerve 4 findings are non-specific (Argov et al., 1998) and have a
stimulation may be abnormal, even in the absence of lower sensitivity and specificity than other tests (Jensen
myasthenia (Finsterer et al., 2002), it should be rou- et al., 2002). Proton MRS allows to in-vivo quantify the
tinely carried out. Electromyography may be normal, amount of lactate within a tissue (Table 10) (Sperl,
neurogenic or myogenic, non-specifically abnormal, 1997; Lin et al., 2003).
showing increased rate of polyphasia, increased rate of Single photon emission tomography may show focal
satellite potentials but normal motor unit action reductions of metabolism and blood flow in patients
potential duration. A myogenic electromyogram with normal MRI (Fadic and Johns, 1996).
(EMG) can be found in only one-third of the cases Positron emission tomography may reveal abnormal
(Finsterer and Fuglsang-Frederiksen, 1999). Alto- cortical metabolism with reduced oxygen or glucose
gether, the EMG is abnormal in only half of the cases consumption in the context of normal cerebral blood
(Finsterer and Fuglsang-Frederiksen, 1999). Visually flow (Schapira and Cock, 1999).

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 179

Near infrared spectroscopy (NIRS) investigations proliferation with ragged-red fibres is typically found in
may demonstrate impaired deoxygenation in working patients with deletions, depletion or point mutations
muscle of RCD patients. However, NIRS cannot dis- in tRNA genes (MELAS, MERRF) (DiMauro, 1996).
tinguish RCD from McArdle disease (Abe et al., 1997). In contrast, ragged-red fibres are almost never observed
Because of the low sensitivity and complicated tech- in patients with mtDNA point mutations of structural
nique, NIRS is not widely used for diagnosing MCP genes (LHON, NARP, Leigh) (Walker et al., 1996).
(Jensen et al., 2002). 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
Muscle biopsy
and COX-negative fibres are a non-specific finding
Muscle biopsy is the most helpful diagnostic procedure and may be also seen in non-RCD myopathies,
for evaluating MCP (Fadic and Johns, 1996; including inclusion body myositis, PDC deficiency,
McFarland et al., 2002). Muscle biopsy can be diag- or carnitine-palmitoyl-transferase deficiency (Walker
nostic even if other tests are normal. Because muscle et al., 1996). Identification of a single ragged-red fibre
biopsy may be also normal and because of its invasive in a subject <30 years is suspicious of MCP and a level
character, risks and costs must be weighted against the >2% is a major diagnostic indicator at any age
chance that biopsy will yield positive results and the (Walker et al., 1996). COX-negative muscle fibres are
benefit gained by the diagnosis (treatment decisions, normal over the age of 40 years, and the proportion
family planning, prognosis, anaesthetic risk). further increases with age. COX-negative fibres >2%
Muscle tissue should be investigated for: (i) Routine under age 50 years or >5% at any age strongly
light microscopy including modified Gomori trichrome suggest RC dysfunction (Walker et al., 1996). Normal
stain (ragged-red fibres). (ii) Immunohistochemistry findings on muscle biopsy, particularly from patients
including COX, succinate dehydrogenase (ragged- with tRNA mutations, do not rule out MCP. Some
blue fibres), NADH, ATPase, PAS, lipid stain. (iii) MELAS patients have unremarkable biopsy findings,
Electron microscopy to view the mitochondrial struc- but a biochemical complex-I defect (McFarland et al.,
ture (proliferation of the cristae mitochondriales 2002).
(whirled cristae), paracrystalline inclusions), and The biochemical phenotype is also different in two
evaluate for mitochondrial proliferation with accumu- situations: a mutation in a structural gene usually
lation of excessive, enlarged mitochondria in the sub- results in reduced activity of the affected enzyme,
sarcolemmal region (pleoconial myopathy). (iv) whereas mutations in genes controlling the protein
Biochemical investigations by spectrophotometry, synthesis result in decreased activities of all RC com-
which can be performed in tissue homogenates and do plexes (DiMauro, 1996). The linked spectrophotometric
not require the use of isolated mitochondria. Spectro- assay of complex I and III or complex II and III can be
photometric studies include analysis of the individual or useful to detect ubiquinone deficiency, causing familial
group complex activity, the b-oxidation spiral and cerebellar ataxia and responding well to ubiquinone
carnitine and acyl-carnitine transport capacity. (v) substitution (McFarland et al., 2002).
Polarography studies include measurement of the oxy-
gen consumption in isolated mitochondria through an
Genetic testing
oxygen electrode after addition of substrates [state III
(plenty of O2, ADP and phosphorus are available) or Genetic testing should be carried out only if the
state IV (absence of ADP limits oxygen consumption)]. clinical features are highly suggestive of one of the
Polarography determines the RC activity, the classical syndromes, such as MELAS, MERRF or
OXPHOS activity, the integrity of the mitochondrial LHON (Fig. 1). However, negative results should be
membranes, and the efficiency of the substrate transport interpreted with caution, because they rarely exclude
(Gillis and Kaye, 2002). (vi) Immunoblot measures MCP when the clinical suspicion is high (McFarland
the molecular weight of various proteins (Sperl, 1997; et al., 2002). Recent studies have shown that mtDNA
Gillis and Kaye, 2002; The Mitochondrial Disease mutations only account for <5% of the MCP cases.
Foundation, 2003). Therefore, if suspicion of MCP is sufficiently strong,
Patients with mtDNA mutations typically exhibit a patients without a mtDNA mutation should undergo
mosaic staining pattern for COX. A uniform low level long-term follow-up. If there is then still clinical,
of COX staining and intense SDH staining are sug- histochemical and biochemical evidence for MCP,
gestive of a nuclear gene defect, but may be also found mtDNA genes, encoding for tRNAs, should be
in cytochorme b mutations. However, normal COX sequenced, as most recognized pathogenic mtDNA
staining does not rule out MCP. Mitochondrial mutations occur in these genes. MtDNA deletions are

