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090795 mitochondrial dna and disease

REVIEW ARTICLE
SEMINARS IN MEDICINE
Mitochondria, which probably evolved from inde- pendent organisms that became part of the cell, are able to replicate, transcribe, and translate their DNA BETH ISRAEL HOSPITAL, BOSTON
independently of nuclear DNA. However, cellular func-tion and mitochondrial function are interdependent.10Nuclear DNA encodes protein subunits of oxidativephosphorylation and the myriad macromolecular com-pounds required for mitochondrial structure and func-tion (e.g., replication, transcription, and translation).
Proteins encoded by nuclear DNA must be importedfrom the cytoplasm into the correct position within the mitochondria.8 During oxidative phosphorylation, ener- LISA H. UNDERHILL, Assistant Editor gy is derived from intermediary metabolites to produceATP by means of an electrochemical gradient. This bio- MITOCHONDRIAL DNA AND DISEASE
chemical process depends on the mitochondrial-DNA–encoded tRNAs that cleave multigene transcripts into Several features of mitochondrial DNA may be relat- THE mitochondrial encephalomyopathies are a di- ed to its frequent association with disease. Mitochon- verse group of disorders that result from the struc- drial DNA mutates more than 10 times as frequently as tural, biochemical, or genetic derangement of mito- nuclear DNA and has no introns, so that a random mu- chondria.1 Since mitochondrial dysfunction can affect tation will usually strike a coding DNA sequence. In ad- virtually all organ systems (Fig. 1), physicians in many dition, mitochondrial DNA has neither protective his- specialties see patients with mitochondrial diseases.
tones nor an effective repair system, and it is exposed Despite a bewildering array of clinical manifestations to oxygen free radicals generated by oxidative phospho- (Tables 1 and 2) and variations in the mode of onset, course, and progression of disease, many mitochondri- Mitochondrial DNA is inherited maternally and does al disorders share prominent systemic effects (Table 2) not recombine; mutations thus accumulate sequentially through maternal lineages. Each mitochondrion con- Our understanding of the role of mitochondrial tains 2 to 10 DNA molecules, and each cell contains DNA in certain diseases has evolved rapidly since 1988, multiple mitochondria. Thus, normal and mutant mi- when the first mutations in mitochondrial DNA were tochondrial DNA can coexist within the same cell. This discovered.2,3 Such mutations have subsequently been condition, known as heteroplasmy, allows an otherwise identified in a variety of diseases,4-7 and the pathogenic lethal mutation to persist. Homoplasmy is the presence role of cumulative mitochondrial-DNA damage is being of either completely normal or completely mutant mi- explored in many common diseases that develop late in tochondrial DNA. Through the process of replicative life, and even in the aging process itself.
segregation, the proportions of mutant and normalmolecules can shift as mitochondrial DNA is parti- STRUCTURE AND FUNCTION OF MITOCHONDRIAL
tioned into daughter cells. Thus, the principles of pop- ulation genetics, rather than those of mendelian genet- To understand mitochondrial disease, one must first ics, govern mitochondrial DNA. Selection pressures examine the unique features of mitochondrial DNA. Mi- occur at the molecular and cellular levels, as well as tochondria generate energy for cellular processes by pro- at the level of the organism itself. The proportion of ducing ATP through oxidative phosphorylation. These mutant mitochondrial DNA required for the occur- organelles contain their own, extrachromosomal DNA, rence of a deleterious phenotype, known as the thresh- which is distinct from DNA in the nucleus.8 Human old effect, varies among persons, among organ systems, mitochondrial DNA (known as “the other human ge- and within a given tissue. The threshold effect depends nome”) is a double-stranded, circular molecule that en- on the delicate balance between oxidative supply and codes 13 protein subunits of 4 biochemical complex- es and the 24 structural RNAs (2 ribosomal RNAs The classic mitochondrial phenotypes described be- [rRNAs] and 22 transfer RNAs [tRNAs]) that are re- low are caused by gross structural rearrangements (sin- quired for the intramitochondrial translation of the pro- gle deletions, multiple deletions, or duplications) or by tein-coding units.9 Mitochondrial-DNA mutations have point mutations in mitochondrial DNA. Mutations with been found in each type of mitochondrial gene (Fig. 2).
the potential to cause a lethal impairment of oxidativephosphorylation (gross structural defects or point mu- From the Division of Neuromuscular Disease, Department of Neurology, Beth tations in critical regions) are viable only if they are Israel Hospital and Harvard Medical School, Boston. Address reprint requests to heteroplasmic. The majority of the milder, missense Dr. Johns at Harvard Medical School, Bldg. B1-242, 220 Longwood Ave., Bos- mutations in protein-coding genes are homoplasmic.
