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PubMed1993

Phenotypic expression of mtDNA heteroplasmy in the skeletal muscle of patients with oculomyopathy: defect in mitochondrial protein synthesis.

The biochemical consequences of mtDNA heteroplasmy, observed in patients with a range of diseases associated with the mitochondrial respiratory enzymes deficiency is of particular interest, as they might provide information with regard to the regulatory interactions which govern the expression of the human mitochondrial genome. Three patients with chronic progressive external ophthalmoplegia (CPEO) were investigated to study the consequences of mtDNA heteroplasmy on mitochondrial protein synthesis. All 3 patients exhibited partially deleted mtDNA species (varying in size from 10.5 to 14 kb) in their skeletal muscle, which co-existed with the normal 16.5 kb mtDNA. The examination of mitochondrial translation products following the incorporation of [35S]methionine by isolated mitochondria, showed grossly abnormal patterns of mitochondrial translation products, suggesting a major disturbance in the regulation of mitochondrial protein synthesis.

Adult↗
PubMed1996

[Chronic progressive external ophthalmoplegia with mitochondrial anomalies. Clinical, histological, biochemical and genetic analysis (9 cases)].

We report the clinical signs and histological findings in nine patients with mitochondrial ocular myopathies. There were four males and five females. Of age ranging from 47 to 82 years. A more often asymetrical ptosis was in all cases of chronic progressive external ophtalmoplegia (CPEO), but muscle weakness in limbs was not usual. The prognosis in this group was good, but ubidecarenone (150 mg/d) used for two cases, did not improve ophtalmoplegia. The serum creatine kinase was normal in eight of nine cases and electromyography showed myopathic changes in three cases. Histoenzymatic analysis of the muscle biopsy and biochemical studies of mitochondria isolated from the muscle sample demonstrated mitochondrial myopathy associated with partial deficiency of complexes I and/or IV of the electron transfer chain. One of seven patients studied had single deletion by Southern blot analysis, in a heteroplasmic state and another an A-->G transition at position 3243 within the mitochondrial tRNA leu (UUR) gene. Chronic progressive external ophtalmoplegia, without large deletion, may have abnormality in other coding regions of mt DNA such as tRNA, rRNA or protein genes.

Aged↗
PubMed1994

Mitochondrial DNA alterations and genetic diseases: a review.

We review the main features of human mitochondrial function and structure, and in particular mitochondrial transcription, translation, and replication cycles. Furthermore, some pecularities such as mitochondria's high polymorphism, the existence of mitochondrial pseudogenes, and the various considerations to take into account when studying mitochondrial diseases will also be mentioned. Mitochondrial syndromes mostly affecting the nervous system have, during the past few years, been associated with mitochondrial DNA (mt DNA) alterations such as deletions, duplications, mutations and depletions. We suggest a possible classification of mitochondrial diseases according to the kind of mt DNA mutations: structural mitochondrial gene mutation as in LHON (Leber's Hereditary Optic Neuropathy) and NARP (Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa) as well as some cases of Leigh's syndrome; transfer RNA and ribosomal RNA mitochondrial gene mutation as in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokelike Episodes) or MERRF (Myoclonic Epilepsy with Ragged Red Fibers) or deafness with aminoglycoside; structural with transfer RNA mitochondrial gene mutations as observed in large-scale deletions or duplications in Kearns-Sayre syndrome, Pearson's syndrome, diabetes mellitus with deafness, and CPEO (Chronic Progressive External Ophtalmoplegia). Depletions of the mt DNA may also be classified in this category. Even though mutations are generally maternally inherited, most of the deletions are sporadic. However, multiple deletions or depletions may be transmitted in a mendelan trait which suggests that nuclear gene products play a primary role in these processes. The relationship between a mutation and a particular phenotype is far from being fully understood. Gene dosage and energic threshold, which are tissue-specific, appear to be the best indicators. However, the recessive or dominant behavior of both the wild type or the mutated genome appears to play a significant role, which can be verified with in vitro studies.

DNA, Mitochondrial↗
PubMed1992

Mitochondrial creatine kinase containing crystals, creatine content and mitochondrial creatine kinase activity in chronic progressive external ophthalmoplegia.

