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This is a heterogenous groups of disorders all sharing DNA mutations or deletions within mitochondrial DNA. Mitochondrial ATP production via oxidative phosphorylation (OXPHOS) is essential for normal function and maintenance of human organ systems. Since OXPHOS biogenesis depends on both nuclear- and mitochondrial-encoded gene products, mutations in both genomes can result in impaired electron transport and ATP synthesis, thus causing tissue dysfunction and, ultimately, human disease. Mitochondria have a pivotal role in cell metabolism, being the major site of ATP production via oxidative phosphorylation (OXPHOS). They also have a critical role in apoptotic cell death; and they also contribute to human genetics since mitochondria have a functional genome separate from that of nuclear DNA.

Defects of mitochondrial metabolism are associated with a wide spectrum of disease. These diseases range from systemic, lethal pediatric disease to late-onset, tissue-specific neurodegenerative disorders. They have been identified mainly in postmitotic tissues like brain, heart and skeletal muscle of healthy humans of advanced age but not in young people. An exponential increase with age was described for deletions of mtDNA. An important part of this spectrum is caused by mutations of mitochondrial DNA (mtDNA). Over 30 mitochondrial DNA (mtDNA) point mutations and over 100 mtDNA rearrangements have now been identified as etiological factors in human disease. Because of the unique characteristics of mtDNA genetics, genotype/phenotype associations are often complex and disease expression can be influenced by a number of factors, including the presence of nuclear modifying or susceptibility alleles. At this present time, no effective treatment has been found for these rare diseases.


Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Prognosis and Treatment
Commonly Used Terms

SYNONYMS Red ragged fiber disease

Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy.

Mashima Y, Yamada K, Wakakura M, Kigasawa K, Kudoh J, Shimizu N, Oguchi Y.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Curr Eye Res 1998 Apr;17(4):403-8 Abstract quote

PURPOSE: To investigate the incidence and clinical significance of primary or proposed secondary mitochondrial DNA (mtDNA) mutations in Japanese patients with Leber's hereditary optic neuropathy (LHON).

METHODS: Blood samples from the 80 unrelated Japanese patients with bilateral optic atrophy were screened for primary LHON mutations. Patients found to have a primary LHON mutation were then tested for 9 proposed secondary LHON mutations. We investigated the association between these mutations and clinical characteristics.

RESULTS: Primary mtDNA mutations were identified in 68 patients: at np 3460 in 3 (4%) of 68 patients, at np 11,778 in 59 patients (87%), and at np 14,484 in 6 patients (9%). We identified 5 secondary mtDNA mutations (at np 3394, 4216, 7444, 9438 or 13,708) in 10 (15%) of 68 LHON patients and 3 mutations (at np 3394, 4216 or 3708) in 6 (7%) of 90 healthy Japanese individuals. No patient was positive for more than one secondary mutation. The frequency of secondary mutations was similar in the 68 LHON patients and 90 controls. The clinical features of the Japanese patients with any of the 3 primary LHON mutations were similar to those of Caucasian patients, despite different mtDNA backgrounds in these populations. The percentage of patients with familial LHON harboring the 3460 or 14,484 mutations was lower in the Japanese population.

CONCLUSIONS: Japanese patients with LHON exhibited a very high incidence (87%) of the 11,778 primary mutation. Most of the proposed secondary LHON mutations were rare in the Japanese population and they, except the 7444 mutation, may not influence the clinical features of LHON.

Molecular epidemiologic study of mitochondrial DNA mutations in patients with mitochondrial diseases in Taiwan.

Pang CY, Huang CC, Yen MY, Wang EK, Kao KP, Chen SS, Wei YH.

Department of Biochemistry and Center for Cellular and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.

J Formos Med Assoc 1999 May;98(5):326-34 Abstract quote

We report an 8-year molecular study of mitochondrial DNA (mtDNA) mutations in patients with mitochondrial diseases in Taiwan.

One hundred and seventy-seven patients met the diagnostic criteria of mitochondrial disease and were recruited into the study. The results showed that 32 patients, including 25 with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, one with Kearns-Sayre syndrome (KSS), one with diabetes mellitus and deafness, and five with chronic progressive external ophthalmoplegia (CPEO), harbored the A3243G mtDNA mutation. The A8344G mutation was found in nine patients, all of whom suffered from myoclonic epilepsy and ragged-red fibers (MERRF) syndrome. The G11778A mtDNA mutation was found in 18 of 22 patients with Leber's hereditary optic neuropathy. The T8993C and T8993G mutations were found, respectively, in one and two patients with Leigh syndrome. Large-scale deletions of mtDNA were found in 17 patients with CPEO, one with KSS, one with MELAS, and two with MERRF syndrome. The mtDNA mutations in patients with each of the mitochondrial diseases found in Taiwan were restricted mainly to a single site, while those reported for the same diseases in other ethnic groups occurred in many sites. Furthermore, significant levels of additional mtDNA mutations occurred in some patients with mitochondrial encephalomyopathies.

We suggest that these additional (or secondary) mtDNA mutations are generated as a consequence of the preexisting primary mtDNA mutations and may contribute to the age-dependent progressive deterioration characteristic of mitochondrial diseases.

The epidemiology of pathogenic mitochondrial DNA mutations.

Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, Taylor RW, Bindoff LA, Turnbull DM.

Department of Neurology, The University of Newcastle upon Tyne, UK.

Ann Neurol 2000 Aug;48(2):188-93 Abstract quote

During the past decade, there have been many descriptions of patients with neurological disorders due to mitochondrial DNA (mtDNA) mutations, but the extent and spectrum of mtDNA disease in the general population have not yet been defined.

