Molecular genetic and clinical aspects of mitochondrial disorders in childhood

Mitochondrion 7 (2007) 241–252 www.elsevier.com/locate/mito

Review

Molecular genetic and clinical aspects of mitochondrial disorders in childhood Ali-Reza Moslemi a

a,*

, Niklas Darin

b

Department of Pathology, Go¨teborg University, Sahlgrenska University Hospital, SE-413 45 Go¨teborg, Sweden b Department of Paediatrics, Go¨teborg University, SE-413 45 Go¨teborg, Sweden Received 6 November 2006; received in revised form 17 January 2007; accepted 2 February 2007 Available online 14 February 2007

Abstract Mitochondrial OXPHOS disorders are caused by mutations in mitochondrial or nuclear genes, which directly or indirectly affect mitochondrial oxidative phosphorylation (OXPHOS). Primary mtDNA abnormalities in children are due to rearrangements (deletions or duplications) and point mutations or insertions. Mutations in the nuclear-encoded polypeptide subunits of OXPHOS result in complex I and II deficiency, whereas mutations in the nuclear proteins involved in the assembly of OXPHOS subunits cause defects in complexes I, III, IV, and V. Here, we review recent progress in the identification of mitochondrial and nuclear gene defects and the associated clinical manifestations of these disorders in childhood.  2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved. Keywords: mtDNA; OXPHOS; Mitochondrial disorders; Mutation

1. Introduction The discovery, in 1988, that mitochondrial DNA (mtDNA) mutations cause disease in humans (Holt et al., 1988; Lestienne and Ponsot, 1988; Zeviani et al., 1988) opened a new research field involving these disorders. Since then, more than 100 pathogenic mtDNA point mutations and numerous mtDNA rearrangements have been discovered, but important questions concerning the relationship between these mutations and their phenotypic expression remain to be resolved. Mutations in mtDNA only explain about 20% of mitochondrial OXPHOS disorders in childhood (Darin et al., 2001). The list of nuclear gene mutations involved in OXPHOS diseases are increasing continuously and may for example involve structural subunits of the respiratory chain, assembly factors, translation factors as well proteins important for the maintenance of mtDNA.

*

Corresponding author. E-mail address: [email protected] (A.-R. Moslemi).

The mitochondrial OXPHOS disorders probably constitute the most common group of neurometabolic diseases in childhood (Darin et al., 2001). The clinical features of these disorders are sometimes characteristic but never specific for any genetic defect. The most commonly affected organs are those with a high energy demand such as skeletal muscle and/or the central nervous system, which explain why the term ‘‘mitochondrial encephalomyopathies’’ (DiMauro et al., 1999) has been applied. However, virtually any organ and tissue can be affected. Heterogeneity in the distribution of mutated mtDNA and the tissue-specific expression of nuclear genes are two plausible explanations for the widely varying clinical phenotypes (Larsson and Clayton, 1995). The major function performed by mitochondria in aerobically active cells is the synthesis of ATP (Fang et al., 1994). The process of ATP synthesis is mediated by the OXPHOS system. The OXPHOS system, located in the mitochondrial inner membrane, is composed of five multisubunit enzyme complexes (Fig. 1). Four of them are NADH-dehydrogenase (NADH–ubiquinone oxidoreductase, complex I), succinate dehydrogenase

1567-7249/$ - see front matter  2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved. doi:10.1016/j.mito.2007.02.002

242

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

Fig. 1. Schematic illustration of the mitochondrial oxidative phosphorylation system showing the electron transport chain enzyme complexes (complexes I–IV) and ATP synthase (complex V). mtDNA-encoded subunits are indicated in orange and nuclear encoded subunits in green. Complex I is composed of 43 subunits, of which 7 are encoded by mtDNA. Nuclear DNA encodes all subunits of complex II. Complex III is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nuclear DNA. Complex IV, the terminal step of the respiratory chain, is composed of 13 structural subunits, three of which are encoded by genes of the mtDNA and form the catalytic core of the enzyme. Complex V couples proton flow from the intermembrane space back to the matrix by the conversion of ADP and inorganic phosphate to ATP. Two subunits in complex V (ATPase 6 and 8 genes) are encoded by mtDNA.

(succinate–ubiquinone oxidoreductase, complex II), cytochrome bc1 complex (ubiquinol–cytochrome c oxidoreductase, complex III), and cytochrome c oxidase (complex IV). Substrates feed reducing equivalents to the respiratory chain at different points. Electrons are passed down the chain and protons are pumped across the inner mitochondrial membrane, buliding up a gradient, which is used to drive ATP production through the reentry of protons via ATP synthase (complex V) (Janssen et al., 2004). Mitochondria also participate in the generation of reactive oxygen species, and the initiation of apoptosis may be an additional mechanism for pathology (Wallace et al., 1998). Human mtDNA is a 16.6 kb double-stranded circular molecule encoding for 13 enzyme subunits involved in the respiratory chain (Fig. 2) (Anderson et al., 1981). They include seven subunits of complex I, cytochrome b of complex III, three subunits of complex IV, and two subunits of complex V. The mtDNA also encodes for two rRNAs and 22 tRNAs necessary for mitochondrial protein synthesis. The replication of mtDNA requires several nuclearencoded factors such as mtRNA polymerase, mitochondrial transcription factor A (mtTFA), DNA polymerase gamma (POLG), deoxyguanosine kinase (DGUOK), and thymidine kinase 2 (TK2) (Larsson and Clayton, 1995; Larsson and Luft, 1999; Kollberg et al., 2005). mtDNA is more vulnerable to mutation than nuclear DNA and the mutation rate is much higher in mtDNA. This can be explained by the lack of histones in mtDNA and the continuous exposure of the molecule to reactive oxygen species. In pathological conditions, there is often a mixture of wild-type and mutated mtDNA, so-called heteroplasmy. mtDNA mutations are functionally recessive and the proportion of mtDNA with a pathogenic mutation must reach a certain level (threshold level) for the phenotypic expression of the mutation. mtDNA is almost exclusively mater-

Fig. 2. Circular map of mtDNA showing the genes for NADH-dehydrogenase (ND) subunits 1–6 and ND4L, cytochrome b (Cyt b), cytochrome c oxidase subunits (COI, II, and III), ATPase 6 and 8 genes and 12S and 16S rRNA. The yellow filled boxes represent 22 tRNA genes. Arrows indicate the origin of replication for the heavy (OH) and the light (OL) strands and the promoters of transcription for the heavy (PH) and light (PL) strands.

nally inherited and many mtDNA disorders therefore display a maternal mode of inheritance. In this article, we review recent progress in the identification of mitochondrial and nuclear gene defects in association with OXPHOS disorders. The genetics and the clinical manifestations of these disorders will be discussed.

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

2. Nuclear gene mutations affecting OXPHOS Nuclear DNA encodes the majority of the approximately 85 structural subunits of the OXPHOS enzyme complexes but there are at least nearly 800 other proteins expressed in the mitochondria that are also synthesized by nuclear genes (Cotter et al., 2004). These proteins may for example be involved in the assembly of the enzyme complexes, maintenance of mtDNA, mitochondrial translation or mitochondrial dynamics. These proteins are synthesized in the cytoplasm, usually as precursors containing an N-terminal extension, which serves as a leader peptide that precisely addresses the protein to mitochondria. 2.1. Mutations in the nuclear-encoded polypeptide subunits of OXPHOS 2.1.1. Complex I Reduced nicotinamide adenine dinucleotide (NADH)– ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone and couples this to proton pumping out of the mitochondrial matrix and into the intermembrane space (Fig. 1). Complex I is the largest enzyme-complex of the respiratory chain and contains at least 43 structural subunits, seven of which are encoded by mtDNA (ND1–ND6, ND4L) (Anderson et al., 1981). Complex I has an L-shaped configuration and can be fragmented into three different fractions. The largest hydrophobic membrane fraction (HP) attaches the complex to the mitochondrial inner membrane while the matrix component is cleaved into the flavoprotein (FP) and the iron–sulphur protein fraction (IP) (Galante and Hatefi, 1979). The complete function of complex I is not yet known. Electron transfer through complex I starts in the FP fraction. The presence of an iron–sulphur cluster in the IP fraction facilitates further electron transport to the HP fraction, which is probably involved in ubiquinone binding and proton translocation (Ohnishi et al., 1998). Isolated complex I deficiency is the most commonly identified biochemical defect in mitochondrial OXPHOS disorders (Darin et al., 2001), but it is probably under-diagnosed, since both lactate levels and muscle morphology may be normal (Kirby et al., 1999; Loeffen et al., 2000). As in other mitochondrial OXPHOS disorders, the clinical features are extremely variable. The most common clinical phenotype in childhood is probably Leigh syndrome (LS, MIM 25600) (Morris et al., 1996). In overall terms, LS is also one of the most common clinical presentations in children with mitochondrial OXPHOS disorders (Darin et al., 2001). In the majority of cases, the disease expresses itself by psychomotor regression, brain stem dysfunction, ataxia, dystonia, and often optic atrophy. A remitting course with acute exacerbations is frequently observed. LS is characterized by distinctive neuropathological features, with focal, bilateral, and symmetric necrotic lesions in the basal ganglia, diencephalon, brain stem, and cerebellum (Leigh,