Mitochondrial crystals containing mitochondrial creatine kinase (Mi-CK) protein were described recently. From in vitro studies it has been suggested that alterations in creatine concentration are connected to the occurrence of these crystals. In the present study free, phosphorylated and total creatine concentrations as well as Mi-CK activity were determined in muscle samples of six patients with chronic progressive external ophthalmoplegia (CPEO). Two of them showed Mi-CK containing mitochondrial crystals. The activity of Mi-CK was found to be clearly enhanced in those muscle samples in which mitochondrial crystals were present. No relationship was found between the concentration of total, free or phosphorylated creatine and the occurrence of mitochondrial crystals. An up to now unknown mechanism seems to cause the formation of Mi-CK containing crystals in human muscle mitochondria.

Adolescent↗
PubMed2006

Oculopharyngeal somatic myopathy in a patient with a novel large-scale 3,399 bp deletion and a homoplasmic T5814C transition of the mitochondrial DNA.

We report a 65-year-old woman with a sporadic form of progressive oculopharyngeal somatic myopathy due to a novel large-scale 3,399 base pair (bp) deletion of the mitochondrial DNA (mtDNA) and co-occurrence of a homoplasmic T5814C transition. The onset of myopathy began from chronic progressive external ophthalmoplegia (CPEO) at age of 20 years. Bulbar weakness, neck and proximal limb paralysis, slowly progressed to eventual respiratory failure. The plasma levels of pyruvate (1.5 mg/dL) and lactate (20.2 mg/dL) were elevated. Muscle biopsy showed decreased enzymatic activity of cytochrome c oxidase, but no ragged-red fibers. Electron microscopy showed "parking-lot" paracrystalline inclusions in the enlarged mitochondria suggestive for mitochondrial myopathy. Sequencing of the whole mitochondrial genome of the patient's muscle and leukocytes showed 3,399 bp deletion of the mtDNA from nucleotide position 8,024 to 11,423 and a homoplasmic thymidine to cytosine transition at nucleotide position 5,814 of the tRNA(Cys) gene of mtDNA (T5814C). T5814C was absent in the white blood cells of the patient's daughter and in 205 normal controls. We conclude that a large-scale deletion may coexist with T5814C transition in patients with sporadic form of mitochondrial cytopathy manifested by slowly progressive oculopharyngeal somatic myopathy.

Aged↗
PubMed2004

Lipoma and opthalmoplegia in mitochondrial diabetes associated with small heteroplasmy level of 3243 tRNA(Leu(UUR)) mutation.

We report a patient with mitochondrial diabetes mellitus associated with the A3243G mutation (MDM3243). The patient is a 77-year man with diabetes. At age 68, he noticed diplopia, due to superior rectus muscle palsy of the right eye. At age 70, he noticed lipoma on the right arm. The pathology of his muscle revealed some ragged-red fibers, and focal cytochrome c oxidase deficiency. Hence, he may have a pathogenetic mechanism in common with CPEO (chronic progressive external ophthalmoplegia) or mitochondria-related autoimmune disorder associated with mononeuropathy. He had the rate of 0.102% for heteroplasmy of 3243 mitochondrial DNA mutation in leukocytes. This case's heteroplasmy level is the smallest among the reported cases of MDM3243 in the literature. 3243 mitochondrial DNA mutation is known to induce a lack of uridine-modification in tRNA(Leu(UUR)) at the first letter of the anticodon, with which the third letter of the codon pairs, and decline of the pairing of the anticodon of tRNA with the codon of mRNA, suggesting the termination of polypeptide-elongation to generate premature proteins. Therefore, we speculate that these premature proteins may accumulate overtime, thereby affecting cells in target organs.

Aged↗
PubMed2004

Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders.

While skeletal muscles generally perform specific limited roles, extraocular muscles (EOMs) have to be responsive over a wider dynamic range. As a result, EOMs have fundamentally distinct structural, functional, biochemical and immunological properties compared to other skeletal muscles. While these properties enable high fatigue resistance and the rapid and precise control of extraocular motility, they might also explain why EOMs are selectively involved in certain disorders, such as chronic progressive external ophthalmoplegia (CPEO), myasthenia gravis and Graves' ophthalmopathy. This review first gives an overview of the novel myofibre classification in EOMs and then focuses on those properties that might explain why ophthalmoplegia should be so prominent in these disorders.