Supported by a grant (R01-EY10864) from the National Eye Institute.
Although mutations have been found in each type of Downloaded from www.nejm.org on December 19, 2008 . Copyright 1995 Massachusetts Medical Society. All rights reserved. SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON Skeletal muscle
Pancreas
Nuclear DNA
Inner ear
Figure 1. Interaction between Genes Encoded by Nuclear DNA and Those Encoded by Mitochondrial DNA in Oxidative The intricate function of the oxidative-phosphorylation complexes can be disrupted by defects in the subunits encoded by nuclear DNAand mitochondrial DNA or by defects in intergenomic communication between the two types of DNA. The resulting deficits in the pro-duction of ATP have deleterious effects on a number of organ systems, causing the disorders shown. The red bar indicates the site of defects in intergenomic communication (depletion and multiple deletions of mitochondrial DNA).
mitochondrial-DNA gene, tRNA mutations predomi- but they were the first molecularly defined examples of nate in the phenotypes of mitochondrial encephalomy- many cardinal neurologic diseases, including stroke opathy, and protein-coding gene mutations predomi- (the syndrome of mitochondrial encephalomyopathy, nate in Leber’s hereditary optic neuropathy. A recent lactic acidosis, and stroke-like episodes [MELAS]), sei- report suggests that a point mutation in the 12S rRNA zures (the MELAS syndrome and myoclonic epilepsy gene is associated with both spontaneous and antibiot-ic-associated sensorineural deafness11 (Fig. 2).
CLASSIC PHENOTYPES OF MITOCHONDRIAL
ENCEPHALOMYOPATHY
Before 1988, when the first abnormal mitochondrial DNA was identified, many diseases were provisionally classified as mitochondrial disorders because of abnor- mal morphologic or biochemical features of mitochon- dria or a pattern of maternal inheritance. The first di- rect evidence that mitochondrial DNA was involved in Elevated levels of cerebrospinal fluid protein a disease came from two observations: the finding of large deletions in mitochondrial DNA from patients with mitochondrial myopathies2 and the detection of a missense mutation in mitochondrial DNA from pa- tients with Leber’s hereditary optic neuropathy.3 Over the next several years, the molecular genetic basis of the classic mitochondrial encephalomyopathies was elucidated.4-7 These disorders are relatively uncommon, Downloaded from www.nejm.org on December 19, 2008 . Copyright 1995 Massachusetts Medical Society. All rights reserved. patterns.18 The pattern of autosomal inheritance sug- gests the existence of a nuclear-DNA–encoded genethat influences the structure of normal mitochondrial DNA. Tissue-specific, autosomally transmitted deple- tion of mitochondrial DNA has also been reported.18 Molecular genetic methods can reliably detect mito- chondrial-DNA deletions,12-15 but these methods re- The MELAS Syndrome
In the MELAS syndrome, seizures and stroke-like events cause subacute brain dysfunction, cerebral struc- tural changes, and several other clinical and laboratory abnormalities (Tables 1, 2, and 3). The disease is inher- ited maternally, but it may not be evident in relatives who do not have all the overt symptoms. In 80 percent of cases, there is a point mutation at nucleotide position Psychiatric disorder (especially depression) 3243 in the tRNALeu(UUR) gene. Other mutations havealso been found in this gene, which appears to be a com-mon target for pathogenetic mutations. The mutation at with ragged-red fibers), and optic neuropathy (Leber’s nucleotide position 3243 apparently has multiple pheno- typic effects, because it is also associated with nondele-tion chronic progressive external ophthalmoplegia, my- Chronic Progressive External Ophthalmoplegia
opathy, deafness, diabetes, and dystonia.17,20,21 The main features of chronic progressive external ophthalmoplegia are ptosis, ophthalmoplegia, and limb Myoclonic Epilepsy with Ragged-Red Fibers
myopathy, but additional clinical features (Tables 1 and The syndrome of myoclonic epilepsy with ragged- 2) and the laboratory abnormalities characteristic of mi- red fibers consists of myoclonus, seizures, cerebellar tochondrial disorders (Table 3) may also be present.