Ó 2004 EFNS European Journal of Neurology 11, 163–186


180 J. Finsterer

hardly ever detected in blood, except for deletions in diagnostic. Ragged-red fibres or mitochondrial abnor-
Pearson syndrome (McFarland et al., 2002). MtDNA malities on electron microscopy are also regarded
rearrangements (single deletions, duplications, mul- diagnostic. Abnormalities found on enzymology or
tiple deletions) can be detected by Southern plot polarography are regarded ÔprobablyÕ diagnostic. First-
analysis or long-range PCR. In the absence of rear- degree relatives of an MCP patient (parents, siblings,
rangements a screen for common mtDNA point children) have ÔprobableÕ MCP (Wolf and Smeitink,
mutations by PCR or RFLP is carried out. Sequen- 2002).
cing of the entire mtDNA should be carried out only
from muscle mtDNA. Evidence for new mtDNA
Differential diagnoses
mutations is best provided by single-fibre PCR-RFLP
analysis (McFarland et al., 2002). Neurological differential diagnoses of MCP are myas-
thenia (Finsterer, 2002), myasthenic syndrome, con-
genital myopathy, motor neuron disease (amyotrophic
Diagnostic scores
lateral sclerosis, spinal muscular atrophy, X-linked
Although there is a need for generally accepted criteria bulbospinal muscular atrophy Kennedy) (Finsterer,
for the diagnosis of RCDs, clear definitions concerning 2002), vasculitis, thyroid dysfunction, and oculopha-
the various clinical and laboratory items are still ryngeal muscular dystrophy.
missing (Thorburn and Smeitink, 2001; Wolf and
Smeitink, 2002). Consensus diagnostic criteria based on
Genetic counselling
clinical, histological, biochemical and genetic items
(adult criteria), were first published in 1996 (Walker Genetic counselling in MCP is difficult because of the
et al., 1996). However, for the biochemical studies no genetic heterogeneity, the uncertainty about hetero-
widely used quality assessment programme is currently plasmy rates, and threshold levels. Confidently, the
available and no gold standard is generally accepted following statements can be given: males with mtDNA
(Wolf and Smeitink, 2002). In the adult criteria bio- mutations will only exceptionally transmit the disease
chemical investigations do not include functional (Schwartz and Vissing, 2002; Williams, 2002); the risk
studies of the whole RC, such as substrate activation of having an affected child increases with the level of
rates or ATP production. To allow the diagnosis of heteroplasmy in the mother, but there is no degree of
paediatric cases, modified adult criteria have been heteroplasmy at which the risk is low enough to be
5 proposed (Bernier et al., 2002). Wolf and Smeitink ignored. Females with single mtDNA deletions, like in
proposed a third scoring system (mitochondrial disease KSS and CPEO have a risk of <8% to transmit the
criteria, MDC), which relies upon symptoms, metabolic disease; with point mutations the chance that MCP is
and imaging findings, skeletal muscle morphology, transmitted increases with the heteroplasmy rate;
biochemical investigations, and genetic data. Applying recurrence risks of an individual with LHON are 30%
the MDC, clinical presentation, metabolic investiga- for brothers, 8% for sisters, 46% for nephews, 10% for
tions, imaging and histopathology each contributes a nieces, and 31 and 6% for male and female cousins,
maximum of four points (Wolf and Smeitink, 2002). respectively (Leonard and Schapira, 2000a); depending
Clinical criteria are divided into three main groups, on the random segregation of normal and mutant
skeletal muscle, CNS and multisystem. Patients are mtDNA during meiosis, none, some or all children of
allocated to one of these groups according to their an affected mother may have MCP. The random seg-
predominant clinical feature. Biochemical investiga- regation of normal and mutant mtDNA during mitosis
tions assessed by the MDC include oxidation rates of in early embryonic development determines the tissues
14C-labelled substrate, ATP and phosphocreatine which are affected. Accordingly, phenotype and severity
production rate and activity of single RC complexes. vary within a single family; once an mtDNA mutation
Difficulties arise from the lack of agreement on optimal is identified it may be detected even in clinically unaf-
biochemical assays and cut-off values and the common fected individuals; most cases with mtDNA mutations
occurrence of secondary RC dysfunction (Wolf and are sporadic cases; 40% of the LHON patients with the
Smeitink, 2002). All available information is scored and commonest mutation have a negative family history; in
the results assigned to one of the four levels ÔunlikelyÕ, patients with tRNA mutations the family history is
ÔpossibleÕ, ÔprobableÕ or ÔdefiniteÕ. Mutations in mtDNA either normal or reveals abnormalities like deafness or
or nDNA are not taken into account as a distinct item, diabetes; a negative family history does not exclude
although the diagnosis of RCD is ÔdefiniteÕ if a known familial MCP. Overall, each mutation manifests differ-
pathogenic mutation is found. A novel heteroplasmic ently, making it difficult to give advice in the clinical
mutation in a symptomatic individual is ÔprobablyÕ routine.