243

1951). Magnetic resonance imaging (MRI) typically reveals increased signals on T2-weighted images from these areas that are sometimes associated with white matter abnormalities (Munoz et al., 1999; Dinopoulos et al., 2005). Other common presentations in children with complex I deficiency include leukodystrophy, Alpers syndrome (AS), cardiomyopathy, hepatopathy, and fatal infantile lactic acidosis (Morris et al., 1996; Kirby et al., 1999; Loeffen et al., 2000; Darin et al., 2001). AS is probably an underrecognized presentation of mitochondrial OXPHOS disorders in early childhood (Darin et al., 2001). It is most often associated with complex I deficiency but has been identified with other biochemical defects as well. Pathogenic mutations have not been identified in any structural subunits of complex I gene in this disorder. In contrast, a frequent cause seems to be mutations in the nuclear-encoded mtDNA polymerase gamma (POLGI) associated with mtDNA depletion (Naviaux and Nguyen, 2004; Kollberg et al., 2006). AS is characterized neuropathologically by neuronal loss, status spongiosus, and astrocytosis affecting the cerebral cortex (Harding et al., 1995) and clinically by early-onset psychomotor retardation (often episodic), refractory seizures (often myoclonic or with epilepsia partialis continua), cortical blindness and liver disease (Darin et al., 2001). Nuclear mutations are probably involved in 90–95% of children with complex I deficiency (Triepels et al., 2001) but it was not until 1998 that the first mutations were identified in the NDUFS4 and NDUFS8 genes by the group in Nijmegen. (Loeffen et al., 1998; van den Heuvel and Smeitink, 2001) An increasing number of pathogenic mutations in genes encoding different structural subunits of complex I have since then been identified. However, the genetic cause remains unclear in about 60% of patients with complex I deficiency. (Triepels et al., 2001). Pathogenic mutations have been identified in numerous structural subunits associated with different clinical phenotypes (Table 1) and in B17.2L, an assembly factor for complex I, in a child with progressive encephalopathy (Ogilvie et al., 2005).

2.1.2. Complex II Succinate–ubiquinone oxidoreductase (SQR) consists of four nuclear-encoded subunits and is part of both the respiratory chain and the Krebs cycle. It catalyzes the oxidation of succinate to fumarate and transfers the electrons to the ubiquinone pool of the respiratory chain (Fig. 1). Subunits A and B form the succinate dehydrogenase (SDH), while subunits C and D anchor the enzyme to the membrane (Rustin et al., 2002). Mutations in the SDH A, encoding the Fp subunit, have been found in occasional children presenting with LS and complex II deficiency (Bourgeron et al., 1995; Parfait et al., 2000), but also in two sisters with a late onset neurodegenerative disease (Birch-Machin, 2000). In contrast, subunits B, C, and D appear to act as tumor suppressor genes and mutations have been identified in familial paraganglioma and familial as well as in appar-

244

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

Table 1 Nuclear genes involved in complex I deficiency Subunit

Clinical phenotype

Reference

NDUFS1 (IP)

Leukodystrophy Leigh-like with hepatomegaly, growth retardation and anemia Leigh-like Leigh-like and cardiomyopathy Neonatal lactic acidosis and cardiomyopathy Leigh Leigh-like Cardiomyopathy

Be´nit et al. (2001)

NDUFS2 (IP)

NDUFS3 (IP) NDUFS4 (IP)

NDUFS8 (IP) NDUFS7 (HP) NDUFV1 (FP) NDUFV2 (FP)

Leigh Leigh Leigh Macrocephaly, Leukodystrophy and myoclonic epilepsy Leigh-like Early onset hypertrophic cardiomyopathy and encephalopathy

ently sporadic pheochromocytoma (Gimm et al., 2000; Astuti et al., 2001; Baysal, 2003). 2.2. Mutations in the proteins involved in the assembly of OXPHOS subunits 2.2.1. Complex III Ubiquinol cytochrome c reductase (complex III) catalyzes the transfer of electrons from the succinate and nicotinamide-linked dehydrogenases to cytochrome c and it couples this reaction to proton pumping across the inner mitochondrial membrane. Complex III is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nuclear DNA. Pathogenic mutations have not been found in any of the nuclear-encoded subunits. BCS1L is an assembly factor for complex III in human (Petruzzella et al., 1998). Mutations in this gene have been identified in children with complex III deficiency and features of tubulopathy, encephalopathy, and liver failure (de Lonlay et al., 2001) and in the GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome (Visapaa et al., 2002). 2.2.2. Complex IV Cytochrome c oxidase (COX or Complex IV) is the terminal enzyme of the respiratory chain. It catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen and it couples this reaction to proton pumping across the inner mitochondrial membrane. The COX enzyme complex is composed of 13 structural subunits, three of which are encoded by genes of the mtDNA and form the catalytic core of the enzyme. The other 10 subunits are all products of nuclear genes that are translated on cytoplasmic ribosomes and transferred to the mitochondria by different modes of transport. Even though a handful of mutations have been identified in each of the three mtDNA-encoded COX subunits, no mutations have as yet been identified in any of the nuclear DNA-encoded

Loeffen et al. (2001)

Be´nit et al. (2004) Van den Heuvel et al. (1998) Budde et al., 2000 Petruzzella et al. (2001) Be´nit et al. (2003) Loeffen et al. (1998) Procaccio et al., 2004 Triepels et al. (1999) Schuelke et al. (1999) Be´nit et al. (2001) Be´nit et al. (2003)

COX subunits (Adams et al., 1997; Jaksch et al., 1998). A large number of proteins are involved in the assembly and maintenance of the COX complex. In fact, more than 30 different genetic complementation groups for COX assembly have been identified in the yeast Saccharomyces cerevisiae (McEwen et al., 1986; Tzagoloff et al., 1990). Many of the identified accessory proteins in yeast have their counterparts in humans and an increasing number of these proteins have been associated with disease. The SURF1 protein is a putative assembly or maintenance factor for COX (Tiranti et al., 1999), while SCO1 and SCO2 are believed to be involved in copper delivery for the copper centers of COX (Glerum et al., 1996). The COX10 gene encodes heme A:farnesyltransferase, which is required for the biogenesis of functional COX in yeast (Nobrega et al., 1990), while the COX15 protein is involved in the synthesis of heme A, the heme prosthetic group of COX (Barros et al., 2001). The SURF1 gene, which is located on chromosome 9q34, has been found to be the most frequently involved gene in LS with COX deficiency (Zhu et al., 1998; Tiranti et al., 1999; Sue et al., 2000; Moslemi et al., 2003). Mutations in the SCO2 gene, located on chromosome 22q13, were initially identified in 5 unrelated infants with fatal cardioencephalopathy (Papadopoulou et al., 1999; Jaksch et al., 2000). Recently, however, three additional infants have been identified with a different phenotype of delayed infantile onset Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic cardiomyopathy (Jaksch et al., 2001). Compared with mutations in the SURF1 gene, SCO2 mutations appear to be a rarer cause of COX-deficiency, judging by the few cases reported in the literature (Darin et al., 2003). The other identified genetic defects of putative assembly or maintenance factors for COX appear to be even less frequent. Mutations in the SCO1 gene, localized on chromosome 17p13.1, have only been found in two siblings with neonatal-onset hepatic failure and encephalopathy (Valnot

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

245

et al., 2000a), while a mutation in the COX10 gene, located on chromosome 17p13.1–q11.1, has only been identified in three consanguineous siblings with mitochondrial encephalopathy and tubulopathy (Valnot et al., 2000b). The latest contribution to the literature, pathogenic mutations in the COX 15 gene, located on chromosome 10q22, has been identified in a single patient with fatal infantile hypertrophic cardiomyopathy (Antonicka et al., 2003).

2007). A nonsense mutation in MRPS16 has been associated in a child with facial dysmorphic features, limb edema, agenesis of the corpus callosum, increased liver transaminases, lactic acidosis and death at 3 years of age. The patient had complexes I and IV and a mitochondrial translation defect.

2.2.3. Complex V ATP synthase or ATPase (complex V) couples proton flow from the intermembrane space back to the matrix by the conversion of ADP and inorganic phosphate to ATP. ATP synthase is made up of an integral membrane component, F0, composed of at least seven subunits, and a peripheral moiety F1, composed of six subunits, which uses the proton gradient to convert ADP to ATP (and vice versa). Nuclear DNA encodes all the subunits of the two subcomplexes, except for ATPase 6 and 8 of the F0 segment (Elston et al., 1998; Kinosita et al., 2004). No pathogenic mutations have been identified in any of the nuclear subunits. Several assembly genes have been studied in yeast and their human analogs have been described (Wang et al., 2001; Ackerman, 2002). Pathogenic mutations have been identified in one of these genes, ATP12, in two unrelated cases with reduced complex V activity. One case had a malformation syndrome resembling COFS (cerebro-oculofacioskeletal) except for the absence of microphtalmia and cataracts, and the other presented with severe lethal neonatal lactic acidosis (De Meirleir et al., 2004).