Adults with suspected mtDNA disease in the North East of England were referred to a single neurology center for investigation over the 10-year period from 1990 to 1999 inclusive.

We defined the genetic defect in these individuals. For the midyear period of 1997, we calculated the minimum point prevalence of mtDNA disease in the adults of working age (> 16-<60 years old for female subjects and <65 years old for male subjects) and the minimum prevalence of adults and children (<60 years for female subjects, <65 years for male subjects) at risk of developing mtDNA disease. mtDNA defects caused disease in 6.57 per 100,000 individuals in the adult population of working age, and 7.59 per 100,000 unaffected adults and children were at risk of developing mtDNA disease. Overall, 12.48 per 100,000 individuals in the adult and child population either had mtDNA disease or were at risk of developing mtDNA disease.

These results reflect the minimum prevalence of mtDNA disease and pathogenic mtDNA mutations and demonstrate that pathogenic mtDNA mutations are a common cause of chronic morbidity. These findings have resource implications, particularly for supportive care and genetic counseling.



A comparison of genetic mitochondrial disease and nucleoside analogue toxicity. Does fetal nucleoside toxicity underlie reports of mitochondrial disease in infants born to women treated for HIV infection?

Haas RH.

Departments of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, California 92093-0935, USA.

Ann N Y Acad Sci 2000 Nov;918:247-61 Abstract quote

Recent reports of mitochondrial disease in infants whose mothers were treated in pregnancy with nucleoside analogues are of concern. Chronic nucleoside analogue treatment of adults has long been known to cause mitochondrial DNA depletion with the risk of multisystem disease. Combination nucleoside analogue treatment regimens may have the greatest risk of toxicity.

This paper briefly presents the underlying biochemical etiologies and phenotypes of some common genetic mitochondrial diseases in order to provide a comparison with reports of infant toxicity. A standardized method for the diagnosis and evaluation of mitochondrial disease is discussed.

A hypothesis, with predictions of the effects of antenatal nucleoside analogue treatment on the fetus, is presented and future directions for research on this problem are suggested.



Evidence for intramitochondrial complementation between deleted and normal mitochondrial DNA in some patients with mitochondrial myopathy.

Hammans SR, Sweeney MG, Holt IJ, Cooper JM, Toscano A, Clark JB, Morgan-Hughes JA, Harding AE.

University Department of Clinical Neurology, Institute of Neurology, London, U.K.

J Neurol Sci 1992 Jan;107(1):87-92 Abstract quote

Twenty-three patients with mitochondrial myopathies and mitochondrial DNA deletions in muscle were studied by means of deletion mapping and sequencing, histochemistry and polarography. Histochemistry showed significantly less focal cytochrome oxidase deficiency relative to number of ragged red fibres when the deletion did not involve reading frames for cytochrome oxidase subunits. Polarography in such patients showed defects exclusively involving complex I, in contrast to the others with larger deletions who generally had more diffuse respiratory chain defects. Analysis of other published histochemical data showed similar findings to our own.

It is concluded that translation of a proportion of deleted mitochondrial DNAs occurs in at least some patients with mitochondrial DNA deletions, implying that deleted and normal mitochondrial genomes share transfer RNAs within mitochondria in such cases.

Independent occurrence of somatic mutations in mitochondrial DNA of human skin from subjects of various ages.

Liu VW, Zhang C, Pang CY, Lee HC, Lu CY, Wei YH, Nagley P.

Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

Hum Mutat 1998;11(3):191-6 Abstract quote

The incidence (frequency of occurrence) and abundance (percentage of mutant out of total mtDNA population) of two different somatic mtDNA mutations in human skin were investigated in 44 subjects ranging from 19 to 87 years of age.

Using quantitative allele-specific polymerase chain reaction (AS-PCR) to analyse the A-->G base substitution at nucleotide 3243, 50% of the samples showed detectable levels of that particular mutation, with abundances ranging from 0.01% to 0.12%. In the same set of skin samples, the overall incidence of the 4977 bp "common" deletion was also approximately 50%. Where detected, the abundance of this deletion ranged from 0.0002% to 0.1%.

Comparative analyses of the incidence and abundance of these two mutations, collectively and in individual skin samples, led to these two conclusions: (1) there is independent occurrence of these two mtDNA mutations in human skin, and (2) whereas the 4977 bp deletion shows an age-associated accumulation in human skin, no age association is apparent for the 3243 A-->G base substitution. Furthermore, in general, there is a much lower incidence of somatic mutations in mtDNA of human skin as compared to that in postmitotic tissues such as skeletal muscle.

Mutations in mitochondrial DNA accumulate differentially in three different human tissues during ageing.

Liu VW, Zhang C, Nagley P.

Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia.

Nucleic Acids Res 1998 Mar 1;26(5):1268-75 Abstract quote

In 60 human tissue samples (encompassing skeletal muscle, heart and kidney) obtained from subjects aged from under 1 to 90 years, we used quantitative PCR procedures to quantify mitochondrial DNA (mtDNA) molecules carrying the 4977 bp deletion (mtDNA4977) and 3243 A-->G base substitution. In addition, the prevalence of multiple mtDNA deletions was assessed in a semi-quantitative manner.

For all three tissues, the correlations between the accumulation of the particular mtDNA mutations and age of the subject are highly significant. However, differential extents of accumulation of the two specific mutations in the various tissues were observed. Thus, the mean abundance (percentage of mutant mtDNA out of total mtDNA) of mtDNA4977in a subset of age-matched adults is substantially higher in skeletal muscle than in heart and kidney. However, the mean abundance of the 3243 A-->G mutation in skeletal muscle was found to be lower than that in heart and kidney. Visualisation of arrays of PCR products arising from multiple mtDNA deletions in DNA extracted from adult skeletal muscle, was readily made after 30 cycles of PCR. By contrast, in DNA extracted from adult heart or kidney, amplification for 35 cycles of PCR was required to detect multiple mtDNA deletions.