ataxia, and mitochondrial myopathy, as well as neuro- Skeletal-muscle biopsies in patients with chronic pro- logic (Table 1) and laboratory (Table 3) abnormalities gressive external ophthalmoplegia reveal abnormal pro- that are common in other mitochondrial encephalomy- liferating mitochondria that cause ragged-red fibers, a opathies. Maternal relatives may be asymptomatic or hallmark of the severe biochemical defects in oxidative have partial clinical syndromes, including lipomas in phosphorylation in many mitochondrial encephalomy- a characteristic “horse collar” distribution and cardio- opathies. The Kearns–Sayre syndrome, a form of chron- vascular disease.22,23 Pathogenetic mutations have been ic progressive external ophthalmoplegia that begins be- demonstrated at nucleotide positions 8344 and 8356 in fore the age of 20 years, is characterized by atypical pigmentary retinopathy, as well as elevated levels of cer-ebrospinal fluid protein, ataxia, and heart block.1 Neuropathy, Ataxia, and Retinitis Pigmentosa and
Most patients with chronic progressive external oph- Maternally Inherited Leigh Disease
thalmoplegia have large, single deletions in mitochon- The syndrome of neuropathy, ataxia, and retinitis drial DNA.2,12-15 Almost all these deletions occur spo- pigmentosa is characterized by proximal-muscle weak- radically by an unknown mechanism.15 In most cases, ness, sensory neuropathy, developmental delay, ataxia, the junction contains directly repeated sequences, in- seizures, dementia, and retinal pigmentary degenera- cluding a molecular “hot spot” that accounts for ap- tion.24 This maternally inherited disorder is associated proximately 25 percent of all deletions.13-15 A few pa- with heteroplasmic missense mutations at nucleotide tients have partially duplicated mitochondrial-DNA position 8993 in the ATPase 6 gene.24 Large propor- molecules.16 Many patients without gross structural ab- tions of the same mutations are also present in patients normalities of mitochondrial DNA have a point muta- with maternally inherited Leigh disease.25 Molecular studies readily detect these point mutations in mito-chondrial DNA extracted from muscle, blood, or urine.
Autosomally Transmitted Multiple Deletions in
Mitochondrial DNA
Leber’s Hereditary Optic Neuropathy
The syndrome of autosomally transmitted multiple Leber’s hereditary optic neuropathy, the first disease deletions in mitochondrial DNA has diverse phenotypic in humans that was linked to heritable point mutations manifestations, most of which are variants of chronic in mitochondrial DNA,3 is the exemplar of mitochon- progressive external ophthalmoplegia.18,19 Multiple de- drial disease caused by homoplasmic missense muta- letions differ from single deletions in their inheritance tions. The main clinical phenotype is painless, sub- pattern, location within the mitochondrial genome, and acute, bilateral visual loss, with central scotomas and molecular structure. Unlike single deletions, which are abnormal color vision.26 The mean age at the onset is almost always sporadic, multiple deletions can be trans- 23 years, and three to four times as many males are af- mitted in autosomal dominant and autosomal recessive Downloaded from www.nejm.org on December 19, 2008 . Copyright 1995 Massachusetts Medical Society. All rights reserved. SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON Figure 2. Diagram of Human Mitochondrial DNA and the Most Common Associated Pathogenetic Mutations.
Point mutations in structural and protein-coding genes are shown inside the circle, with the clinical phenotype indicated and the nu-cleotide position of the mutation shown in parentheses. The position of the most common single deletion, which is 5 kilobases (kb)long, and the multiple deletions are indicated by the arcs outside the circle. MERRF denotes myoclonic epilepsy with ragged-red fibers;NARP, neuropathy, ataxia, and retinitis pigmentosa; Leigh, maternally inherited Leigh disease; LHON, Leber’s hereditary optic neu-ropathy; and MELAS, the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. O denotes the origin of heavy-stranded DNA replication, and O the origin of light-stranded DNA replication. CYT-b denotes the apocytochrome-b subunit; ND-1, ND-2, ND-3, ND-4L, ND-5, and ND-6, NADH dehydrogenase subunits; CO I, CO II, and CO III, cytochrome-c oxidasesubunits; 12S and 16S, ribosomal RNA subunits; and A6 and A8, ATPase subunits. The large open space at the top (which includes O ) is the noncoding D (displacement) loop.