All the factors responsible for mtDNA replication are encoded in nuclear DNA. Defects in the cross-talk between the two genomes are thus due to primary mutations in nuclear DNA which cause pathogenic secondary alterations in mtDNA, either multiple mtDNA deletions and/ or a reduced copy number of mtDNA (mt DNA depletion). The mtDNA depletion syndromes are the most common disorders due to defects in intergenomic communication in childhood. This group of autosomal recessive diseases display a very variable phenotype, which may involve muscle, liver, brain, heart, and other organs (Macmillan and Shoubridge, 1996; Vu et al., 1998), including the syndromes of Leigh (Absalon et al., 2001) and Alpers (Naviaux et al., 1999). These disorders may well be under-diagnosed in childhood and broad-based suspicion is warranted, since they may present prenatally with dysmorphic features (Macmillan and Shoubridge, 1996) and with non-specific symptoms in infancy, such as vomiting, failure to thrive, and developmental delay, before multiorgan involvement occurs. (Tsao et al., 2000). Muscle biopsy typically shows ragged red fibers while biochemical investigations often show COX deficiency, sometimes associated with decreased activity in other respiratory chain complexes (Vu et al., 1998). Mutations have recently been identified in the deoxyguanosine kinase gene (DGUOK) and MPV17 associated with a hepatocerebral form and the thymidine kinase gene (TK2) described in a myopathic variant (Mandel et al., 2001; Saada et al., 2001; Spinazzola et al., 2006). In the vast majority of cases, however, the genetic cause remains unclear (Carrozzo et al., 2003). POLG1 encodes the catalytic subunit of mitochondrial DNA polymerase that is the only known polymerase for mtDNA (Clayton, 1982). POLG1 is probably the most frequently involved nuclear gene giving rise to mitochondrial diseases. The pathogenesis involves mtDNA depletion and/ or the accumulation of multiple mtDNA deletions in clinically affected tissues (Kollberg et al., 2006). There is a broad clinical spectrum, from fatal encephalopathy and liver failure in early childhood to mild ataxia or external ophthalmoplegia in late adulthood. In fact, the phenotypic spectrum overlaps. In adults, pathogenic mutations in POLG1 have been associated with autosomal dominant and recessive forms of progressive external ophthalmoplegia (PEO) (Van Goethem et al., 2001), sensory ataxic neuropathy , dysarthria and ophthalmoparesis (SANDO) (Van Goethem et al., 2003), recessive ataxic syndromes, and

2.3. Mutations in proteins involved in mitochondrial translation In addition to mitochondrial tRNAs and rRNAs, several nuclear-encoded factors, such as pseudouridine synthase 1 (PUS1), elongation factor G1 (EFG1), the mitochondrial elongation factor Tu (EFTu), and ribosomal protein S16 (MRPS16), are involved in the mitochondrial translation machinery. Mutations in these genes have recently been linked to a new class of OXPHOS disorders characterized by reduced activity in all the mtDNAencoded respiratory chain complexes and a mitochondrial translation defect. Mutation in the PUS1 gene has been associated with mitochondrial myopathy and sideroblastic anemia (MLASA), which is a rare autosomal recessive disease in children and adults. Affected individuals express progressive exercise intolerance during childhood and the onset of sideroblastic anemia with basal lactic acidemia and mitochondrial myopathy in adolescence (Casas and Fischel-Ghodsian, 2004). Mutation in the EFG1 gene have been associated with prenatal onset of encephalopathy and hepatopathy and early onset LS (Coenen et al., 2004; Valente et al., 2007). Mutations in the EFTu had been described in a patient with severe infantile macrocystic leukodystrophy with micropolygyria (Valente et al.,

2.4. Mutations in proteins involved in mtDNA maintenance

246

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

Parkinsonism (Luoma et al., 2004; Davidzon et al., 2006). The clinical phenotype in the recessive variant is sometimes more severe with onset in childhood of PEO (Van Goethem et al., 2003), MERRF-like features (Van Goethem et al., 2003), or ataxic syndromes (Kollberg et al., 2006; Tzoulis et al., 2006). In children, homozygous or compound heterozygous mutations have frequently been associated with Alpers syndrome (MIM 203700) with liver involvement, also called Alpers-Huttenlocher syndrome (Brandon et al., 2005; Davidzon et al., 2005; Naviaux and Nguyen, 2005). Characteristic clinical features include early-onset psychomotor regression, with a relapsing and remitting course frequently exacerbated by infections, ataxia, refractory seizures with myoclonias and status epilepticus, stroke-like episodes, and frequently liver failure. Patients run a high risk of deterioration if they are exposed to valporate (Horvath et al., 2006; Kollberg et al., 2006; Tzoulis et al., 2006). Multiple mtDNA deletions, mtDNA depletion, and site-specific point mutations have also been described in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) (Hirano et al., 1994; Papadimitriou et al., 1998; Nishigaki et al., 2003). In this disorder, pathogenic mutations have been identified in the thymidine phosphorylase (TP) gene, located on chromosome 22q13.32qter (Nishino et al., 1999). MNGIE is an autosomal recessive disease, characterized by PEO, gastrointestinal dysmotility, thin body habitus, peripheral neuropathy, myopathy, leukoencephalopathy, and lactic acidosis. Although this is predominantly a disease of adults, childhood-onset variants have also been described (Teitelbaum et al., 2002). 2.5. Mutations in genes involved in the fusion and fission of mitochondrial membranes The mitochondria are dynamic organelles that constantly fuse and divide. The balance of these opposing processes regulates the morphology of the mitochondrial network (Chen and Chan, 2005). Mutations in the two pro-fusion genes, Mitofusin 2 (MFN2) and optic atrophy type 1(OPA1), have recently been identified in human diseases. Pathogenic mutations in MFN2 have been identified in the most common form of axonal Charcot– Marie–Tooth neuropathy (CMT2A2, MIM 609260) (Zuchner et al., 2004) as well as in hereditary motor and sensory neuropathy VI (HMSN VI), which is an axonal CMT neuropathy with optic atrophy (Zuchner et al., 2006). Other features of CNS involvement have also been described in this disorder such as pyramidal signs and white matter changes on cerebral MRI (Vucic et al., 2003; Chung et al., 2006). Optic atrophy type 1 (OPA1, MIM 165500) is a major locus for dominantly inherited optic neuropathy leading to progressive visual loss (Delettre et al., 2000). This disorder is sometimes associated with sensorineural hearing impairment (Hoyt, 1980).

2.6. Other defects in nuclear-encoded proteins affecting the OXPHOS system 2.6.1. Friedreich’s ataxia (FA) FA(MIM 229300) is a neurodegenerative disorder, which usually starts with progressive ataxia between 5 and 16 years of age leading to wheel-chair dependency by 25 years of age on average. It is characterized by combined involvement of peripheral nerves, cerebellar tracts, pyramidal tracts, and posterior columns. Skeletal deformities and cardiac involvement are common and involvement of optic pathways and diabetes mellitus are sometimes associated (Harding, 1981). FRDA results from a triplet expansion in the first intron of the frataxin gene, and is associated with a decreased frataxin protein (Campuzano et al., 1996; Campuzano et al., 1997). This nuclear-encoded protein is localized in the mitochondrial matrix and although the exact role of frataxin is not known, mitochondrial respiratory chain deficiency, oxidative stress and mitochondrial iron accumulation have been shown to be important components of the disease mechanism (Rotig et al., 1997). This knowledge has led to the initiation of therapy with antioxidants, which has been shown to be effective against the hypertrophic cardiomyopathy in this disease (Rustin et al., 1999). 2.6.2. Hereditary spastic paraplegia (HSP) HSP constitute a group of disorders with variable age of onset and inheritance, characterized by progressive weakness and spasticity of the lower limbs due to degeneration of corticospinal axons (Fink, 2003). Mutations in the paraplegin gene, a mitochondrial metalloprotease localized to chromosome 16q24.3 have been associated with an autosomal recessive HSP (HSP7) (Casari et al., 1998). A complex I–III deficiency of the respiratory chain has been found in this disorder and may reflect excess free radical-mediated damage, judged by the similarities in this aspect to FA and the SOD2 knockout mouse (Wilkinson et al., 2004). Mutations in the gene encoding mitochondrial chaperonin Hsp60, on chromosome 2q24–34, have been identified in a French family with an autosomal dominant form (Hansen et al., 2002). Recently, respiratory chain defects have also been identified in several other HSPs, indicating that mitochondrial dysfunction might be an important pathogenic mechanism in these disorders (Piemonte et al., 2001; McDermott et al., 2003). 3. Primary mtDNA abnormalities affecting OXPHOS Primary mtDNA abnormalities in children are due to mtDNA rearrangements (deletions or duplications) and point mutations or insertions. Single mtDNA deletions are usually sporadic and females with mtDNA deletions usually do not transmit the deletion to their children. mtDNA point mutations show usually maternally mode of inheritance with males and females equally affected but sporadic mutations occur as well.