Although such multiple deletions are less abundant in heart and kidney than in skeletal muscle, in all tissue extracts there are unique patterns of bands, even from different tissues of the same subject. The differential accumulation of mtDNA4977, other mtDNA deletions and the 3243 A-->G mutation in the three tissues analysed presumably reflects different metabolic and senescence characteristics of these various tissues.

Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals.

Howell N, Ghosh SS, Fahy E, Bindoff LA.

Department of Radiation Oncology, Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, TX 77555-0656, USA.

J Neurol Sci 2000 Jan 1;172(1):1-6 Abstract quote

The mutation load of the pathogenic LHON (Leber hereditary optic neuropathy) mtDNA mutation at nucleotide 3460 has been followed over time in the WBC/platelet fraction from members of a matrilineal pedigree.

Longitudinal analysis over a sampling period of five to six years indicates that, in all five heteroplasmic family members, the mutation load decreases at a mean overall rate of approximately 1% per year. There was no change in mutation load in homoplasmic wildtype or in homoplasmic mutant individuals. For the purposes of comparison, a longitudinal analysis of a silent mtDNA polymorphism at nucleotide 14560 was also carried out for members of a second matrilineal pedigree. In contrast to the results for the pathogenic mtDNA mutation, there was no change in the proportion of the silent polymorphism in the WBC/platelet fraction of four family members over a period of seven years.

These results indicate that the pathogenic 3460 LHON mutation segregates under negative selection in these cell populations. One possible mechanism through which selection may operate is that, in heteroplasmic individuals, the hematopoietic stem cells are generally homoplasmic, either for the wildtype or for the mutant allele. The homoplasmic mutant stem cells, because of their mitochondrial respiratory chain defect, produce fewer mature WBCs and platelets over time than do the wildtype stem cells. Alternatively, the stem cells may be heteroplasmic and selection may act to favor proliferation of mitochondria with lower levels of the pathogenic mutation in the WBC/platelet cell populations.

Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family.

de la Pena P, Bornstein B, del Hoyo P, Fernandez-Moreno MA, Martin MA, Campos Y, Gomez-Escalonilla C, Molina JA, Cabello A, Arenas J, Garesse R.

Departamento de Bioquimica, Instituto de Investigaciones Biomedicas "Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autonoma de Madrid, Spain.

Neurology 2001 Oct 9;57(7):1235-8 Abstract quote

BACKGROUND: Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development.

OBJECTIVE: To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene.

METHODS: Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed.

RESULTS: In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N(55e11) in Drosophila decreases the activity of mitochondrial respiratory complexes I and V.

CONCLUSIONS: Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.

Early-onset multisystem mitochondrial disorder caused by a nonsense mutation in the mitochondrial DNA cytochrome C oxidase II gene.

Campos Y, Garcia-Redondo A, Fernandez-Moreno MA, Martinez-Pardo M, Goda G, Rubio JC, Martin MA, del Hoyo P, Cabello A, Bornstein B, Garesse R, Arenas J.

Centro de Investigacion and Departamento de Neuropatologia, Hospital Universitario, Madrid, Spain.

Ann Neurol 2001 Sep;50(3):409-13 Abstract quote

We report the first nonsense mutation (G7896A) in the mtDNA gene for subunit II of cytochrome c oxidase (COX) in a patient with early-onset multisystem disease and COX deficiency in muscle.

The mutation was heteroplasmic in muscle, blood, and fibroblasts from the patient and abundantly present in COX-deficient fibers, but less abundant in COX-positive fibers; it was not found in blood samples from the patient's asymptomatic maternal relatives. Immunoblot analysis showed a reduced concentration of both COX II and COX I polypeptides, suggesting impaired assembly of COX holoenzyme.




Evaluation of patients with lactic acidosis using microphotometric mitochondrial enzyme assay in single muscle fibers.

Sugie H, Sugie Y, Ito M, Tsurui S, Shimizu K, Nakajima H, Fukuda T, Ishikawa A, Sato H, Hirano K.

Department of Pediatric Neurology, Hamamatsu City Medical Center for Developmental Medicine, Japan

Brain Dev 1994 Jul-Aug;16(4):315-9 Abstract quote

Microphotometric enzyme assay in single muscle fibers was performed on two patients with lactic acidosis.

Neither case showed ragged red fibers upon histochemical evaluation. Biochemical analysis of mitochondrial enzymes demonstrated low normal cytochrome c oxidase (COX) activity in Case 1 and deficient COX in Case 2. Quantitative single muscle fiber analysis in patients showed marked variation in COX activity in Case 1, reflecting mosaic distribution of fibers with near-normal COX activity and with defective COX activity.

These data suggest that this microphotometric assay may be valuable for elucidating the significance of 'partial enzyme deficiency'. In addition, this assay method may be applied to needle biopsy specimens

Detection and analysis of mitochondrial DNA deletions by whole genome PCR.

Tengan CH, Moraes CT.

Department of Neurology, University of Miami School of Medicine, Florida 33136, USA

Biochem Mol Med 1996 Jun;58(1):130-4 Abstract quote

Southern blot analysis has been the best method available for the screening and detection of mitochondrial DNA (mtDNA) rearrangements. Recent developments in polymerase chain reaction (PCR) technology allowed the amplification of the whole mitochondrial genome (16.6 kb), making PCR a potentially useful technique for the detection of mtDNA deletions.