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 181

Because the individual mtDNA genotype is most General measures comprise: (i) Regular physiother-
likely determined by the relative proportions of wild- apy, plenty of sleep, physical exercise below the max-
type to mutant mtDNA in the oocyte, the heteroplasmy imal individual limit. (ii) Avoidance of mental and
rate of a blastomere, ought to be a random sample of physical stress, cold stress, heat stress, alcohol, nicotine,
the oocyte’s mtDNA complement. This could be a good infections and drugs known to induce secondary MCP.
predictor of the foetal mtDNA genotype. The fact that (iii) Dietary (no fasting, ketogenic dietary (65% fat)
little segregation of mtDNA sequence variants occurs except for PDC deficiency, no glutamate, instead of fat
during foetal life suggests that sampling of any foetal carbohydrates). (iv) Elimination of toxic substances like
tissue ought to provide a reliable indicator of the overall lactate by dichloroacetate. Dichloracetate reduces lac-
mtDNA mutation load. tate but has no effect on the clinical course. If there is
severe lactacidosis, plasmapheresis is recommended
(Sperl, 1997). However, there are indications that lactic
Treatment
acidosis, at least in part, compensates for impaired RC
Treatment of patients with MCP is woefully inad- activity (Chinnery and Turnbull, 1997). (v) Supple-
equate. There is no causal but only symptomatic or mentation of RC components like coenzyme Q (par-
supportive therapy for MCP. No treatment is able to ticularly effective in ubiquinone deficiency). (vi)
reverse already sustained damage. Thus, goal of each Administration of artificial electron acceptors like
treatment is to alleviate symptoms or to cure secondary vitamin C and K. In single cases with complex I and III
problems with specific treatment. Generally, an indi- defect vitamin D, vitamin K3, vitamin C proved to have
vidual therapy should be tailored to optimally meet a some effect. (vii) Administration of metabolites and
patient’s needs. An individualized treatment is usually cofactors like carnitine, thiamin and riboflavin. How-
more effective than Ôempirical treatmentÕ (treatment ever, substitution of carnitine is indicated only if there is
makes sense, but the benefit is not obvious or effective). secondary carnitine deficiency (Chinnery and Turnbull,
This is particularly important, as many of the therapies 1997). In general, the benefit of vitamins and cofactors
are ineffective. In such a case therapy would be a waste is minimal. High doses of corticosteroids have been
of time, money and effort. In some cases, therapy even reported beneficial in single cases, but in one case it
can be dangerous (corticosteroids). Supportive care proved fatal, why it is not recommended in MCPs
forms the mainstay of patients with MCP. A team of (Table 11). (viii) Care should be taken with general
specialists involving the neurologist, cardiologist, end- anaesthesia and with local anaesthetics (Finsterer et al.,
ocrinologist, otologist, ophthalmologist, nephrologist 1998, unpublished data). MCP patients are susceptible
and gastroenterologist, nurses, physiotherapists and particularly to complications from general anaesthesia.
speech therapists should be involved (Table 11). 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