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

3.1. Point mutations Disorders associated with mtDNA point mutations in children may be due to either point mutations/insertions in tRNA, rRNA or protein coding genes (DiMauro and Moraes, 1993; Wallace, 1994; Larsson and Clayton, 1995). Mutations in tRNA genes cause impaired protein synthesis affecting all polypeptides encoded by mtDNA. More than 100 different pathogenic tRNA mutations have been reported in adults and children in association with different endocrine, neurological, cardiological, and neuromuscular disorders (Chinnery and Turnbull, 2000; Brandon et al., 2005). The earliest discovered pathogenic tRNA mutations were the tRNALys A8344G and tRNALeu(UUR) A3243G (Goto et al., 1990; Shoffner et al., 1990). These genes have been shown to be particular ‘hotspots’ for mutations in mtDNA. The tRNALys A8344G was first described in association with myoclonus epilepsy and ragged red fibers (MERRF, MIM 545000). The most characteristic symptom of MERRF is myoclonus epilepsy, generalized convulsions, cerebellar ataxia, myopathy, mental deterioration, and lactic acidosis (Kishi et al., 1988). Clinical manifestation of the tRNALys A8344G may be quite variable (Silvestri et al., 1992; Hammans et al., 1993). The mutation changes a conserved nucleotide in the TwC arm, which is involved in the interaction of the tRNA with the ribosomal surface (Shoffner et al., 1990). PCR analysis of single muscle fibers has demonstrated that high levels of the mutation, >95%, cause dysfunction of complex IV in muscle fibers (Moslemi et al., 1998). The clinical manifestations of the tRNALeu(UUR) A3243G mutation may vary to an even greater extent than the tRNALys A8344G but is typically found in association with miochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS, MIM 540000). MELAS is characterized by short stature, seizure, lactic acidosis and recurrent cerebral insults causing hemiplegia, hemianopia or cortical blindness (Hirano and Pavlakis, 1994). Onset of the disease is in childhood or later in life. In adults, the A3243G mutation may in addition manifest as maternally inherited diabetes-deafness and hypertrophic cardiomyopathy (Reardon et al., 1992; van den Ouweland et al., 1992; Manouvrier et al., 1995). Pathogenic mutations in mitochondrial rRNA have been reported in association with maternally inherited hearing loss (Fischel-Ghodsian, 1999; Zhao et al., 2004). mtDNA encodes 13 enzyme subunits involved in the respiratory chain complexes (I, III, IV, and V). Mutations in these genes lead to impaired function of the affected enzyme complex. Complex I, the largest of the OXPHOS complexes, consist of 43 subunits, seven of which are encoded by mtDNA (ND1–ND6 and ND4L). Mutations in these genes are associated with Leber’s hereditary optic neuropathy (LHON, MIM 535000), which predominantly affects males in the late twenties, is characterized by acute or subacute visual loss with maternal inheritance. The majority

247

(approximately 90%) of LHON patients have pathogenic mutations in either one of the G11778A in ND4, A3460G in ND1 or 14484 in ND6 genes (Wallace et al., 1988; Poulton et al., 1991; Brandon et al., 2005). Even though pathology of LHON in general is limited to the optic system, in rare case, complication by Leigh-like encephalopathy or more frequently a multiple sclerosis-like syndrome may occur (Harding et al., 1992; Vanopdenbosch et al., 2000; Funalot et al., 2002). Although only one subunit of complex III, cytochrome b, is encoded by mtDNA, several mutations in this gene have been associated with various OXPHOS disorders such as LHON, mitochondrial encephalomyopathy, hypertrophic cardiomyopathy, and exercise intolerance (Johns and Neufeld, 1991; Andreu et al., 1999; Keightley et al., 2000). Complex IV, the terminal step of the respiratory chain, consists of 13 enzyme–subunits, of which three are mitochondrially encoded (COXI, II and III). COXI, II, and III constitute the catalytic core of the complex and pathogenic mutations in these subunits have been associated with Leigh-like syndrome, mitochondrial myopathy, rhabdomyolysis and myopathy with exercise intolerance (Rahman et al., 1999; Tiranti et al., 2000; McFarland et al., 2004). Pathogenic mutations in the ATPase 6 gene leading to partial complex V deficiency have been described in various neurological diseases. Among these mutations the T8993G mutation, converting a conserved leucine into arginine (L155R), is the most common. This mutation causes neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP, MIM 551500) (Holt et al., 1990), when the mutant load is high. The same mutation, at levels close to homoplasmy, causes MILS (Tatuch et al., 1992). A second mutation at the same position (T8993C), replacing leucine to proline (L155P) is usually associated with milder clinical phenotypes (de Vries et al., 1993). Other mutations in ATPase 6 gene, e.g. T9176G (L217P), T9185C (L220P) and T9191C (L222P) have also been described in association with LS and familial bilateral striatal necrosis (FBSN) (Thyagarajan et al., 1995; Wilson et al., 2000; Moslemi et al., 2005) (Dionisi-Vici et al., 1998; Carrozzo et al., 2000). 3.2. mtDNA rearrangements Single mtDNA deletions in children are associated with multisystem disorders. In infants mtDNA deletions have been associated with Pearson’s syndrome (PS, MIM 557000), which is characterized by sideroblastic anemia, hepatic, renal, and exocrine pancreatic dysfunction (Rotig et al., 1990; Smith et al., 1995). In addition to mtDNA deletions several cases with PS with mtDNA duplications have been described (Smith et al., 1995; Muraki et al., 2001; Jacobs et al., 2004). Infants with PS usually die in the first year of age. The survivors may develop Kearns–Sayres syndrome (KSS, MIM 530000) later on in childhood (Larsson et al., 1990). KSS is usually a disease with onset in adolescence, clinically associated with heart block, growth failure,

248

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

mental retardation, ataxia, progressive external ophtalmoplegia, and pigmentary degeneration of the retina (Zeviani et al., 1988; Oldfors et al., 1990). Muscle biopsy in KSS usually shows ragged red fibers with deficient COX activity. In addition to PS and KSS, mtDNA deletions may occasionally be the cause of severe to fatal dilated cardiomyopathy (Marin-Garcia et al., 1996; Moslemi et al., 2000; Ruppert and Maisch, 2000) and atypical multisystem presentations have also been described (Tulinius et al., 1995). In summary, OXPHOS related disorders are relatively frequent causes of disease in childhood with a broad spectrum of clinical presentations. They are caused by mutations in mitochondrial or nuclear genes, which directly or indirectly affect mitochondrial oxidative phosphorylation (OXPHOS). The recent progresses in DNA research presented in this article have broadened the understanding of the pathogenesis behind these disorders and have facilitated prenatal diagnosis. References Absalon, M.J., Harding, C.O., Fain, D.R., Li, L., Mack, K.J., 2001. Leigh syndrome in an infant resulting from mitochondrial DNA depletion. Pediatr. Neurol. 24 (1), 60–63. Ackerman, S.H., 2002. Atp11p and Atp12p are chaperones for F(1)ATPase biogenesis in mitochondria. Biochim. Biophys. Acta 1555 (1–3), 101–105. Adams, P.L., Lightowlers, R.N., Turnbull, D.M., 1997. Molecular analysis of cytochrome c oxidase deficiency in Leigh’s syndrome. Ann. Neurol. 41 (2), 268–270. Anderson, S., Bankier, A.T., Barrell, B.G., de Bruijn, M.H., Coulson, A.R., Drouin, J., Eperon, I.C., Nierlich, D.P., Roe, B.A., Sanger, F., Schreier, P.H., Smith, A.J., Staden, R., Young, I.G., 1981. Sequence and organization of the human mitochondrial genome. Nature 290 (5806), 457–465. Andreu, A.L., Hanna, M.G., Reichmann, H., Bruno, C., Penn, A.S., Tanji, K., Pallotti, F., Iwata, S., Bonilla, E., Lach, B., MorganHughes, J., DiMauro, S., 1999. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. 341 (14), 1037–1044. Antonicka, H., Ogilvie, I., Taivassalo, T., Anitori, R.P., Haller, R.G., Vissing, J., Kennaway, N.G., Shoubridge, E.A., 2003. Identification and characterization of a common set of complex I assembly intermediates in mitochondria from patients with complex I deficiency. J. Biol. Chem. 278 (44), 43081–43088. Astuti, D., Latif, F., Dallol, A., Dahia, P.L., Douglas, F., George, E., Skoldberg, F., Husebye, E.S., Eng, C., Maher, E.R., 2001. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69 (1), 49–54, Epub 2001 Jun 12. Barros, M.H., Carlson, C.G., Glerum, D.M., Tzagoloff, A., 2001. Involvement of mitochondrial ferredoxin and Cox15p in hydroxylation of heme O. FEBS Lett. 492 (1–2), 133–138. Baysal, B.E., 2003. On the association of succinate dehydrogenase mutations with hereditary paraganglioma. Trends Endocrinol. Metab. 14 (10), 453–459. Be´nit, P., Chretien, D., Kadhom, N., de Lonlay-Debeney, P., CormierDaire, V., Cabral, A., Peudenier, S., Rustin, P., Munnich, A., Rotig, A., 2001. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am. J. Hum. Genet. 68 (6), 1344–1352.