We tested the usefulness of whole mitochondrial genome PCR by studying skeletal muscle DNA from seven patients with single and multiple deletions and controls from ages 3 to 91 years old. Specific patterns for single and multiple deletions were obtained with whole genome PCR, which were confirmed by the Southern analysis with probes hybridizing to mtDNA sequences. Amplifications from young controls (3 to 23 years old) yielded only one band (16.5 kh) while amplification from older controls revealed one or more additional smaller bands. The amplification from the 91-year-old control showed a pattern similar to amplifications from patients with multiple mtDNA deletions. Although single and multiple mtDNA deletions could be readily detected from patient samples, the high sensitivity of this method can lead to false positive results due to the presence of age-related deletions in old control samples.

Despite its limitations, whole mitochondrial genome PCR can be useful for the detection of single deletions in muscle samples obtained from young individuals since the levels of age-related deletions are too low to be amplified.

Method for in situ investigation of mitochondrial DNA deletions.

Kovalenko SA, Harms PJ, Tanaka M, Baumer A, Kelso J, Ozawa T, Linnane AW.

Centre for Molecular Biology and Medicine, Austin and Repatriation Medical Centre, Victoria, Australia

Hum Mutat 1997;10(6):489-95 Abstract quote

A number of mitochondrial DNA (mtDNA) deletions have been recently identified in the tissues of patients with mitochondrial diseases and in elderly individuals.

To investigate the distribution of mutant mitochondrial genomes within any particular tissue, we have developed a sensitive method based on indirect in situ PCR. Our experiments have shown that the new method had the advantage of selectively amplifying only mtDNA bearing the 4,977 bp deletion. We show that this method is more sensitive than in situ hybridization for detecting the 4977 bp mtDNA deletion while using only a low number of PCR cycles that minimize damage to tissue architecture. By using this method, we have demonstrated that the mutation does not occur uniformly among the cells of a given tissue/organ.

This technique will be useful studying the distribution/localization of mtDNA mutations in individual cells of tissues and when combined with enzyme histochemical procedures in adjacent sections will enable the correlation between mtDNA mutations and bioenergy defects in single cells.

Diagnosis of mitochondrial disease: assessment of mitochondrial DNA heteroplasmy in blood.

Taylor RW, Taylor GA, Morris CM, Edwardson JM, Turnbull DM.

Department of Neurology, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Biochem Biophys Res Commun 1998 Oct 29;251(3):883-7 Abstract quote

Mitochondrial DNA (mtDNA) mutations are an important cause of neurological disease. The identification of causative mtDNA mutations may be particularly troublesome in blood where there are often low levels of mutant mtDNA. This is evident from a recent study in which heteroplasmic mtDNA mutations in cytochrome c oxidase genes were incorrectly thought to be linked to Alzheimer's disease.

We wished to explore whether analysis of blood mtDNA, prepared by a number of DNA extraction procedures, influenced the diagnosis of mtDNA disease. DNA was extracted by different procedures from 4 patients with heteroplasmic mtDNA mutations, and the level of heteroplasmy investigated by radioactive PCR-RFLP analysis. Whilst there was no consistent decrease in the level of mtDNA heteroplasmy, we observed the coamplification of a novel mtDNA pseudogene from DNA samples extracted by a simple 'boiling' procedure using primers designed to screen for the tRNALeu(UUR) A3243G mutation. This pseudogene was readily amplified from DNA extracted from rho degrees (mtDNA-less) cells, confirming its nuclear location.

We believe that mtDNA pseudogenes may therefore present significant difficulties in the accurate identification of pathogenic heteroplasmic mtDNA mutations in blood.

Amplification of DNA sequences in polar bodies from human oocytes for diagnosis of mitochondrial disease.

Briggs DA, Power NJ, Lamb V, Rutherford AJ, Gosden RG.

Lancet 2000 Apr 29;355(9214):1520-1 Abstract quote

When a preovulatory oocyte reinitiates meiosis, it sheds a cytoplasmic fragment containing mitochondria and a redundant set of chromosomes.

We have detected DNA sequences from both the mitochondrial and nuclear genomes in polar bodies from unfertilised human oocytes, demonstrating the feasibility of diagnosing mitochondrial diseases before conception.



Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations.

Nikoskelainen EK, Huoponen K, Juvonen V, Lamminen T, Nummelin K, Savontaus ML.

Department of Ophthalmology, University of Turku, Finland.

Ophthalmology 1996 Mar;103(3):504-14 Abstract quote

BACKGROUND: Leber hereditary optic neuropathy (LHON) is associated with primary and secondary mutations in mitochondrial DNA. Clinical studies suggest that there is a wide spectrum of clinical expression.

METHODS: Fifty-three affected and 131 unaffected maternal relatives from 21 pedigrees with LHON were studied neuro-ophthalmologically and followed over a period of 14 years. Mitochondrial DNA analysis was performed on their blood specimens.

RESULTS: Thirty-two affected (60%) individuals from ten families harbored the 11778 mutation and ten individuals (19%) from three families harbored the 3460 mutation. No confirmed primary mutation was detected in 11 (21%) affected individuals from eight families. The visual outcome was better in families with the 3460 mutation than in those with the 11778 mutation. Secondary mutations did not affect the penetrance or the visual outcome. Fifteen patients had a favorable outcome; seven of whom had subclinical disease, two had slowly progressive LHON with a favorable visual outcome, and six had classic LHON with spontaneous recovery. In seven patients, the onset of the disease had been in childhood. These patients had a more favorable prognosis than the adults. Results of eye examinations of asymptomatic maternal relatives showed subclinically affected individuals.