Leber’s hereditary optic neuropathy, which bears otide position 13,708 in subunit 5 of the NADH dehy- little clinical resemblance to the other mitochondrial drogenase gene increases significantly in association diseases, was first classified as such a disease because with four different primary mutations.31 An X-linked of its pattern of maternal inheritance.26 The visual nuclear-DNA factor may explain the marked predomi- loss appears to involve both genetic and epigenetic fac- nance of symptomatic Leber’s hereditary optic neurop- tors.28 The mitochondrial-DNA mutations are hetero- athy in males, but the evidence is conflicting.29 The geneous, with mutations in at least eight genes that en- most important epigenetic factors are consumption of code subunits of three biochemical complexes. Four mutations, at nucleotide position 11,778, position 3460, The diversity of the primary mitochondrial-DNA position 15,257, and position 14,484, may have primary mutations in Leber’s hereditary optic neuropathy has pathogenetic importance29 (Fig. 2). Two other mito- clinical relevance. For example, the probability of visu- chondrial-DNA mutations were recently found in cyto- al recovery varies widely, depending on the mutation.27 chrome-c oxidase subunit III in patients with Leber’s Some variants of the disorder, such as Leber’s heredi- tary optic neuropathy plus dystonia33 and subacute op- Several other mitochondrial-DNA mutations may tic neuropathy and myelopathy,34 are also associated have secondary roles in Leber’s hereditary optic neurop- with specific mitochondrial-DNA mutations.
athy.29 The prevalence of a secondary mutation at nucle- Leber’s hereditary optic neuropathy illustrates the Downloaded from www.nejm.org on December 19, 2008 . Copyright 1995 Massachusetts Medical Society. All rights reserved. Table 3. Possible Laboratory Findings in Patients associated with this mutation, such as the MELAS syn- drome or nondeletion chronic progressive external oph-thalmoplegia, were not found. Diabetes mellitus, which Ragged-red fibers in skeletal-muscle–biopsy specimens is a treatable feature of a number of mitochondrial dis- Elevated lactate concentrations in serum and cerebrospinal fluid eases, can thus be the predominant manifestation of a Axonal and demyelinating peripheral neuropathy on nerve- Gastrointestinal manifestations of mitochondrial- Sensorineural hearing loss on audiography DNA mutations include colonic pseudo-obstruction,19 hepatopathy, and weight loss. The most prominent renal Basal-ganglia calcification or focal signal abnormalities on manifestation is a type of nonselective proximal-neph- Abnormalities on phosphorus-31 nuclear-magnetic-resonance ron dysfunction, with aminoaciduria, phosphaturia, and glycosuria, that resembles Fanconi’s syndrome. Lactic Defective oxidative phosphorylation on biochemical studies acidosis and an acid–base disturbance or glomerulopa- Molecular genetic evidence of mitochondrial-DNA mutation thy may bring patients to the attention of nephrologists.
Pearson’s syndrome of exocrine pancreatic dysfunc-tion, a sideroblastic hypoproliferative anemia, and pan- problems involved in determining the pathogenicity of cytopenia occurs in association with large-scale, single any mitochondrial-DNA mutation.35 It can be difficult deletions in mitochondrial DNA. Other forms of sider- to link a mutation to a clinical disease for several rea- oblastic anemia or aplastic anemia may also be associ- sons: mitochondrial DNA is highly polymorphic, there ated with acquired or inherited mitochondrial-DNA is a dissociation between the genotype and the pheno- mutations. Multiple symmetric lipomas, with their char- type, different mutations can be associated with the acteristic horse-collar distribution on the thorax, occur same phenotype,29 the same mutation can be associat- in association with the mitochondrial-DNA mutation at ed with different phenotypes,17 and epigenetic factors The most prominent pulmonary manifestations of mitochondrial-DNA mutations are the central hypoven- SYSTEMIC MANIFESTATIONS OF MITOCHONDRIAL-
tilatory abnormalities of Leigh disease and severe cases DNA MUTATIONS
of myoclonic epilepsy with ragged-red fibers. Mild ele- Virtually all tissues in the body depend to some ex- vations of creatine kinase levels, along with muscle fati- tent on oxidative metabolism and can therefore be af- gability, poor stamina, and poor endurance, may bring fected by mitochondrial-DNA mutations. Patients often patients with mitochondrial disease to the attention of first seek care because of the systemic manifestations rheumatologists, perhaps resulting in an evaluation for listed in Table 2, which may thus provide the first op- an inflammatory myopathy. Psychiatric manifestations, portunity to consider the diagnosis of a mitochondrial especially depression, have been noted in association disease. Since these manifestations may be important with multiple mitochondrial-DNA deletions.37 comorbid features of the disease, they should be diag-nosed and vigorously treated.