Be´nit, P., Beugnot, R., Chretien, D., Giurgea, I., De Lonlay-Debeney, P., Issartel, J.P., Corral-Debrinski, M., Kerscher, S., Rustin, P., Rotig, A., Munnich, A., 2003. Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. Hum. Mutat. 21 (6), 582–596. Be´nit, P., Slama, A., Cartault, F., Giurgea, I., Chretien, D., Lebon, S., Marsac, C., Munnich, A., Rotig, A., Rustin, P., 2004. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J. Med. Genet. 41 (1), 14–27. Birch-Machin, M.A., 2000. Mitochondria and skin disease. Clin. Exp. Dermatol. 25 (2), 141–146. Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A., 1995. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat. Genet. 11 (2), 144–149. Brandon, M.C., Lott, M.T., Nguyen, K.C., Spolim, S., Navathe, S.B., Baldi, P., Wallace, D.C., 2005. MITOMAP: a human mitochondrial genome database – 2004 update. Nucleic Acids Res. 33 (Database issue), D611–D613. Campuzano, V., Montermini, L., Lutz, Y., Cova, L., Hindelang, C., Jiralerspong, S., Trottier, Y., Kish, S.J., Faucheux, B., Trouillas, P., Authier, F.J., Durr, A., Mandel, J.L., Vescovi, A., Pandolfo, M., Koenig, M., 1996. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271 (5254), 1423–1427. Campuzano, V., Montermini, L., Molto, M.D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., et al., 1997. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum. Mol. Genet. 6 (11), 1771–1780. Carrozzo, R., Murray, J., Capuano, O., Tessa, A., Chichierchia, G., Neglia, M.R., Capaldi, R.A., Santorelli, F.M., 2000. A novel mtDNA mutation in the ATPase6 gene studied by E. coli modeling. Neurol. Sci. 21 (Suppl. 5), S983–S984. Carrozzo, R., Bornstein, B., Lucioli, S., Campos, Y., de la Pena, P., Petit, N., Dionisi-Vici, C., Vilarinho, L., Rizza, T., Bertini, E., Garesse, R., Santorelli, F.M., Arenas, J., 2003. Mutation analysis in 16 patients with mtDNA depletion. Hum. Mutat. 21 (4), 453–454. Casari, G., De Fusco, M., Ciarmatori, S., Zeviani, M., Mora, M., Fernandez, P., De Michele, G., Filla, A., Cocozza, S., Marconi, R., Durr, A., Fontaine, B., Ballabio, A., 1998. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93 (6), 973–983. Casas, K.A., Fischel-Ghodsian, N., 2004. Mitochondrial myopathy and sideroblastic anemia. Am. J. Med. Genet. A 125 (2), 201–204. Chen, H., Chan, D.C., 2005. Emerging functions of mammalian mitochondrial fusion and fission. Hum. Mol. Genet. 14 (Spec No. 2), R283–R289. Chinnery, P.F., Turnbull, D.M., 2000. Mitochondrial DNA mutations in the pathogenesis of human disease. Mol. Med. Today 6 (11), 425–432. Chung, K.W., Kim, S.B., Park, K.D., Choi, K.G., Lee, J.H., Eun, H.W., Suh, J.S., Hwang, J.H., Kim, W.K., Seo, B.C., Kim, S.H., Son, I.H., Kim, S.M., Sunwoo, I.N., Choi, B.O., 2006. Early onset severe and late-onset mild Charcot–Marie–Tooth disease with mitofusin 2 (MFN2) mutations. Brain 129 (Pt 8), 2103–2118. Clayton, D.A., 1982. Replication of animal mitochondrial DNA. Cell 28 (4), 693–705. Coenen, M.J., Antonicka, H., Ugalde, C., Sasarman, F., Rossi, R., Heister, J.G., Newbold, R.F., Trijbels, F.J., van den Heuvel, L.P., Shoubridge, E.A., Smeitink, J.A., 2004. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N. Engl. J. Med. 351 (20), 2080–2086. Cotter, D., Guda, P., Fahy, E., Subramaniam, S., 2004. MitoProteome: mitochondrial protein sequence database and annotation system. Nucleic Acids Res. 32 (Database issue), D463–D467.

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252 Darin, N., Oldfors, A., Moslemi, A.R., Holme, E., Tulinius, M., 2001. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann. Neurol. 49 (3), 377–383. Darin, N., Moslemi, A.R., Lebon, S., Rustin, P., Holme, E., Oldfors, A., Tulinius, M., 2003. Genotypes and clinical phenotypes in children with cytochrome-c oxidase deficiency. Neuropediatrics 34 (6), 311–317. Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H.L., Kirby, D., Thorburn, D.R., DiMauro, S., 2005. POLG mutations and Alpers syndrome. Ann. Neurol. 57 (6), 921–923. Davidzon, G., Greene, P., Mancuso, M., Klos, K.J., Ahlskog, J.E., Hirano, M., DiMauro, S., 2006. Early-onset familial parkinsonism due to POLG mutations. Ann. Neurol. 59 (5), 859–862. Delettre, C., Lenaers, G., Griffoin, J.M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C.P., 2000. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat. Genet. 26 (2), 207–210. de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J.W., Benayoun, E., Chretien, D., Kadhom, N., Lombes, A., de Baulny, H.O., Niaudet, P., Munnich, A., Rustin, P., Rotig, A., 2001. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nat. Genet. 29 (1), 57–60. De Meirleir, L., Seneca, S., Lissens, W., De Clercq, I., Eyskens, F., Gerlo, E., Smet, J., Van Coster, R., 2004. Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J. Med. Genet. 41 (2), 120–124. de Vries, D.D., van Engelen, B.G., Gabreels, F.J., Ruitenbeek, W., van Oost, B.A., 1993. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh’s syndrome. Ann. Neurol. 34 (3), 410–412. DiMauro, S., Moraes, C.T., 1993. Mitochondrial encephalomyopathies. Arch. Neurol. 50 (11), 1197–1208. DiMauro, S., Bonilla, E., De Vivo, D.C., 1999. Does the patient have a mitochondrial encephalomyopathy? J. Child. Neurol. 14 (Suppl. 1), S23–S35. Dinopoulos, A., Cecil, K.M., Schapiro, M.B., Papadimitriou, A., Hadjigeorgiou, G.M., Wong, B., deGrauw, T., Egelhoff, J.C., 2005. Brain MRI and proton MRS findings in infants and children with respiratory chain defects. Neuropediatrics 36 (5), 290–301. Dionisi-Vici, C., Seneca, S., Zeviani, M., Fariello, G., Rimoldi, M., Bertini, E., De Meirleir, L., 1998. Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J. Inherit. Metab. Dis. 21 (1), 2–8. Elston, T., Wang, H., Oster, G., 1998. Energy transduction in ATP synthase. Nature 391 (6666), 510–513. Fang, W., Huang, C.C., Chu, N.S., Lee, C.C., Chen, R.S., Pang, C.Y., Shih, K.D., Wei, Y.H., 1994. Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome: report of a Chinese family with mitochondrial DNA point mutation in tRNA(Lys) gene. Muscle Nerve 17 (1), 52–57. Fink, J.K., 2003. Advances in the hereditary spastic paraplegias. Exp. Neurol. 184 (Suppl. 1), S106–S110. Fischel-Ghodsian, N., 1999. Mitochondrial deafness mutations reviewed. Hum. Mutat. 13 (4), 261–270. Funalot, B., Reynier, P., Vighetto, A., Ranoux, D., Bonnefont, J.P., Godinot, C., Malthiery, Y., Mas, J.L., 2002. Leigh-like encephalopathy complicating Leber’s hereditary optic neuropathy. Ann. Neurol. 52 (3), 374–377. Galante, Y.M., Hatefi, Y., 1979. Purification and molecular and enzymic properties of mitochondrial NADH dehydrogenase. Arch. Biochem. Biophys. 192 (2), 559–568. Gimm, O., Armanios, M., Dziema, H., Neumann, H.P., Eng, C., 2000. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res. 60 (24), 6822–6825.