Ó 2004 EFNS European Journal of Neurology 11, 163–186


182 J. Finsterer

thiopental. Hypoxia and CO2 should be avoided during confirmed or ruled out. Longitudinal observation by a
anaesthesia. single specialist will be more effective than repeated
Generally, non-specific pharmacological treatment is visits by different doctors. In fact, there is considerable
of limited benefit and short lived, suggesting a strong lack of consensus as to what is or is not an MCP. A
placebo effect. The effectiveness of treatment varies known pathogenic mutation in a symptomatic individ-
from patient to patient, depending on the particular ual is regarded diagnostic. However, if a patient pre-
disorder and its severity. As a general rule, mild degrees sents with a ÔclassicÕ maternally inherited disorder
tend to respond better to therapy than severe disease. In (MELAS, MERRF, LHON) or a phenotype classic for
some MCPs, treatment may be noted immediately, an nDNA mutation (MNGIE), appropriate nDNA or
whereas in other MCPs its benefit may take a few mtDNA studies should be initiated first. If the pheno-
months to be noticed (Lodi et al., 2001). In other cases, type is non-specific, the clinician should start with
the benefit of treatment may never be noticed, although blood, urine or CSF investigations. If these investiga-
the treatment may be effective in delaying or stopping tions are abnormal, one should proceed with more
progression of the disease (Leonard and Schapira, invasive investigations, like morphological and bio-
2000a). There may be also patients who do not benefit chemical studies. Concerning the prognosis, it is diffi-
from any therapy at all. cult to chart the future of an affected individual.
Specific treatment is available in case of epilepsy, Generally, those with a high degree of abnormal
dementia, spasticity, Parkinsonism, myalgia, muscle mtDNA heteroplasmy do worse than those with a lesser
cramps, dysaesthesias, restless legs syndrome, or endo- degree. Usually, it is not possible to predict the course
crine dysfunction. Therapy of heart failure and rhythm of first-degree family members based upon the pheno-
abnormalities, renal failure or diabetes follows estab- type of the first family member identified. It is also not
lished guidelines (Table 11). Surgical therapy may be possible to predict the response to treatment before
indicated for ptosis, cataract and glaucoma (Finsterer, tried. The rapidly increasing understanding of the
2002) (Table 11). In case of severe dysphagia or weight pathophysiological background of MCPs may further
loss percutaneous gastrotomy is helpful (Fadic and facilitate the diagnostic approach and open perspectives
Johns, 1996). Patients with cochlear defects benefit to future, possibly causative therapies.
from cochlear implants (McFarland et al., 2002).
References
Conclusion Abe K, Matsuo Y, Kadekawa J, Inoue S, Yanagihara T
(1997). Measurement of tissue oxygen consumption in
Mitochondriopathies are usually multisystem disorders,
patients with mitochondrial myopathy by non-invasive
which predominantly manifest in tissues or organs with tissue oximetry. Neurology 49:837–841.
high oxygen consumption like skeletal muscle, brain, Ackrell BA (2002). Cytopathies involving mitochondrial
myelon, endocrinium, myocardium, eyes, ears, intes- complex II. Mol Aspects Med 23:369–384.
tines, kidneys and bone marrow. More than 95% of the Agostino A, Valletta L, Chinnery PF et al. (2003). Mutations
of ANT1, Twinkle, and POLG1 in sporadic progressive
MCPs are caused by nDNA mutations, of which only a
external ophthalmoplegia (PEO). Neurology 60:1354–1356.
few have been identified thus far. Less than 5% of the Anderson S, Bankier AT, Barrell BG et al. (1981). Sequence
MCPs are due to mtDNA mutations. MtDNA-derived and organisation of the human mitochondrial genome.
MCPs may be due to inherited (germline) mutations or Nature 290:457–465.
due to acquired (somatic) mutations. Concerning both Antonicka H, Mattman A, Carlson CG et al. (2003).
Mutations in COX15 produce a defect in the mitochondrial
their genetic background and their phenotype, MCPs
heme biosynthetic pathway, causing early-onset fatal hyper-
are extremely heterogeneous. Although various typical trophic cardiomyopathy. Am J Hum Genet 72:101–114.
syndromes have been identified, they frequently overlap Argov Z, Taivassalo T, De Stefano N, Genge A, Karpati G,
and some even think that each affected individual has Arnold DL (1998). Intracellular phosphates in inclusion
its unique phenotype. MCPs are more frequent than body myositis: a 31P magnetic resonance spectroscopy
study. Muscle Nerve 21:1523–1525.
previously thought. There is no gold diagnostic stand-
Barrientos A, Casademont J, Saiz A et al. (1996a). Autosomal
ard to identify MCP. Frequently, even exhaustive recessive Wolfram syndrome associated with an 8.5-kb
evaluations are not informative. Not all MCPs develop mtDNA single deletion. Am J Hum Genet 58:963–970.
lactic acidosis. There are several cases in which serum Barrientos A, Volpini V, Casademont J et al. (1996b). A
lactate levels decrease with age. As MCPs are progres- nuclear defect in the 4p16 region predisposes to multiple
mitochondrial DNA deletions in families with Wolfram
sive diseases, normal laboratory tests at a certain point
syndrome. J Clin Invest 97:1570–1576.
do not rule out MCP. Thus, if MCP is suspected and Bauer MF, Neupert W (2001). Import of proteins into
cannot be confirmed by any investigation, patients have mitochondria: a novel pathomechanism for progressive
to be vigilantly pursued until the suspicion is either neurodegeneration. J Inherit Metab Dis 24:166–180.