MITOCHONDRIAL-DNA MUTATIONS IN COMMON
The neurologic manifestations of mitochondrial dis- DISEASES
orders, involving both the central and the peripheral One of the next challenges for researchers is to define nervous systems, have been reported extensively and the role of mitochondrial-DNA mutations in common reviewed elsewhere.1,4,6 Less well known are the non- diseases. The genetic basis of many prevalent diseases is neurologic manifestations of mitochondrial-DNA mu- complex and does not follow a simple, single-gene men- tations. Ophthalmologic manifestations are very com- delian inheritance. Leber’s hereditary optic neuropathy mon, involving virtually the entire visual axis from illustrates the complex interactions between genetic and the lids, cornea, and extraocular muscles to the occip- epigenetic factors.28,32 These interactions may involve ital cortex.36 The cardinal findings include ptosis, oph- mitochondrial-DNA mutations in subgroups of common thalmoplegia, optic neuropathy, pigmentary retinopa- diseases, such as diabetes mellitus, in which the pattern thy, and cortical visual-field defects.36 Cardiac findings, of maternal inheritance is not prominent.
which are also common and can be life-threatening, in- Thus far, I have focused on inherited mutations or clude cardiomyopathy, conduction disease and heart gross structural derangements at the gametic level. An- block, the Wolff–Parkinson–White syndrome, and hy- other category of mitochondrial-DNA mutations that may be relevant to late-onset degenerative disorders is Endocrine manifestations are frequent, and the inci- the tissue-specific accumulation of somatic (noninherit- dence of diabetes mellitus is relatively high. Pancreatic ed) mutations.38 Because of the high rate of mutations islet cells are extremely active metabolically and are in mitochondrial DNA, postmitotic tissues or those thus susceptible to the disruption of oxidative phospho- with a slow turnover of DNA accumulate the largest rylation. Diabetes mellitus associated with mitochon- number of somatic mitochondrial-DNA mutations. Ex- drial-DNA mutations is mainly due to a defect in insu- ternal factors may also affect mitochondrial DNA; for lin secretion. The disorder has been linked with a example, the antiretroviral drug zidovudine depletes heteroplasmic point mutation in the tRNALeu(UUR) gene muscle mitochondrial DNA and causes an acquired mi- at nucleotide position 3243, usually in association with sensorineural hearing loss.20 Other neurologic findings The accumulation of mitochondrial-DNA mutations Downloaded from www.nejm.org on December 19, 2008 . Copyright 1995 Massachusetts Medical Society. All rights reserved. SEMINARS IN MEDICINE OF THE BETH ISRAEL HOSPITAL, BOSTON above a threshold level in certain critical neuronal sub- DR. JOHNS: I am unaware of any data on this topic, populations and the consequent deficit in the produc- but I can speculate that overnutrition may increase ox- tion of ATP may contribute to the pathogenesis of neu- idative damage to mitochondrial DNA that results in rodegenerative diseases,40 particularly those that are dysfunctional oxidative phosphorylation within mito- more common with advanced age, such as Alzheimer’s chondria. These mitochondria may then become the disease and Parkinson’s disease. Mitochondrial energy source of excess free radicals that further damage mi- deficits may contribute to neuronal injury through ex- tochondrial DNA and other macromolecules in a feed- Such mechanisms may also contribute to aging itself.