249

Glerum, D.M., Shtanko, A., Tzagoloff, A., 1996. SCO1 and SCO2 act as high copy suppressors of a mitochondrial copper recruitment defect in Saccharomyces cerevisiae. J. Biol. Chem. 271 (34), 20531–20535. Goto, Y., Nonaka, I., Horai, S., 1990. A mutation in the tRNA (Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348 (6302), 651–653. Hammans, S.R., Sweeney, M.G., Brockington, M., Lennox, G.G., Lawton, N.F., Kennedy, C.R., Morgan-Hughes, J.A., Harding, A.E., 1993. The mitochondrial DNA transfer RNA(Lys)A fi G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain 116 (Pt 3), 617–632. Hansen, J.J., Durr, A., Cournu-Rebeix, I., Georgopoulos, C., Ang, D., Nielsen, M.N., Davoine, C.S., Brice, A., Fontaine, B., Gregersen, N., Bross, P., 2002. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am. J. Hum. Genet. 70 (5), 1328–1332, Epub 2002 Mar 15. Harding, A.E., 1981. Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich’s ataxia. J. Neurol. Neurosurg. Psychiatry 44 (6), 503–508. Harding, A.E., Sweeney, M.G., Miller, D.H., Mumford, C.J., KellarWood, H., Menard, D., McDonald, W.I., Compston, D.A., 1992. Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 115 (Pt 4), 979–989. Harding, B.N., Alsanjari, N., Smith, S.J., Wiles, C.M., Thrush, D., Miller, D.H., Scaravilli, F., Harding, A.E., 1995. Progressive neuronal degeneration of childhood with liver disease (Alpers’ disease) presenting in young adults. J. Neurol. Neurosurg. Psychiatry 58 (3), 320–325. Hirano, M., Pavlakis, S.G., 1994. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts. J. Child Neurol. 9 (1), 4–13. Hirano, M., Silvestri, G., Blake, D.M., Lombes, A., Minetti, C., Bonilla, E., Hays, A.P., Lovelace, R.E., Butler, I., Bertorini, T.E., et al., 1994. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology 44 (4), 721–727. Holt, I.J., Harding, A.E., Morgan-Hughes, J.A., 1988. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331 (6158), 717–719. Holt, I.J., Harding, A.E., Petty, R.K., Morgan-Hughes, J.A., 1990. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46 (3), 428–433. Horvath, R., Hudson, G., Ferrari, G., Futterer, N., Ahola, S., Lamantea, E., Prokisch, H., Lochmuller, H., McFarland, R., Ramesh, V., Klopstock, T., Freisinger, P., Salvi, F., Mayr, J.A., Santer, R., Tesarova, M., Zeman, J., Udd, B., Taylor, R.W., Turnbull, D., Hanna, M., Fialho, D., Suomalainen, A., Zeviani, M., Chinnery, P.F., 2006. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 129 (Pt. 7), 1674–1684. Hoyt, C.S., 1980. Autosomal dominant optic atrophy. A spectrum of disability. Ophthalmology 87 (3), 245–251. Jacobs, L.J., Jongbloed, R.J., Wijburg, F.A., de Klerk, J.B., Geraedts, J.P., Nijland, J.G., Scholte, H.R., de Coo, I.F., Smeets, H.J., 2004. Pearson syndrome and the role of deletion dimers and duplications in the mtDNA. J. Inherit. Metab. Dis. 27 (1), 47–55. Jaksch, M., Hofmann, S., Kleinle, S., Liechti-Gallati, S., Pongratz, D.E., Muller-Hocker, J., Jedele, K.B., Meitinger, T., Gerbitz, K.D., 1998. A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy. J. Med. Genet. 35 (11), 895–900. Jaksch, M., Ogilvie, I., Yao, J., Kortenhaus, G., Bresser, H.G., Gerbitz, K.D., Shoubridge, E.A., 2000. Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum. Mol. Genet. 9 (5), 795–801. Jaksch, M., Horvath, R., Horn, N., Auer, D.P., Macmillan, C., Peters, J., Gerbitz, K.D., Kraegeloh-Mann, I., Muntau, A., Karcagi, V.,

250

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

Kalmanchey, Lochmuller, H., Shoubridge, E.A., Freisinger, P., 2001. Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy. Neurology 57 (8), 1440–1446. Janssen, R.J., van den Heuvel, L.P., Smeitink, J.A., 2004. Genetic defects in the oxidative phosphorylation (OXPHOS) system. Expert Rev. Mol. Diagn. 4 (2), 143–156. Johns, D.R., Neufeld, M.J., 1991. Cytochrome b mutations in Leber hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 181 (3), 1358–1364. Keightley, J.A., Anitori, R., Burton, M.D., Quan, F., Buist, N.R., Kennaway, N.G., 2000. Mitochondrial encephalomyopathy and complex III deficiency associated with a stop-codon mutation in the cytochrome b gene. Am. J. Hum. Genet. 67 (6), 1400–1410. Kinosita Jr., K., Adachi, K., Itoh, H., 2004. Rotation of F1-ATPase: how an ATP-driven molecular machine may work. Annu. Rev. Biophys. Biomol. Struct 33, 245–268. Kirby, D.M., Crawford, M., Cleary, M.A., Dahl, H.H., Dennett, X., Thorburn, D.R., 1999. Respiratory chain complex I deficiency: an underdiagnosed energy generation disorder. Neurology 52 (6), 1255–1264. Kishi, M., Yamamura, Y., Kurihara, T., Fukuhara, N., Tsuruta, K., Matsukura, S., Hayashi, T., Nakagawa, M., Kuriyama, M., 1988. An autopsy case of mitochondrial encephalomyopathy: biochemical and electron microscopic studies of the brain. J. Neurol. Sci. 86 (1), 31–40. Kollberg, G., Jansson, M., Perez-Bercoff, A., Melberg, A., Lindberg, C., Holme, E., Moslemi, A.R., Oldfors, A., 2005. Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations. Eur. J. Hum. Genet.. Kollberg, G., Moslemi, A.R., Darin, N., Nennesmo, I., Bjarnadottir, I., Uvebrant, P., Holme, E., Melberg, A., Tulinius, M., Oldfors, A., 2006. POLG1 mutations associated with progressive encephalopathy in childhood. J. Neuropathol. Exp. Neurol. 65 (8), 758–768. Larsson, N.G., Clayton, D.A., 1995. Molecular genetic aspects of human mitochondrial disorders. Annu. Rev. Genet. 29, 151–178. Larsson, N.G., Luft, R., 1999. Revolution in mitochondrial medicine. FEBS Lett. 455 (3), 199–202. Larsson, N.G., Holme, E., Kristiansson, B., Oldfors, A., Tulinius, M., 1990. Progressive increase of the mutated mitochondrial DNA fraction in Kearns–Sayre syndrome. Pediatr Res. 28 (2), 131–136. Leigh, D., 1951. Subacute necrotizing encephalomyelopathy in an infant. J. Neurochem. 14 (3), 216–221. Lestienne, P., Ponsot, G., 1988. Kearns–Sayre syndrome with muscle mitochondrial DNA deletion. Lancet 1 (8590), 885. Loeffen, J., Elpeleg, O., Smeitink, J., Smeets, R., Stockler-Ipsiroglu, S., Mandel, H., Sengers, R., Trijbels, F., van den Heuvel, L., 1998. The first nuclear-encoded complex I mutation in a patient with Leigh syndrome. Am. J. Hum. Genet. 63 (6), 1598–1608. Loeffen, J.L., Smeitink, J.A., Trijbels, J.M., Janssen, A.J., Triepels, R.H., Sengers, R.C., van den Heuvel, L.P., 2000. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum. Mutat. 15 (2), 123–134. Loeffen, J., Elpeleg, O., Smeitink, J., Smeets, R., Stockler-Ipsiroglu, S., Mandel, H., Sengers, R., Trijbels, F., van den Heuvel, L., 2001. Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy. Ann. Neurol. 49 (2), 195–201. Luoma, P., Melberg, A., Rinne, J.O., Kaukonen, J.A., Nupponen, N.N., Chalmers, R.M., Oldfors, A., Rautakorpi, I., Peltonen, L., Majamaa, K., Somer, H., Suomalainen, A., 2004. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364 (9437), 875–882. Macmillan, C.J., Shoubridge, E.A., 1996. Mitochondrial DNA depletion: prevalence in a pediatric population referred for neurologic evaluation. Pediatr. Neurol. 14 (3), 203–210. Mandel, H., Szargel, R., Labay, V., Elpeleg, O., Saada, A., Shalata, A., Anbinder, Y., Berkowitz, D., Hartman, C., Barak, M., Eriksson, S., Cohen, N., 2001. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat. Genet. 29 (3), 337–341.