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 183

Bauer MF, Rothbauer U, Muhlenbein N et al. (1999). The Ernster L, Ikkos D, Luft R (1959). Enzymatic activities of
mitochondrial TIM22 preprotein translocase is highly human skeletal muscle mitochondria: a tool in clinical
conserved throughout the eukaryotic kingdom. FEBS Lett metabolic research. Nature 184:1851.
464:41–47. Fadic R, Johns DR (1996). Clinical spectrum of mitochond-
Benit P, Chretien D, Kadhom N et al. (2001). Large-scale rial diseases. Sem Neurol 16:11–22.
deletion and point mutations of the nuclear NDUFV1 and Fadic R, Russell JA, Vedanarayanan VV, Lehar M, Kuncl
NDUFS1 genes in mitochondrial complex I deficiency. RW, Johns DR (1997). Sensory ataxic neuropathy as the
Am J Hum Genet 68:1344–1352. presenting feature of a novel mitochondrial disease. Neur-
Benit P, Steffann J, Lebon S et al. (2003). Genotyping ology 49:239–245.
microsatellite DNA markers at putative disease loci in Fellman V (2002). The GRACILE syndrome, a neonatal
inbred/multiplex families with respiratory chain complex I lethal metabolic disorder with iron overload. Blood Cells
deficiency allows rapid identification of a novel nonsense Mol Dis 29:444–450.
mutation (IVS1nt-1) in the NDUFS4 gene in Leigh Finsterer J (1997). Mitochondriopathies. Akt Neurol 24:231–
6 syndrome. Hum Genet 112:563–566. 241.
Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Finsterer J (2001). Cerebrospinal-fluid lactate in adult mito-
Thorburn D (2002). Diagnostic criteria for respiratory chondriopathy with and without encephalopathy. Acta Med
chain disorders in adults and children. Neurology 59:1406– Aust 28:152–155.
1411. Finsterer J (2002). Mitochondriopathy as a differential
Blumenthal DT, Shanske S, Schochet SS et al. (1998). diagnosis of amyotrophic lateral sclerosis. Amyotrophic
Myoclonus epilepsy with ragged red fibers and multiple 7 Lateral Sclerosis and Other Motor Neuron Disorders 3:219–
mtDNA deletions. Neurology 50:524–525. 224.
Bohlega S, Tanji K, Santorelli FM, Hirano M, al-Jishi A, Finsterer J, Fuglsang-Frederiksen A (1999). Macro-EMG in
DiMauro S (1996). Multiple mitochondrial DNA deletions mitochondriopathy. Clin Neurophysiol 110:1466–1470.
associated with autosomal recessive ophthalmoplegia and Finsterer J, Milvay E (2002). Lactate stress testing in 155
severe cardiomyopathy. Neurology 46:1329–1334. patients with respiratory chain disorders. Can J Neurol Sci
Bourgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, 29:49–53.
Aicardi J (1992). Deficiency in complex II of the respiratory Finsterer J, Stratil U, Bittner R, Sporn P (1998). Increased
chain presenting as a leukodystrophy in two sisters with sensitivity to rocuronium and atracurium in mitochondrial
Leigh syndrome. Brain Dev 14:404–408. myopathy. Can J Anaesth 45:781–784.
Bourgeron T, Rustin P, Chretien D et al. (1995). Mutation Finsterer J, Obermann I, Milvay E (2000). Diagnostic yield of
of a nuclear succinate dehydrogenase gene results in the lactate stress test in 160 patients with suspected
mitochondrial respiratory chain deficiency. Nat Genet respiratory chain disorder. Metab Brain Dis 15:163–171.
11:144–149. Finsterer J, Jarius C, Eichberger H, Jaksch M (2001).
Carrozzo R, Hirano M, Fromenty B et al. (1998). Multiple Phenotype variability in 130 adult patients with respiratory
mtDNA deletions features in autosomal dominant and chain disorder. J Inher Metab Dis 24:560–576.
recessive diseases suggest distinct pathogeneses. Neurology Finsterer J, Obermann I, Reitner A (2002). Respiratory chain
50:99–106. complex-I defect mimicking myasthenia. Metab Brain Dis
Casademont J, Barrientos A, Cardellach F et al. (1994). 17:41–46.
Multiple deletions of mtDNA in two brothers with Garrido N, Griparic L, Jokitalo E, Wartiovaara J, Van Der
sideroblastic anemia and mitochondrial myopathy and in Bliek AM, Spelbrink JN (2003). Composition and dynamics
their asymptomatic mother. Hum Mol Genet 3:1945– of human mitochondrial nucleoids. Mol Biol Cell 14:1583–
1949. 1596.
Chen XJ (2002). Induction of an unregulated channel by Gillis L, Kaye E (2002). Diagnosis and management of
mutations in adenine nucleotide translocase suggests an mitochondrial diseases. Pediatr Clin N Am 49:203–219.
explanation for human ophthalmoplegia. Hum Mol Genet Hansen JJ, Bross P, Westergaard M et al. (2003). Genomic
11:1835–1843. structure of the human mitochondrial chaperonin genes:
Chinnery PF, Turnbull DM (1997). Clinical features, inves- HSP60 and HSP10 are localised head to head on chromo-
tigation, and management of patients with defects of some 2 separated by a bidirectional promoter. Hum Genet
mitochondrial DNA. J Neurol Neurosurg Psychiatry 112:71–77.
63:559–663. Harding AE, Hammans SR (1992). Deletions of the mitoch-
Chow CW, Thorburn DR (2000). Morphological correlates of ondrial genome. J Inher Metab Dis 15:480–486.
mitochondrial dysfunction in children. Hum Reprod Hasegawa H, Matsuoka T, Goto Y, Nonaka I (1991).
15(Suppl. 2):68–78. Strongly succinate dehydrogenase-reactive blood vessels in
Cormier V, Rotig A, Tardieu M, Colonna M, Saudubray JM, muscle from patients with mitochondrial myopathy,
Munnich A (1991). Autosomal dominant deletions of the encephalomyopathy, lactic acidosis and stroke-like epi-
mitochondrial genome in a case of progressive encephal- sodes. Ann Neurol 29:601–605.
omyopathy. Am J Hum Genet 48:643–648. Hirano M, Silvestri G, Blake DM et al. (1994). Mitochondrial
DiMauro S (1996). Mitochondrial myopathies: what next? neurogastrointestinal encephalomyopathy (MNGIE): clin-
J Inher Metab Dis 19:489–503. ical, biochemical and genetic features of an autosomal
DiMauro S, Schon EA (2003). Mitochondrial respiratory- recessive mitochondrial disorder. Neurology 44:721–727.
chain diseases. N Engl J Med 348:2656–2668. Hirano M, Marti R, Ferreiro-Barros C et al. (2001). Defects
Elpeleg O, Mandel H, Saada A (2002). Depletion of the other of intergenomic communication: autosomal disorders that
genome-mitochondrial DNA depletion syndromes in cause multiple deletions and depletion of mitochondrial
humans. J Mol Med 80:389–396. DNA. Semin Cell Dev Biol 12:417–427.