CONCLUSIONS: In addition to classic LHON, the disease can manifest itself in three different atypical forms: subclinical disease, slowly progressive LHON with a favorable visual outcome, and LHON with the classic acute stage but spontaneous visual recovery. The current study suggests that the ophthalmologic findings and outcome in LHON are independent of secondary mutations.

Autosomal dominant limb girdle myopathy with ragged-red fibers and cardiomyopathy. A pedigree study by in vivo 31P-MR spectroscopy indicating a multisystem mitochondrial defect.

Fabrizi GM, Lodi R, D'Ettorre M, Malandrini A, Cavallaro T, Rimoldi M, Zaniol P, Barbiroli B, Guazzi G.

Istituto di Scienze Neurologiche, Universitat di Siena, Policlinico Le Scotte, Italy.

J Neurol Sci 1996 Apr;137(1):20-7 Abstract quote

We describe a late-onset autosomal dominant limb girdle myopathy, associated with dilated cardiomyopathy and mental deterioration.

In two affected members of the pedigree with histochemical (ragged-red and cytocrome c oxidase - negative fibers) and ultrastructural abnormalities of muscle mitochondria, in vivo muscle phosphorus MR spectroscopy disclosed a slow rate of phosphocreatine resynthesis after exercise. Brain phosphorus MR spectroscopy revealed a defect of the energy metabolism in the two patients and in a third asymptomatic member, as shown by a significantly low phosphocreatine, increased ADP and decreased phosphorylation potential. Molecular analysis of muscle mitochondrial DNA failed to reveal any known mutation, including multiple deletions of the mtDNA which have been associated with some autosomal dominant mitochondrial diseases.

The multisystem clinical involvement, the presence of ragged-red fibers and the alterations revealed by in vivo brain and muscle 31P-MRS suggest that this limb-girdle syndrome represents an unusual phenotype of mitochondrial cytopathy.

Strabismus and mitochondrial defects in chronic progressive external ophthalmoplegia.

Sorkin JA, Shoffner JM, Grossniklaus HE, Drack AV, Lambert SR.

Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Am J Ophthalmol 1997 Feb;123(2):235-42 Abstract quote

PURPOSE: To describe the results of strabismus surgery on three patients with chronic progressive external ophthalmoplegia, a group of rare disorders characterized by ptosis and slowly progressive ophthalmoparesis that has been shown to result from defects in mitochondrial DNA.

METHODS: Strabismus surgery using the adjustable suture technique was performed in three patients with strabismus and chronic progressive external ophthalmoplegia confirmed by clinical, biochemical, histopathologic, and genetic criteria. All three patients had mitochondrial DNA deletions. Two patients were exotropic; one patient was esotropic.

RESULTS: Rectus muscle recessions were initially unsuccessful in correcting strabismus in one patient, although a subsequent procedure employing rectus muscle resections was successful in alleviating a significant head turn and improved ocular alignment. In the two other patients, a single procedure consisting of rectus muscle recessions combined with large rectus muscle resections successfully achieved good postoperative alignment. The amount of surgery performed in these three patients exceeded that predicted in standard strabismus tables.

CONCLUSIONS: The myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective compared with resections for correcting the associated strabismus seen in these patients. Rectus muscle resections therefore should be an integral procedure in the surgical management of the strabismus associated with chronic progressive external ophthalmoplegia.

Clinical manifestations of mitochondrial DNA depletion.

Vu TH, Sciacco M, Tanji K, Nichter C, Bonilla E, Chatkupt S, Maertens P, Shanske S, Mendell J, Koenigsberger MR, Sharer L, Schon EA, DiMauro S, DeVivo DC. H.

Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia University, New York, NY 10032, USA.

Neurology 1998 Jun;50(6):1783-90 Abstract quote

OBJECTIVE: We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder.

BACKGROUND: mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established.

METHODS: We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients.

RESULTS: Age at onset ranged from 3 months to 5 years, and one patient survived until age 10 1/2 years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some.

CONCLUSIONS: Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondrial disorders of uncertain etiology, and criteria for diagnosis are proposed.

Clinical differences in patients with mitochondriocytopathies due to nuclear versus mitochondrial DNA mutations.

Rubio-Gozalbo ME, Dijkman KP, van den Heuvel LP, Sengers RC, Wendel U, Smeitink JA.

Nijmegen Center for Mitochondrial Disorders, University Medical Center, Department of Pediatrics, Nijmegen, The Netherlands.

Hum Mutat 2000;15(6):522-32 Abstract quote

Defects in oxidative phosphorylation (OXPHOS) are genetically unique because the different components involved in this process, respiratory chain enzyme complexes (I, III, and IV) and complex V, are encoded by nuclear and mitochondrial genome.

The objective of the study was to assess whether there are clinical differences in patients suffering from OXPHOS defects caused by nuclear or mitochondrial DNA (mtDNA) mutations. We studied 16 families with > or = two siblings with a genetically established OXPHOS deficiency, four due to a nuclear gene mutation and 12 due to a mtDNA mutation. Siblings with a nuclear gene mutation showed very similar clinical pictures that became manifest in the first years (ranging from first months to early childhood). There was a severe progressive course. Seven of the eight children died in their first decade. Conversely, siblings with a mtDNA mutation had clinical pictures that varied from almost alike to very distinct. They became symptomatic at an older age (ranging from childhood to adulthood), with the exception of defects associated with Leigh or Leigh-like phenotype. The clinical course was more gradual and relatively less severe; four of the 26 patients died, one in his second year, another in her second decade and two in their sixth decade. T

There are differences in age at onset, severity of clinical course, outcome, and intrafamilial variability in patients affected of an OXPHOS defect due to nuclear or mtDNA mutations. Patients with nuclear mutations become symptomatic at a young age, and have a severe clinical course. Patients with mtDNA mutations show a wider clinical spectrum of age at onset and severity. These differences may be of importance regarding the choice of which genome to study in affected patients as well as with respect to genetic counseling.