DR. DAVID MOLLER: Because the ratio of mutant Shigenaga and colleagues have outlined an elegant con- mitochondrial DNA to the wild type varies so much cept of aging that incorporates the role of mitochon- among tissues, how do you go about ruling out a mito- dria.38 These researchers argue that cumulative, age- chondrial mutation, especially one that may be inherit- dependent mitochondrial dysfunction, mediated to a ed, when you cannot obtain biopsy specimens of the rel- substantial degree by oxidative damage to mitochon- evant tissue (e.g., beta cells of the pancreas or the optic drial DNA and other mitochondrial macromolecules, nerve)? If you do not have a candidate mutation, how plays an important part in the aging of cells, tissues, organ systems, and even the whole organism.
DR. JOHNS: With respect to the availability of DNA from the relevant tissue, virtually all the point muta- tions can be detected readily in available tissues, such Data on the role of mitochondrial-DNA mutations as leukocytes. Homoplasmic mutations are the same in in the pathogenesis of several diseases have accumulat- all tissues. The proportions of heteroplasmic point mu- ed at a breathtaking pace in the seven years since the tations may vary according to the type of tissue, but all first pathogenetic mutations in mitochondrial DNA that is needed to demonstrate the presence of the mu- were discovered. Elucidation of the complete mito- tation is a detectable proportion. Major structural mu- chondrial-DNA sequence in humans and knowledge tations, such as deletions, do require the analysis of about variations in that sequence44 have contributed to skeletal muscle. There is no easy, overall screening test a nascent understanding of the clinical implications of that is sensitive and specific for the presence of mito- mitochondrial-DNA mutations. The rapid accumula- chondrial-DNA mutations. Sequencing the entire mito- tion of disease-specific knowledge about “the other hu- chondrial-DNA region is impractical, and it is easy to man genome” may well foreshadow advances in our un- miss heteroplasmic mutations. My colleagues and I use derstanding of diseases involving the nuclear genome, very specific molecular genetic assays for particular which will emerge from the Human Genome Project.
mutations, and we are interested in developing a meth- Detailed studies of mitochondrial disease have also od of analyzing larger mitochondrial-DNA regions.
provided insight into fundamental biologic processes, DR. JOSEPH MAZJOUB: Do particular tissues have such as oxidative phosphorylation and aging.
characteristic ratios of mutant mitochondrial DNA to Mitochondrial-DNA mutations appear to cause an the wild type, or do the ratios vary? If they vary, what extensive array of disorders. As the number and types factors control the variation? Is the half-life of a defec- of mitochondrial diseases increase, internists and sub- tive mitochondrion any different from that of a normal specialists will be in a pivotal position to recognize and treat these diseases. The advances in our understand- DR. JOHNS: For heteroplasmic mutations, the ratio ing of the molecular genetic basis of mitochondrial dis- of normal-to-mutant mitochondrial DNA varies with- eases have already had a profound effect on the detec- in a tissue — for example, from fiber to fiber in skel- tion and evaluation of mitochondrial diseases. A set of etal muscle. The initial differences within and be- sensitive and specific molecular genetic tests has been tween tissues are determined by mitotic segregation developed for a number of the mitochondrial encepha- during embryogenesis. These ratios may change over lomyopathies.45 The unequivocal diagnosis of a mito- time, depending on a complex interplay of selection chondrial disease by such methods is obviously the first pressures at the molecular, organelle, cellular, tissue, step in appropriate genetic counseling and treatment.
and organismal levels. Mitochondria are not static Although the advances in treatment have not paral- structures within a cell; they undergo dynamic morpho- leled the advances in diagnosis,46 at least we are now logic changes. I am unaware of any specific data on a aware of the biochemical targets. Mitochondrial gene difference in the half-lives of defective and normal mi- therapy for these disorders must overcome obstacles that are different from those encountered in the search DR. FLIER: What is known about the rate of muta- for effective nuclear gene therapy, but such therapy is not beyond the realm of possibility.