Ó 2004 EFNS European Journal of Neurology 11, 163–186


184 J. Finsterer

Hofmann S, Rothbauer U, Muhlenbein N et al. (2002). The Lodi R, Hart PE, Rajagopalan B et al. (2001). Antioxidant
C66W mutation in the deafness dystonia peptide 1 (DDP1) treatment improves in vivo cardiac and skeletal muscle
affects the formation of functional DDP1.TIM13 com- bioenergetics in patients with Friedreich’s ataxia. Ann
plexes in the mitochondrial intermembrane space. J Biol Neurol 49:590–596.
Chem 277:23287–23293. Lodi R, Rajagopalan B, Bradley JL et al. (2002a). Mitoch-
Holt IJ, Harding AE, Morgan-Hughes JA (1988). Deletions of ondrial dysfunction in Friedreich’s ataxia: from patho-
muscle mitochondrial DNA in patients with mitochondrial genesis to treatment perspective. Free Radic Res 36:
myopathies. Nature 331:717–719. 461–466.
Holt IJ, Harding AE, Cooper JM et al. (1989). Mitochondrial Lodi R, Carelli V, Cortelli P et al. (2002b). Phosphorus MR
myopathies: clinical and biochemical features of 30 patients spectroscopy shows a tissue specific in vivo distribution of
with major deletions of muscle mitochondrial DNA. Ann biochemical expression of the G3460A mutation in Leber’s
Neurol 26:699–708. hereditary optic neuropathy. J Neurol Neurosurg Psychiatry
Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA (1990). 72:805–807.
A new mitochondrial disease associated with mitochondrial Loeffen J, Smeitink J, Triepels R et al. (1998). The first
DNA heteroplasmy. Am J Hum Genet 46:428–433. nuclear-encoded complex I mutation in a patient with Leigh
Huckriede A, Agsteribbe E (1994). Decreased synthesis and syndrome. Am J Hum Genet 63:1598–1608.
inefficient mitochondrial import of hsp60 in a patient with Loeffen J, Elpeleg O, Smeitink J et al. (2001). Mutations in the
mitochondrial encephalomyopathy. Biochim Biophys Acta complex I NDUFS2 gene of patients with cardiomyopathy
1227:200–206. and encephalomyopathy. Ann Neurol 49:195–201.
Ionasescu V (1983). Oculogastrointestinal muscular dystro- de Lonlay P, Valnot I, Barrientos A et al. (2001). A mutant
phy. Am J Med Genet S15:103–112. mitochondrial respiratory chain assembly protein causes
Jackson MJ, Schaefer JA, Johnson MA, Morris AAM, complex III deficiency in patients with tubulopathy,
Turnbull DM, Bindoff LA (1995). Presentation and clinical encephalopathy and liver failure. Nat Genet 29:57–60.
investigation of mitochondrial respiratory chain disease. Luft R, Ikkos D, Palieri G, Ernster L, Afzelius B (1962). A
A study of 51 patients. Brain 118:339–357. case of severe hypermetabolism of nonthyroid origin with a
Jensen TD, Kazemi-Esfarjani P, Skomorowska E, Vissing J defect in the maintenance of mitochondrial respiratory
(2002). A forearm screening test for mitochondrial myop- control: a correlated clinical, biochemical and morphologi-
athy. Neurology 58:1533–1538. cal study. J Clin Invest 41:1776–1804.
Kaukonen JA, Amati P, Suomalainen A et al. (1996). An McFarland R, Taylor RW, Turnbull DM (2002). The
autosomal locus predisposing to multiple deletions of neurology of mitochondrial DNA disease. Lancet Neurol
mtDNA on chromosome 3p. Am J Hum Genet 58:763–769. 1:343–351.
Kaukonen J, Zeviani M, Comi GP, Piscaglia MG, Peltonen L, Man PY, Turnbull DM, Chinnery PF (2002). Leber hereditary
Suomalainen A (1999). A third locus predisposing to optic neuropathy. J Med Genet 39:162–169.
multiple deletions of mtDNA in autosomal dominant Martinez-Fernandez E, Gil-Peralta A, Garcia-Lozano R et al.
progressive external ophthalmoplegia. Am J Hum Genet (2001). Mitochondrial disease and stroke. Stroke 32:2507–
65:256–261. 2510.
Kearns TP, Sayre GP (1958). Retinitis pigmentosa, external Mazziotta MR, Ricci E, Bertini E et al. (1992). Fatal infantile
ophthalmoplegia and complete heart block. Ophthalmology liver failure associated with mitochondrial DNA depletion.
60:280–289. J Pediatr 121:896–901.
Kirches EJ, Winkler K, Warich-Kirches M et al. (1998). MITOMAP (2003). A human mitochondrial genome data-
mtDNA depletion and impairment of mitochondrial func- base, http://www.mitomap.org.
tion in a case of a multisystem disorder including severe Mitsui T, Azuma H, Nagasawa M et al. (2002). Chronic
myopathy. J Inherit Metab Dis 21:400–408. corticosteroid administration causes mitochondrial dys-
Kornblum C, Broichner R, Walther E et al. (2001). function in skeletal muscle. J Neurol 249:1004–1009.
Cricopharyngeal achalasia is a common cause of dys- Moraes CT, Shanske S, Tritschler HJ et al. (1991). MtDNA
phagia in patients with mtDNA deletions. Neurology depletion with variable tissue expression: a novel genetic
56:1409–1412. abnormality in mitochondrial diseases. Am J Hum Genet
Leonard JV, Schapira AHV (2000a). Mitochondrial respirat- 48:492–501.
ory chain disorders I: mitochondrial DNA defects. Lancet Morgan-Hughes JA (1994). The mitochondrial myopathies.
355:299–304. In: Engel AG, Franzini-Armstrong C, eds. Myology Basic
Leonard JV, Schapira AHV (2000b). Mitochondrial respirat- and Clinical. McGraw-Hill, New York, pp. 1610–1651.
ory chain disorders II: neurodegenerative disorders and Moskowitz MA, Lo EH (2003). Neurogenesis and apoptotic
nuclear gene defects. Lancet 355:389–394. cell death. Stroke 34:324–326.
Lev D, Vanoov-Sharav M, Watemberg N, Leshinsky-Silver E, Musumeci O, Naini A, Slonim AE et al. (2001). Familial
Lerma Sagie T (2002). White matter abnormalities in cerebellar ataxia with muscle coenzyme Q10 efficiency.
Leber’s hereditary optic neuropathy due to the 3460 Neurology 56:849–855.
mitochondrial DNA mutation. Eur J Paediatr Neurol Nardin RA, Johns DR (2001). Mitochondrial dysfunction
6:121–123. and neuromuscular disease. Muscle Nerve 24:170–191.
Lewis S, Hutchison W, Thyagarajan D, Dahl HH (2002). Naviaux RK, Nyhan WL, Barshop BA et al. (1999). Mitoch-
Clinical and molecular features of adPEO due to mutations ondrial DNA polymerase gamma deficiency and mtDNA
in the Twinkle gene. J Neurol Sci 201:39–44. depletion in a child with AlpersÕ syndrome. Ann Neurol
Lin DD, Crawford TO, Barker PB (2003). Proton MR 45:54–58.
spectroscopy in the diagnostic evaluation of suspected Niemann S, Muller U, Engelhardt D, Lohse P (2003).
mitochondrial disease. Am J Neuroradiol 24:33–41. Autosomal dominant malignant and catecholamine-