Hearing Impairment Is Common in Various Phenotypes of the Mitochondrial DNA A3243G Mutation.

Deschauer M, Muller T, Wieser T, Schulte-Mattler W, Kornhuber M, Zierz S.

Department of Neurology, Martin-Luther-Universitat Halle-Wittenberg, Ernst-Grube-Str. 40, D-06097 Halle, Germany.

Arch Neurol 2001 Nov;58(11):1885-1888 Abstract quote

OBJECTIVE: To determine whether there are common symptoms within different phenotypes of the mitochondrial DNA A3243G mutation.

DESIGN: A series of 52 adults with mitochondrial encephalomyopathies and their symptomatic relatives were screened for the A3243G mutation using restriction enzyme analysis. In addition to clinical examination, patients with the mutation underwent audiometry.

RESULTS: The A3243G mutation was identified in 16 patients (10 index patients and 6 symptomatic relatives). Six of these patients presented with strokelike episodes and met the classical criteria of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), and one had MELAS/MERRF (myoclonic epilepsy with ragged-red fibers) overlap syndrome. Two patients presented with strokelike episodes but did not meet the classical criteria of MELAS. Predominant features of the 8 other patients were myopathy with hearing loss and diabetes mellitus (n = 1), chronic progressive external ophthalmoplegia (n = 1), diabetes mellitus with hearing loss (n = 1), painful muscle stiffness with hearing loss (n = 1), cardiomyopathy (n = 1), diabetes mellitus (n = 1), and hearing loss (n = 2). In 11 of 16 patients, hearing impairment was obvious on clinical examination. Furthermore, all 5 patients with normal hearing on clinical examination showed subclinical hearing loss; in 4, hearing loss was more pronounced than age-related hearing impairment and in 1, hearing loss can be age related as well.

CONCLUSIONS: A variety of phenotypes represent the variable multisystemic involvement of the A3243G mutation. Less than half of the patients presented with MELAS. Hearing impairment, the most common symptom, was clinically or subclinically relevant in 15 (94%) of 16 patients.

Infantile presentation of the mtDNA A3243G tRNA(Leu (UUR)) mutation.

Okhuijsen-Kroes EJ, Trijbels JM, Sengers RC, Mariman E, van den Heuvel LP, Wendel U, Koch G, Smeitink JA.

Nijmegen Center for Mitochondrial Disorders at the Department of Pediatrics, University Medical Center Nijmegen, The Netherlands.

Neuropediatrics 2001 Aug;32(4):183-90 Abstract quote

Mitochondrial DNA (mtDNA) disorders are clinically very heterogeneous, ranging from single organ involvement to severe multisystem disease. One of the most frequently observed mtDNA mutations is the A-to-G transition at position 3243 of the tRNA(Leu (UUR)) gene. This mutation is often related to MELAS syndrome. However, not all patients with the A3243G mutation share the same clinical disease expression and, on the contrary, patients clinically exhibiting MELAS syndrome may have other mtDNA mutations.

Here we describe two patients with a very early infantile presentation of disease associated with the A3243G mutation. Patient 1 presented with hypotonia, feeding difficulties and failure to thrive (FTT) at the age of 3 months. Laboratory investigations showed persistent hyperlactic acidemia, elevated lactate/pyruvate ratios and elevated alanine concentrations in blood. Developmental delay was progressive and he developed cardiomyopathy and seizures. Death occurred at the age of 3.5 years. Patient 2 was born prematurely and had persistent, severe lactic acidosis from birth on. Moderate biventricular hypertrophy was seen on ultrasound studies of the heart and, suffering from progressive lactic acidosis, he died at the age of 13 days. Because of the rarity of this very early presentation, we searched the literature for other infantile cases associated with the A3243G mutation and found 8 additional ones.

In infants presenting with lactic acidosis/hyperlactic acidemia, failure to thrive, hypotonia, seizures and/or cardiomyopathy, mtDNA mutational analysis, also for the disease entities, usually only observed in juveniles or adults is warranted.



Diagnostic yield muscle biopsy in patients with clinical evidence of mitochondrial cytopathy.

Rollins S, Prayson RA, McMahon JT, Cohen BH.

Ohio State University College of Medicine and Public Health, Cleveland, USA.

Am J Clin Pathol 2001 Sep;116(3):326-30 Abstract quote

We retrospectively reviewed 118 muscle biopsy specimens from 113 patients with clinical and/or biochemical evidence of mitochondrial cytopathy.

Light microscopic evaluation revealed histologic abnormalities in 65 specimens.

The most common histologic findings included angular atrophic esterase-positive muscle fibers, type II muscle atrophy, regenerating muscle fibers, and scattered cytochrome-oxidase deficient fibers. Ragged red fibers were noted in 3 specimens on a Gomori trichrome stain. Electron microscopic evaluation was performed in 113 muscle specimens, and in 34, no abnormalities were identified. Increased numbers of mitochondria, particularly in the subsarcolemmal region, were identified in 54 specimens. Increased mitochondrial size was seen in 8 specimens and paracrystalline mitochondrial inclusions in 3. Other ultrastructural findings included focally increased glycogen deposition, focal Z-band streaming, and focally increased lipid accumulation. For 39 cases, concomitant skin biopsy specimens were available; abnormalities were identified by electron microscopy in 12. The majority of biopsy specimens demonstrated some light or electron microscopic abnormality.