DR. JOHNS: I am not aware of studies of mitochon- drial-DNA mutations in normal brown fat. However, DISCUSSION
the lipomas that occur in association with the mito- DR. JEFFREY FLIER: Undernutrition is known to pro- chondrial-DNA mutation at position 8344 are found in tect against aging and nuclear-DNA mutations. Does the areas where brown fat is more abundant.
overnutrition damage mitochondrial DNA, and if so, DR. CHAIM MAYMAN: What is the role of mitochon- could this process be related to any of the pathogenic drial-DNA mutations in the optic neuropathies associ- Downloaded from www.nejm.org on December 19, 2008 . Copyright 1995 Massachusetts Medical Society. All rights reserved. DR. JOHNS: The presence of mitochondrial-DNA 17. Moraes CT, Ciacci F, Silvestri G, et al. Atypical clinical presentations asso- mutations in patients with tobacco–alcohol amblyopia ciated with the MELAS mutation at position 3243 of human mitochondrialDNA. Neuromuscul Disord 1993;3:43-50.
illustrates the interplay between genetic and epigenetic 18. Zeviani M. Nucleus-driven mutations of human mitochondrial DNA. J In- factors.32 The mutations appear to confer a genetic sus- 19. Johns DR, Threlkeld AB, Miller NR, Hurko O. Multiple mitochondrial DNA ceptibility to the deleterious effects of tobacco, alcohol, deletions in myo-neuro-gastrointestinal encephalopathy syndrome. Am J or both on the optic nerve. However, not all patients with tobacco–alcohol amblyopia have detectable mito- 20. van den Ouweland JMW, Lemkes HHPJ, Ruitenbeek W, et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally trans- chondrial-DNA mutations, and my colleagues and I mitted type II diabetes mellitus and deafness. Nat Genet 1992;1:368-71.
postulate that other mutations are present elsewhere in 21. Johns DR, Plotkin GM, Logigian EL, Sudarsky LR. Dystonia as a manifes- tation of the 3243 mtDNA mutation. Ann Neurol 1994;36:315. abstract.
22. Silvestri G, Ciafaloni E, Santorelli FM, et al. Clinical features associated DR. LAKSHMI KANTHAM: Are there animal models with the A→G transition at nucleotide 8344 of mtDNA (“MERRF muta- 23. Austin SG, Thandroyen FT, Hecht JT, Vriesendorp FJ, Jones OW, Johns DR.
DR. JOHNS: No. There is a large gap in our knowl- Expanding the phenotype of the 8344 tRNAlys mitochondrial DNA mutation.
edge of these diseases. We have extensive knowledge Neurology 1994;44:Suppl 2:A403. abstract.
at the molecular and in vitro cellular levels (rho0 cell 24. Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet lines), and we also have extensive knowledge of the clinical phenotypes in humans. However, we have few 25. Santorelli FM, Shanske S, Macaya A, DeVivo DC, DiMauro S. The mutation data on organ systems and no data obtained under ex- at nt 8993 of mitochondrial DNA is a common cause of Leigh’s syndrome.
Ann Neurol 1993;34:827-34.
perimental conditions. The rho0 human cell lines, which 26. Nikoskelainen EK, Savontaus M-L, Wanne OP, Katila MJ, Nummelin KU.
are depleted of endogenous mitochondrial DNA and Leber’s hereditary optic neuroretinopathy, a maternally inherited disease: agenealogic study in four pedigrees. Arch Ophthalmol 1987;105:665-71.
repopulated with mutant mitochondria, have been in- 27. Johns DR. Genotype-specific phenotypes in Leber hereditary optic neurop- dispensable systems for pathophysiologic studies at the 28. Johns DR, Smith KH, Miller NR, Sulewski ME, Bias WB. Identical twins who are discordant for Leber’s hereditary optic neuropathy. Arch Ophthal- DR. COLIN M. COSSI: What do you think is the cur- rent level of public and medical awareness of the mito- 29. Newman NJ. Leber’s hereditary optic neuropathy: new genetic consider- 30. Johns DR, Neufeld MJ. Cytochrome c oxidase mutations in Leber hereditary DR. JOHNS: I believe that we are at a crucial juncture optic neuropathy. Biochem Biophys Res Commun 1993;196:810-5.
in the perception of these disorders. The recent an- 31. Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res nouncement by the American cyclist Greg Le Mond that he is retiring from competitive cycling because of 32. Cullom ME, Heher KL, Miller NR, Savino PJ, Johns DR. Leber’s hereditary a mitochondrial myopathy48 has brought these “myste- optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Oph-thalmol 1993;111:1482-5.
rious” disorders to the attention of the public.
33. Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucle- otide pair 14459 of the NADH dehydrogenase subunit 6 gene associated REFERENCES
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Source: http://childneuro.narod.ru/mito2.pdf

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