Manouvrier, S., Rotig, A., Hannebique, G., Gheerbrandt, J.D., RoyerLegrain, G., Munnich, A., Parent, M., Grunfeld, J.P., Largilliere, C., Lombes, A., et al., 1995. Point mutation of the mitochondrial tRNA(Leu) gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness. J. Med. Genet. 32 (8), 654–656. Marin-Garcia, J., Goldenthal, M.J., Ananthakrishnan, R., Pierpont, M.E., Fricker, F.J., Lipshultz, S.E., Perez-Atayde, A., 1996. Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy. Cardiovasc. Res. 31 (2), 306–313. McDermott, C.J., Taylor, R.W., Hayes, C., Johnson, M., Bushby, K.M., Turnbull, D.M., Shaw, P.J., 2003. Investigation of mitochondrial function in hereditary spastic paraparesis. Neuroreport 14 (3), 485–488. McEwen, J.E., Ko, C., Kloeckner-Gruissem, B., Poyton, R.O., 1986. Nuclear functions required for cytochrome c oxidase biogenesis in Saccharomyces cerevisiae. Characterization of mutants in 34 complementation groups. J. Biol. Chem. 261 (25), 11872–11879. McFarland, R., Taylor, R.W., Chinnery, P.F., Howell, N., Turnbull, D.M., 2004. A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul. Disord. 14 (2), 162–166. Morris, A.A., Leonard, J.V., Brown, G.K., Bidouki, S.K., Bindoff, L.A., Woodward, C.E., Harding, A.E., Lake, B.D., Harding, B.N., Farrell, M.A., Bell, J.E., Mirakhur, M., Turnbull, D.M., 1996. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann. Neurol. 40 (1), 25–30. Moslemi, A.R., Tulinius, M., Holme, E., Oldfors, A., 1998. Threshold expression of the tRNA(Lys) A8344G mutation in single muscle fibres. Neuromuscul. Disord. 8 (5), 345–349. Moslemi, A.R., Selimovic, N., Bergh, C.H., Oldfors, A., 2000. Fatal dilated cardiomyopathy associated with a mitochondrial DNA deletion. Cardiology 94 (1), 68–71. Moslemi, A.R., Tulinius, M., Darin, N., Aman, P., Holme, E., Oldfors, A., 2003. SURF1 gene mutations in three cases with Leigh syndrome and cytochrome c oxidase deficiency. Neurology 61 (7), 991–993. Moslemi, A.R., Darin, N., Tulinius, M., Oldfors, A., Holme, E., 2005. Two new mutations in the MTATP6 gene associated with Leigh syndrome. Neuropediatrics 36 (5), 314–318. Munoz, A., Mateos, F., Simon, R., Garcia-Silva, M.T., Cabello, S., Arenas, J., 1999. Mitochondrial diseases in children: neuroradiological and clinical features in 17 patients. Neuroradiology 41 (12), 920– 928. Muraki, K., Sakura, N., Ueda, H., Kihara, H., Goto, Y., 2001. Clinical implications of duplicated mtDNA in Pearson syndrome. Am. J. Med. Genet. 98 (3), 205–209. Naviaux, R.K., Nguyen, K.V., 2004. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann. Neurol. 55 (5), 706–712. Naviaux, R.K., Nguyen, K.V., 2005. POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann. Neurol. 58 (3), 491. Naviaux, R.K., Nyhan, W.L., Barshop, B.A., Poulton, J., Markusic, D., Karpinski, N.C., Haas, R.H., 1999. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann. Neurol. 45 (1), 54–58. Nishigaki, Y., Marti, R., Copeland, W.C., Hirano, M., 2003. Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J. Clin. Invest. 111 (12), 1913–1921. Nishino, I., Spinazzola, A., Hirano, M., 1999. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283 (5402), 689–692. Nobrega, M.P., Nobrega, F.G., Tzagoloff, A., 1990. COX10 codes for a protein homologous to the ORF1 product of Paracoccus denitrificans and is required for the synthesis of yeast cytochrome oxidase. J. Biol. Chem. 265 (24), 14220–14226. Ogilvie, I., Kennaway, N.G., Shoubridge, E.A., 2005. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J. Clin. Invest. 115 (10), 2784–2792.

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252 Ohnishi, T., Tsuji, K., Ohmura, T., Matsumoto, H., Wang, X., Takahashi, A., Nagaoka, S., Takabayashi, A., Takahahsi, A., 1998. Accumulation of stress protein 72 (HSP72) in muscle and spleen of goldfish taken into space. Adv. Space Res. 21 (8–9), 1077–1080. Oldfors, A., Fyhr, I.M., Holme, E., Larsson, N.G., Tulinius, M., 1990. Neuropathology in Kearns–Sayre syndrome. Acta. Neuropathol. (Berl.) 80 (5), 541–546. Papadimitriou, A., Comi, G.P., Hadjigeorgiou, G.M., Bordoni, A., Sciacco, M., Napoli, L., Prelle, A., Moggio, M., Fagiolari, G., Bresolin, N., Salani, S., Anastasopoulos, I., Giassakis, G., Divari, R., Scarlato, G., 1998. Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome. Neurology 51 (4), 1086–1092. Papadopoulou, L.C., Sue, C.M., Davidson, M.M., Tanji, K., Nishino, I., Sadlock, J.E., Krishna, S., Walker, W., Selby, J., Glerum, D.M., Coster, R.V., Lyon, G., Scalais, E., Lebel, R., Kaplan, P., Shanske, S., De Vivo, D.C., Bonilla, E., Hirano, M., DiMauro, S., Schon, E.A., 1999. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat. Genet. 23 (3), 333–337. Parfait, B., Chretien, D., Rotig, A., Marsac, C., Munnich, A., Rustin, P., 2000. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum. Genet. 106 (2), 236–243. Petruzzella, V., Tiranti, V., Fernandez, P., Ianna, P., Carrozzo, R., Zeviani, M., 1998. Identification and characterization of human cDNAs specific to BCS1, PET112, SCO1, COX15, and COX11, five genes involved in the formation and function of the mitochondrial respiratory chain. Genomics 54 (3), 494–504. Petruzzella, V., Vergari, R., Puzziferri, I., Boffoli, D., Lamantea, E., Zeviani, M., Papa, S., 2001. A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome. Hum. Mol. Genet. 10 (5), 529–535. Piemonte, F., Casali, C., Carrozzo, R., Schagger, H., Patrono, C., Tessa, A., Tozzi, G., Cricchi, F., Di Capua, M., Siciliano, G., Amabile, G.A., Morocutti, C., Bertini, E., Santorelli, F.M., 2001. Respiratory chain defects in hereditary spastic paraplegias. Neuromuscul. Disord. 11 (6–7), 565–569. Poulton, J., Deadman, M.E., Bronte-Stewart, J., Foulds, W.S., Gardiner, R.M., 1991. Analysis of mitochondrial DNA in Leber’s hereditary optic neuropathy. J. Med. Genet. 28 (11), 765–770. Procaccio, V., Wallace, D.C., 2004. Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. Neurology 62 (10), 1899–1901. Rahman, S., Taanman, J.W., Cooper, J.M., Nelson, I., Hargreaves, I., Meunier, B., Hanna, M.G., Garcia, J.J., Capaldi, R.A., Lake, B.D., Leonard, J.V., Schapira, A.H., 1999. A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy. Am. J. Hum. Genet. 65 (4), 1030–1039. Reardon, W., Ross, R.J., Sweeney, M.G., Luxon, L.M., Pembrey, M.E., Harding, A.E., Trembath, R.C., 1992. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340 (8832), 1376–1379. Rotig, A., Cormier, V., Blanche, S., Bonnefont, J.P., Ledeist, F., Romero, N., Schmitz, J., Rustin, P., Fischer, A., Saudubray, J.M., et al., 1990. Pearson’s marrow-pancreas syndrome. A multisystem mitochondrial disorder in infancy. J. Clin. Invest. 86 (5), 1601–1608. Rotig, A., de Lonlay, P., Chretien, D., Foury, F., Koenig, M., Sidi, D., Munnich, A., Rustin, P., 1997. Aconitase and mitochondrial iron– sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17 (2), 215–217. Ruppert, V., Maisch, B., 2000. Mitochondrial DNA deletions in cardiomyopathies. Herz 25 (3), 161–167. Rustin, P., Munnich, A., Rotig, A., 1999. Quinone analogs prevent enzymes targeted in Friedreich ataxia from iron-induced injury in vitro. Biofactors 9 (2–4), 247–251.

251

Rustin, P., Munnich, A., Rotig, A., 2002. Succinate dehydrogenase and human diseases: new insights into a well-known enzyme. Eur. J. Hum. Genet. 10 (5), 289–291. Saada, A., Shaag, A., Mandel, H., Nevo, Y., Eriksson, S., Elpeleg, O., 2001. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat. Genet. 29 (3), 342–344. Schuelke, M., Smeitink, J., Mariman, E., Loeffen, J., Plecko, B., Trijbels, F., Stockler-Ipsiroglu, S., van den Heuvel, L., 1999. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat. Genet. 21 (3), 260–261. Shoffner, J.M., Lott, M.T., Lezza, A.M., Seibel, P., Ballinger, S.W., Wallace, D.C., 1990. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61 (6), 931–937. Silvestri, G., Moraes, C.T., Shanske, S., Oh, S.J., DiMauro, S., 1992. A new mtDNA mutation in the tRNA(Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51 (6), 1213–1217. Smith, O.P., Hann, I.M., Woodward, C.E., Brockington, M., 1995. Pearson’s marrow/pancreas syndrome: haematological features associated with deletion and duplication of mitochondrial DNA. Br. J. Haematol. 90 (2), 469–472. Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D’Adamo, P., Calvo, S., Marsano, R.M., Donnini, C., Weiher, H., Strisciuglio, P., Parini, R., Sarzi, E., Chan, A., DiMauro, S., Rotig, A., Gasparini, P., Ferrero, I., Mootha, V.K., Tiranti, V., Zeviani, M., 2006. MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat. Genet. 38 (5), 570–575. Sue, C.M., Karadimas, C., Checcarelli, N., Tanji, K., Papadopoulou, L.C., Pallotti, F., Guo, F.L., Shanske, S., Hirano, M., De Vivo, D.C., Van Coster, R., Kaplan, P., Bonilla, E., DiMauro, S., 2000. Differential features of patients with mutations in two COX assembly genes, SURF-1 and SCO2. Ann. Neurol. 47 (5), 589–595. Tatuch, Y., Christodoulou, J., Feigenbaum, A., Clarke, J.T., Wherret, J., Smith, C., Rudd, N., Petrova-Benedict, R., Robinson, B.H., 1992. Heteroplasmic mtDNA mutation (T–G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am. J. Hum. Genet. 50 (4), 852–858. Teitelbaum, J.E., Berde, C.B., Nurko, S., Buonomo, C., Perez-Atayde, A.R., Fox, V.L., 2002. Diagnosis and management of MNGIE syndrome in children: case report and review of the literature. J. Pediatr. Gastroenterol. Nutr. 35 (3), 377–383. Thyagarajan, D., Shanske, S., Vazquez-Memije, M., De Vivo, D., DiMauro, S., 1995. A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann. Neurol. 38 (3), 468–472. Tiranti, V., Galimberti, C., Nijtmans, L., Bovolenta, S., Perini, M.P., Zeviani, M., 1999. Characterization of SURF-1 expression and Surf1p function in normal and disease conditions. Hum. Mol. Genet. 8 (13), 2533–2540. Tiranti, V., Corona, P., Greco, M., Taanman, J.W., Carrara, F., Lamantea, E., Nijtmans, L., Uziel, G., Zeviani, M., 2000. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum. Mol. Genet. 9 (18), 2733–2742. Triepels, R.H., van den Heuvel, L.P., Loeffen, J.L., Buskens, C.A., Smeets, R.J., Rubio Gozalbo, M.E., Budde, S.M., Mariman, E.C., Wijburg, F.A., Barth, P.G., Trijbels, J.M., Smeitink, J.A., 1999. Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I. Ann. Neurol. 45 (6), 787–790. Triepels, R.H., Van Den Heuvel, L.P., Trijbels, J.M., Smeitink, J.A., 2001. Respiratory chain complex I deficiency. Am. J. Med. Genet. 106 (1), 37–45. Tsao, C.Y., Mendell, J.R., Luquette, M., Dixon, B., Morrow, G., 3rd, 2000. Mitochondrial DNA depletion in children. J. Child Neurol. 15 (12), 822–824. Tulinius, M.H., Oldfors, A., Holme, E., Larsson, N.G., Houshmand, M., Fahleson, P., Sigstrom, L., Kristiansson, B., 1995. Atypical presenta-