Specific histologic findings suggestive of mitochondrial abnormalities (partial cytochrome oxidase deficiency, ragged red fibers) were noted in a minority of cases. Ultrastructural evidence of mitochondrial abnormalities was noted in the majority of cases.

Histopathological features of peripheral nerve and muscle in mitochondrial disease.

Sladky JT.

Division of Pediatric Neurology, Emory University School of Medicine, Atlanta, Georgia.

Semin Neurol 2001;21(3):293-302 Abstract quote

Despite enormous strides in the molecular diagnosis of mitochondrial disease, this approach is currently applicable to only a minority of patients who are affected with these disorders.

The phenotypic spectrum in this category of disease is large and, in the absence of genotypic confirmation, a pattern recognition paradigm is probably the most sensitive means to reinforce the suspicion of mitochondrial disease. Along with clinical, biochemical, radiographic, and electrophysiological markers, histopathological features from nerve and muscle biopsy are useful indices to factor into a complex equation permitting a presumptive diagnosis or to justify more elaborate diagnostic undertakings. The combination of electrophysiological evidence of demyelinating neuropathy on nerve conduction studies and mild myopathic features on electromyography is one such constellation that should instigate a high index of suspicion for mitochondrial disease.

The histopathological hallmarks of mitochondrial cytopathies on muscle biopsy are the "ragged-red fiber" on light level evaluation and paracrystalline inclusions at the electron microscopic level. Neither of these is exclusive to mitochondrial disease and both may be identified among other nonspecific changes seen in biopsy specimens. Histopathological evaluation of muscle and nerve can provide information to reinforce the likelihood of mitochondrial disease or to indicate an alternative diagnosis as the more probable cause of a patient's symptoms.


Progression of myopathology in Kearns-Sayre syndrome: a morphological follow-up study.

Reichmann H, Gold R, Meurers B, Naumann M, Seibel P, Walter U, Klopstock T.

Department of Neurology, University of Wurzburg, Germany.

Acta Neuropathol (Berl) 1993;85(6):679-81 Abstract quote

We report on the progression of myopathology by comparing two biopsies from a patient with a Kearns-Sayre-Syndrome.

The first biopsy was taken in 1979 and showed 10% ragged-red fibers. Myopathic changes were slight including internal nuclei and fiber splitting in 10% of the fibers. Electron microscopy revealed typical mitochondrial abnormalities with regard to number and shape. In 1989 a second biopsy was performed for an extended analysis of mitochondrial DNA. This time less than 5% of all fibers were ragged-red.

Severe myopathic changes could be detected which so far has rarely been reported in mitochondrial cytopathy.

mtDNA deletion in a patient with symptoms of mitochondrial cytopathy but without ragged red fibers.

Blok RB, Thorburn DR, Danks DM, Dahl HH.

Murdoch Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

Biochem Mol Med 1995 Oct;56(1):26-30 Abstract quote

We describe a heteroplasmic 4237-bp mitochondrial DNA (mtDNA) deletion in an 11-year-old girl who has suffered from progressive illness since birth.

Her clinical features include global developmental delay with regression, brainstem dysfunction, lactic acidosis, and a history of pancytopenia and failure to thrive. The deletion spanned nt 9498 to nt 13734 and was flanked by a 12-bp direct repeat. Southern blot analysis also revealed an altered ApaI restriction site caused by a G --> A nucleotide substitution at nt 1462 in the 12S rRNA gene. This homoplasmic nucleotide change was presumed to be a mtDNA nucleotide variant. No abnormalities of mitochondrial ultrastructure or distribution were observed, although mild deficiencies were noted for complexes IV, II + III, and I of the mitochondrial respiratory chain.

The absence of ragged red fibers and COX-negative fibers in this patient shows that mtDNA deletions do not always result in these classical hallmarks of mitochondrial cytopathies.

Familial myopathy with conspicuous depletion of mitochondria in muscle fibers: a morphologically distinct disease.

Genge A, Karpati G, Arnold D, Shoubridge EA, Carpenter S.

Neuromuscular Research Group, Montreal Neurological Institute, Quebec, Canada.

Neuromuscul Disord 1995 Mar;5(2):139-44 Abstract quote

Three patients (two of them siblings) presented with easy fatiguability and prominent postexercise pain. Muscle biopsy showed that large areas of about one third of the type II fibers were completely devoid of mitochondria. The remaining mitochondria were unusually large in size, but otherwise normal ultrastructurally. In two patients, 31P in vivo MRS showed low phosphocreatine (PCr), high ADP, low phosphorylation potential at rest and slow ADP and PCr recovery after aerobic exercise.

This appears to be a pathologically unique form of metabolic myopathy. The cause of the focal mitochondrial depletion is not known. It should be distinguished from the mtDNA depletion syndrome in which muscle mitochondria are not reduced, but proliferate.

Association of age-related mitochondrial abnormalities with skeletal muscle fiber atrophy.

Lee CM, Lopez ME, Weindruch R, Aiken JM.

Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison 53706, USA.

Free Radic Biol Med 1998 Nov 15;25(8):964-72 Abstract quote

The hypothesis that mitochondrial dysfunction contributes to the senescent loss of skeletal muscle was investigated in quadriceps from 2- to 39-year old rhesus monkeys.