Ó 2004 EFNS European Journal of Neurology 11, 163–186


Mitochondriopathies 185

producing paraganglioma caused by a splice donor site Siciliano G, Renna M, Manca ML et al. (1999). The
8 mutation in SDHC. Hum Genet 113:92–94. relationship of plasma catecholamine and lactate during
Nishino I, Spinazzola A, Hirano A (1999). Thymidine anaerobic threshold exercise in mitochondrial myopathies.
phosphorylase gene mutations in MNGIE. A human Neuromuscul Disord 9:411–416.
9 mitochondrial disorder. Science 283:689–692. Siciliano G, Tessa A, Petrini S et al. (2003). Autosomal
Nishino I, Spinazzola A, Hirano M (2001). MNGIE: from dominant external ophthalmoplegia and bipolar affective
nuclear DNA to mitochondrial DNA. Neuromuscul Disord disorder associated with a mutation in the ANT1 gene.
11:7–10. Neuromuscul Disord 13:162–165.
Ohno K, Tanaka M, Sahashi K et al. (1991). Mitochondrial Sperl W (1997). Diagnosis and therapy of mitochondriopa-
DNA deletions in inherited recurrent myoglobinuria. Ann thies. Wien Klin Wochenschr 109:93–99.
Neurol 29:364–369. Stryer L (1996). Biochemie. Spektrum Akademischer Verlag,
Papadopoulou LC, Sue CM, Davidson MM et al. (1999). Heidelberg.
Fatal infantile cardioencephalomyopathy with COX defici- Sue CM, Schon EA (2000). Mitochondrial respiratory chain
ency and mutations in SCO2, a COX assembly gene. Nat diseases and mutations in nuclear DNA: a promising start?
Genet 23:333–337. Brain Pathol 10:442–450.
Parvari R, Brodyansky I, Elpeleg O, Moses S, Landau D, Suomalainen A, Majander A, Haltia M et al. (1992). Multiple
Hershkovitz E (2001). A recessive contiguous gene deletion deletions of mitochondrial DNA in several tissues of a
of chromosome 2p16 associated with cystinuria and a patient with severe retarded depression and familial pro-
mitochondrial disease. Am J Hum Genet 69:869–875. gressive external ophthalmoplegia. J Clin Invest 90:61–66.
Paschen SA, Rothbauer U, Kaldi K, Bauer MF, Neupert W, Suomalainen A, Kaukonen J, Amati P et al. (1995). An
Brunner M (2000). The role of the TIM8–13 complex in the autosomal dominant locus predisposing to deletions of
import of Tim23 into mitochondria. EMBO J 19:6392– mitochondrial DNA. Nature Genet 9:146–151.
6400. Suzuki T, Suzuki T, Wada T, Saigo K, Watanabe K (2002).
Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Taurine as a constituent of mitochondrial tRNAs: new
Rowland LP (1984). Mitochondrial myopathy, encephalo- insights into the functions of taurine an human mitoch-
pathy lactic acidosis, and stroke-like episodes. Ann Neurol ondrial diseases. EMBO J 21:6581–6589.
16:481–488. The Mitochondrial Disease Foundation (2003). Pittsburgh.
Pearson HA, Lobel JS, Kocoshis SA et al. (1979). A new info@umdf.org.
syndrome of refractory sideroblastic anaemia with vacuo- Thorburn DR, Smeitink J (2001). Diagnosis of mitochondrial
lisation of marrow precursors and exocrine pancreas disorders: clinical and biochemical approach. J Inherit
dysfunction. J Pediatr 95:976–984. Metab Dis 24:312–316.
Pestronk A (2003). Neuromuscular Disease Center, Washing- Tiranti V, Hoertnagel K, Carrozzo R et al. (1998). Mutations
ton University. http://www.neuro.wustl.edu/neuromuscular. of SURF-1 in Leigh disease associated with cytochrome c
Poulton J, Morten K, Freeman-Emmerson C et al. (1994). oxidase deficiency. Am J Hum Genet 63:1609–1621.
Deficiency of the human mitochondrial transcription factor Triepels RH, van den Heuvel LP, Loeffen JL et al. (1999).
HmTFA in infantile mitochondrial myopathy is associated Leigh syndrome associated with a mutation in the NDUFS7
with mtDNA depletion. Hum Mol Genet 3:1763–1769. (PSST) nuclear encoded subunit of complex I. Ann Neurol
Roesch K, Curran SP, Tranebjaerg L, Koehler CM (2002). 45:787–790.
Human deafness dystonia syndrome is caused by a defect in Triepels RH, Hanson BJ, van den Heuvel LP et al. (2001).
assembly of the DDP1/TIMM8a-TIMM13 complex. Hum Human complex I defects can be resolved by monoclonal
10 Mol Genet 11:477–486. antibody analysis into distinct subunit assembly patterns.
Sacconi S, Salviati L, Sue CM et al. (2003). Mutation J Biol Chem 276:8892–8897.
screening in patients with isolated cytochrome c oxidase Tritschler HJ, Andretta F, Moraes CT et al. (1992). Mitoch-
deficiency. Pediatr Res 53:224–230. ondrial myopathy of childhood associated with depletion of
Schapira AHV (2002). The ÔnewÕ mitochondrial disorders. mitochondrial DNA. Neurology 42:209–217.
J Neurol Neurosurg Psychiatry 72:144–149. Tsaris P, Engel WK, Kark P (1973). Familial myoclonic
Schapira AHV, Cock HR (1999). Mitochondrial myopathies epilepsy syndrome associated with skeletal muscle mitoch-
and encephalomyopathies. Eur J Clin Invest 29:886–898. ondrial abnormalities. Neurology 23:408.
Schapira AHV, DiMauro S (1994). Mitochondrial Disorders in Valentine JS (2002). Do oxidatively modified proteins cause
Neurology. Butterworth Heinemann, Oxford, pp. 1–76. ALS? Free Radic Biol Med 33:1314–1320.
Schuelke M, Smeitink J, Mariman E et al. (1999). Mutant Van den Heuvel L, Ruitenbeek W, Smeets R et al. (1998).
NDUFV1 subunit of mitochondrial complex I causes Demonstration of a new pathogenic mutation in human
leukodystrophy and myoclonic epilepsy. Nat Genet complex I deficiency: a 5-bp duplication in the nuclear gene
21:260–261. encoding the 18-kD (AQDQ) subunit. Am J Hum Genet
Schwartz M, Vissing JN (2002). Paternal inheritance of 62:262–268.
mitochondrial DNA. N Engl J Med 347:576–580. Van Goethem G, Martin JJ, Dermaut B et al. (2003).
Sciacco M, Prelle A, Comi GP et al. (2001). Retrospective Recessive POLG mutations presenting with sensory and
study of a large population of patients affected with ataxic neuropathy in compound heterozygote patients with
mitochondrial disorders: clinical, morphological and progressive external ophthalmoplegia. Neuromuscul Disord
molecular genetic evaluation. J Neurol 248:778–788. 13:133–142.
Servidei S (2004). Mitochondrial encephalomyopathies: gene Visapaa I, Fellman V, Vesa J et al. (2002). GRACILE
mutation. Neuromusc Disord 14:107–116. syndrome, a lethal metabolic disorder with iron overload is
Shoubridge EA (2001). Cytochrome c oxidase deficiency. Am caused by a point mutation in BCS1L. Am J Hum Genet
J Med Genet 106:46–52. 71:863–876.