252

A.-R. Moslemi, N. Darin / Mitochondrion 7 (2007) 241–252

tion of multisystem disorders in two girls with mitochondrial DNA deletions. Eur. J. Pediatr 154 (1), 35–42. Tzagoloff, A., Capitanio, N., Nobrega, M.P., Gatti, D., 1990. Cytochrome oxidase assembly in yeast requires the product of COX11, a homolog of the P. denitrificans protein encoded by ORF3. EMBO J. 9 (9), 2759–2764. Tzoulis, C., Engelsen, B.A., Telstad, W., Aasly, J., Zeviani, M., Winterthun, S., Ferrari, G., Aarseth, J.H., Bindoff, L.A., 2006. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 129 (Pt 7), 1685–1692. Valente, L., Tiranti, V., Marsano, R.M., Malfatti, E., Fernandez-Vizarra, E., Donnini, C., Mereghetti, P., De Gioia, L., Burlina, A., Castellan, C., Comi, G.P., Savasta, S., Ferrero, I., Zeviani, M., 2007. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am. J. Hum. Genet. 80 (1), 44–58. Valnot, I., Osmond, S., Gigarel, N., Mehaye, B., Amiel, J., CormierDaire, V., Munnich, A., Bonnefont, J.P., Rustin, P., Rotig, A., 2000a. Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am. J. Hum. Genet. 67 (5), 1104–1109, Epub 2000 Sep 28. Valnot, I., von Kleist-Retzow, J.C., Barrientos, A., Gorbatyuk, M., Taanman, J.W., Mehaye, B., Rustin, P., Tzagoloff, A., Munnich, A., Rotig, A., 2000b. A mutation in the human heme A: farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum. Mol. Genet. 9 (8), 1245–1249. van den Heuvel, L., Smeitink, J., 2001. The oxidative phosphorylation (OXPHOS) system: nuclear genes and human genetic diseases. Bioessays 23 (6), 518–525. van den Heuvel, L., Ruitenbeek, W., Smeets, R., Gelman-Kohan, Z., Elpeleg, O., Loeffen, J., Trijbels, F., Mariman, E., de Bruijn, D., Smeitink, J., 1998. Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am. J. Hum. Genet. 62, 262–268. van den Ouweland, J.M., Lemkes, H.H., Ruitenbeek, W., Sandkuijl, L.A., de Vijlder, M.F., Struyvenberg, P.A., van de Kamp, J.J., Maassen, J.A., 1992. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat. Genet. 1 (5), 368–371. Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.J., Van Broeckhoven, C., 2001. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat. Genet. 28 (3), 211–212. Van Goethem, G., Martin, J.J., Dermaut, B., Lofgren, A., Wibail, A., Ververken, D., Tack, P., Dehaene, I., Van Zandijcke, M., Moonen, M., Ceuterick, C., De Jonghe, P., Van Broeckhoven, C., 2003a. Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul. Disord. 13 (2), 133–142. Van Goethem, G., Mercelis, R., Lofgren, A., Seneca, S., Ceuterick, C., Martin, J.J., Van Broeckhoven, C., 2003b. Patient homozygous for a recessive POLG mutation presents with features of MERRF. Neurology 61 (12), 1811–1813. Vanopdenbosch, L., Dubois, B., D’Hooghe, M.B., Meire, F., Carton, H., 2000. Mitochondrial mutations of Leber’s hereditary optic neuropathy: a risk factor for multiple sclerosis. J. Neurol. 247 (7), 535–543.

Visapaa, I., Fellman, V., Lanyi, L., Peltonen, L., 2002. ABCB6 (MTABC3) excluded as the causative gene for the growth retardation syndrome with aminoaciduria, cholestasis, iron overload, and lactacidosis. Am. J. Med. Genet. 109 (3), 202–205. Vucic, S., Kennerson, M., Zhu, D., Miedema, E., Kok, C., Nicholson, G.A., 2003. CMT with pyramidal features. Charcot-Marie-Tooth. Neurology 60 (4), 696–699. Vu, T.H., Sciacco, M., Tanji, K., Nichter, C., Bonilla, E., Chatkupt, S., Maertens, P., Shanske, S., Mendell, J., Koenigsberger, M.R., Sharer, L., Schon, E.A., DiMauro, S., DeVivo, D.C., 1998. Clinical manifestations of mitochondrial DNA depletion. Neurology 50 (6), 1783–1790. Wallace, D.C., 1994. Mitochondrial DNA mutations in diseases of energy metabolism. J. Bioenerg. Biomembr. 26 (3), 241–250. Wallace, D.C., Singh, G., Lott, M.T., Hodge, J.A., Schurr, T.G., Lezza, A.M., Elsas, L.J., 2nd, Nikoskelainen, E.K., 1988. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242 (4884), 1427–1430. Wallace, D.C., Brown, M.D., Melov, S., Graham, B., Lott, M., 1998. Mitochondrial biology, degenerative diseases and aging. Biofactors 7 (3), 187–190. Wang, Z.G., White, P.S., Ackerman, S.H., 2001. Atp11p and Atp12p are assembly factors for the F(1)-ATPase in human mitochondria. J. Biol. Chem. 276 (33), 30773–30778, Epub 2001 Jun 15. Wilkinson, P.A., Crosby, A.H., Turner, C., Bradley, L.J., Ginsberg, L., Wood, N.W., Schapira, A.H., Warner, T.T., 2004. A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia. Brain 127 (Pt 5), 973–980, Epub 2004 Feb 25. Wilson, C.J., Wood, N.W., Leonard, J.V., Surtees, R., Rahman, S., 2000. Mitochondrial DNA point mutation T9176C in Leigh syndrome. J. Child. Neurol. 15 (12), 830–833. Zeviani, M., Moraes, C.T., DiMauro, S., Nakase, H., Bonilla, E., Schon, E.A., Rowland, L.P., 1988. Deletions of mitochondrial DNA in Kearns–Sayre syndrome. Neurology 38 (9), 1339–1346. Zhao, H., Li, R., Wang, Q., Yan, Q., Deng, J.H., Han, D., Bai, Y., Young, W.Y., Guan, M.X., 2004. Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am. J. Hum. Genet. 74 (1), 139–152. Zhu, Z., Yao, J., Johns, T., Fu, K., De Bie, I., Macmillan, C., Cuthbert, A.P., Newbold, R.F., Wang, J., Chevrette, M., Brown, G.K., Brown, R.M., Shoubridge, E.A., 1998. SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat. Genet. 20 (4), 337–343. Zuchner, S., Mersiyanova, I.V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E.L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., Jonghe, P.D., Takahashi, Y., Tsuji, S., Pericak-Vance, M.A., Quattrone, A., Battaloglu, E., Polyakov, A.V., Timmerman, V., Schroder, J.M., Vance, J.M., 2004. Mutations in the mitochondrial GTPase mitofusin 2 cause CharcotMarie-Tooth neuropathy type 2A. Nat. Genet. 36 (5), 449–451. Zuchner, S., De Jonghe, P., Jordanova, A., Claeys, K.G., Guergueltcheva, V., Cherninkova, S., Hamilton, S.R., Van Stavern, G., Krajewski, K.M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C.T., de Visser, M., Baas, F., Bird, T., Timmerman, V., Shy, M., Vance, J.M., 2006. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann. Neurol. 59 (2), 276–281.