Histological approaches, both cross-sectional (a single cross-section of the muscle) and longitudinal (multiple cross-sections of individual fibers spanning a 350-1600 microm region), were used to identify muscle fibers with abnormal mitochondrial electron transport system (ETS) enzyme activities and mitochondrial DNA deletions. Fibers were examined for two ETS activities, succinate dehydrogenase (SDH, ETS complex II) and cytochrome c oxidase (COX, ETS complex IV). The number of individual fibers containing ETS abnormalities (predominately negative for cytochrome c oxidase activity and/or hyperreactive for succinate dehydrogenase) increased with age. Deletions of the mitochondrial genome were observed in 89% of these ETS abnormal fibers. Longitudinal analysis allowed characterization of the ETS abnormal phenotype along their length.

A decrease in cross-sectional area in 14% of the ETS abnormal fibers supports the hypothesis that deleted mitochondrial genomes may contribute to age-related fiber atrophy.



Contrasting histochemical features of various mitochondrial syndromes.

Collins S, Byrne E, Dennett X.

Department of Clinical Neurosciences, St Vincent's Hospital, Fitzroy, Victoria, Australia.

Acta Neurol Scand 1995 Apr;91(4):287-93 Abstract quote

A comparative histochemical analysis of the prevalence and cytochrome oxidase staining characteristics of ragged-red fibres in limb skeletal muscles was performed in 19 patients spanning four distinct mitochondrial syndromes: chronic progressive external ophthalmoplegia; myoclonus epilepsy with ragged-red fibres; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and pure limb myopathy.

The percentage occurrence of non-ragged red but cytochrome oxidase negative fibres was additionally noted. Ragged-red fibres and cytochrome oxidase-negative fibres were generally more prevalent in the chronic progressive external ophthalmoplegia syndrome than in myoclonus epilepsy ragged-red fibres syndrome or mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes syndrome. Isolated cytochrome oxidase-negative fibres were a common finding in each phenotypic syndrome except pure limb myopathy and could involve any of the major fibre types non-specifically.

Ragged-red fibres were devoid of cytochrome oxidase activity in chronic progressive external ophthalmoplegia, but commonly displayed activity in the other three syndromes providing a clue to syndromal differentiation on a histochemical basis.


Mitochondrial diseases and myopathies: a series of muscle biopsy specimens with ultrastructural changes in the mitochondria.

Lindal S, Lund I, Torbergsen T, Aasly J, Mellgren SI, Borud O, Monstad P.

Department of Pathology, University Hospital, Regionsykehuset i Tromso, Norway.

Ultrastruct Pathol 1992 May-Jun;16(3):263-75 Abstract quote

From 1986 to 1991, 472 muscle biopsy specimens from patients from different hospitals in Norway were examined. Of these, 364 were embedded for electron microscopy, and 194 were examined with electron microscopy.

Ultrastructural alterations in the mitochondria were detected in 49 of these specimens. Characteristic electron microscopic findings included subsarcolemmal accumulation of abnormal mitochondria of various shapes and sizes, often containing electron-dense granules and sometimes lipid vacuoles in the mitochondria and diffusely electron-lucent matrix space. Paracrystalline inclusion bodies were seldom seen in specimens from young patients, but in some cases mitochondrial electron-dense granules at the cristae were found. These amorphous densities are consistent with lipoproteins, suggesting that they may represent an early stage of paracrystalline inclusions. Biochemical and genetic exploration of the patients with biopsy specimens suggesting mitochondrial disease indicated maternally genetic inheritance and an enzyme defect in the respiratory chain in 21 patients in two families. Three patients had MELAS syndrome, 7 Marinesco-Sjogren syndrome, and 2 Kearns-Sayre syndrome. Five family members had ptosis, cardiomyopathy, mild myopathy, and increased lactate in cerebrospinal fluid and serum. In addition to the diseases mentioned above, changes in the mitochondria were detected in other conditions such as Rett's syndrome (n = 1), ornithine transcarbamylase deficiency (n = 2), and hypothyroidism (n = 2) as well as in 3 patients with clinical and laboratory results indicative of inflammatory myopathy and 3 patients with clinical and laboratory findings consistent with peripheral neuropathy.

It is concluded that, although ultrastructural changes in the mitochondria may represent unspecific findings, electron microscopic examination of muscle biopsy specimens is a useful screening method to select specimens for further biochemical analysis and to obtain an early and more precise diagnosis of the disease.


TREATMENT In general, there is no effective treatment for any of the disorders

Strabismus and mitochondrial defects in chronic progressive external ophthalmoplegia.

Sorkin JA, Shoffner JM, Grossniklaus HE, Drack AV, Lambert SR.

Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Am J Ophthalmol 1997 Feb;123(2):235-42 Abstract quote

PURPOSE: To describe the results of strabismus surgery on three patients with chronic progressive external ophthalmoplegia, a group of rare disorders characterized by ptosis and slowly progressive ophthalmoparesis that has been shown to result from defects in mitochondrial DNA.

METHODS: Strabismus surgery using the adjustable suture technique was performed in three patients with strabismus and chronic progressive external ophthalmoplegia confirmed by clinical, biochemical, histopathologic, and genetic criteria. All three patients had mitochondrial DNA deletions. Two patients were exotropic; one patient was esotropic.

RESULTS: Rectus muscle recessions were initially unsuccessful in correcting strabismus in one patient, although a subsequent procedure employing rectus muscle resections was successful in alleviating a significant head turn and improved ocular alignment. In the two other patients, a single procedure consisting of rectus muscle recessions combined with large rectus muscle resections successfully achieved good postoperative alignment. The amount of surgery performed in these three patients exceeded that predicted in standard strabismus tables.

CONCLUSIONS: The myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective compared with resections for correcting the associated strabismus seen in these patients. Rectus muscle resections therefore should be an integral procedure in the surgical management of the strabismus associated with chronic progressive external ophthalmoplegia.

Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

Commonly Used Terms

Neuromuscular Disorders

Last Updated 11/23/2001

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