Ó 2004 EFNS European Journal of Neurology 11, 163–186


186 J. Finsterer

Vissing J, Gansted U, Quistorff B (2001). Exercise intolerance Williams BS (2002). Another surprise from the mitochondrial
in mitochondrial myopathy is not related to lactic acidosis. genome. N Engl J Med 347:609–612.
Ann Neurol 49:672–676. Wolf NI, Smeitink JAM (2002). Mitochondrial disorders.
Walker UA (2002). Inherited and acquired disorders of Neurology 59:1402–1405.
mitochondrial DNA. Schweiz Rundsch Med Prax 91:2129– Yuzaki M, Ohkoshi N, Kanazawa I, Kagawa Y, Ohta S
2138. (1989). Multiple deletions in mitochondrial DNA at direct
Walker UA, Collins S, Byrne E (1996). Respiratory chain repeats of non-D-loop regions in cases of familial mitoch-
encephalomyopathies: a diagnostic classification. Eur Neu- ondrial myopathy. Biochem Biophys Res Commun
rol 36:260–267. 164:1352–1357.
Wallace DC, Singh G, Lott MT et al. (1988). Mitochondrial Zeviani M, Servidei S, Gellers C, Bertini E, DiMauro S,
DNA mutation associated with Leber’s hereditary optic DiDonato S (1989). An autosomal dominant disorder with
neuropathy. Science 242:1427–1430. multiple deletions of mitochondrial DNA starting at the
Willems JL, Monnens LA, Trijbels JM et al. (1977). D-loop region. Nature 339:309–311.
Leigh’s encephalomyopathy in a patient with cytochrome Zeviani M, Corona P, Nijtmans L, Tiranti V (2000). Nuclear
c oxidase deficiency in muscle tissue. Pediatrics 60:850– gene defects in mitochondrial disorders. Ital J Neurol Sci
857. 20:401–408.

Ó 2004 EFNS European Journal of Neurology 11, 163–186