Adaptation, Physiological↗
PubMed1999

Common deletion of mitochondrial DNA in a 5-year-old girl with failure to thrive, ptosis, ophthalmoplegia and ragged-red fibers.

A girl aged 4 years and 10 months presented with failure to thrive, ptosis, ragged-red fibers and the common 4.9 kb mitochondrial DNA deletion. She had elevated serum lactic and pyruvic acids. The onset was at around 18 months. There were no signs of retinitis, and abnormal renal, liver or pancreatic functions. She later developed mild ophthalmoplegia at 6 years of age. Additional features of chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) are the conditions that should be watched and investigated in the long-term follow-up of this girl.

Adenosine Triphosphatases↗
PubMed2001

[Eye diseases in mitochondrial encephalomyopathies].

Mitochondria are the principal site of generation of energy in form of adenosine triphosphate (ATP). They contain the enzymes of the Krebs and fatty acid cycles and the respiratory pathway. Ocular tissues with high energy consumption and dependence on oxidative energy production like the optic nerve, the retina, and the pigment epithelium are often involved in mitochondrial diseases. This article reviews the genetic mitochondrial diseases involving the visual system. Their most important ocular findings include: acute or slowly progressive bilateral visual loss and visual field loss due to an optic neuropathy or retinal degeneration, bilateral progressive decreased ocular motility, and bilateral upper lid ptosis. The following diseases are discussed: Leber's Hereditary Optic Neuropathy (LHON); Kearns-Sayre Syndrom (KSS); Chronic Progressive External Ophthalmoplegia (CPEO); Autosomal Recessive Cardiomyopathy, Ophthalmoplegia (ARCO); Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-Like Episodes (MELAS); Neuropathy, Ataxia, Retinitis Pigmentosa (NARP); Mitochondrial Neuropathy, Gastro-Intestinal Encephalomyopathy (MNGIE); Myoclonus Epilepsy, Ragged-Red-Fibers (MERRF); Wilson's disease; Friedreich's ataxia. Diagnosis of mitochondrial encephalomyopathies is established by screening for mutations in blood or muscle biopsy samples. No specific therapies which influence the course of mitochondrial encephalomyopathies are known. Drugs interacting with the mitochondria function, alcohol consumption and smoking should be avoided.

DNA Mutational Analysis↗
PubMed2006

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes.

There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

Animals↗
PubMed2002

Frontalis suspension sling using a silicone rod in patients affected by myogenic blepharoptosis.

The charts of 10 patients affected by myogenic ptosis who underwent surgical correction by means of a frontalis suspension sling using a silicone rod were reviewed. The patients included in the study were affected by ptosis secondary to myasthenia gravis (MG), chronic progressive external ophthalmoplegia (CPEO) or mitochondrial myopathy (MM). In every patient the ptosis was severe (MRD( 1) < 2 mm), with the eyelid partially or totally occluding the visual axis; levator function was poor (<5 mm), Bell's phenomenon was poor or absent and the orbicularis function was reduced. Final eyelid height, patient satisfaction and the presence of complications were our main outcome measures. Analysis of the results showed that the ptosis was corrected in every patient with a clear visual axis. One patient with absent Bell's and poor levator function had exposure keratopathy resistant to medical treatment and required surgical revision. We believe that the frontalis suspension sling is safe, effective and is the procedure of choice for patients affected by poor-function acquired ptosis. A silicone rod, because of its elasticity, is the material of choice in this selected category of patients.

Adult↗
PubMed1994

Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction.

Intergenomic variation in the human mitochondrial genome was examined in 27 mtDNA sequences using a pairwise analysis technique. Analysis of 16 of these mtDNA sequences from patients with mitochondrial cytopathies indicated a wide range between different mitochondrial genes in the degree of nucleotide variation from the standard Cambridge sequence. Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t). Total mean sequence divergence (mean number of diverging nucleotides between two sequences per 100 bp) over the entire mtDNA coding region was 0.21% for cytopathies (n = 16) as opposed to 0.18% for a control group (n = 4). Within the cytopathy group, the greatest pairwise divergence was observed in ND3 and ND6 subunits of complex I (0.46 and 0.70% respectively) and the magnitude of specific gene divergences differed considerably from those observed for the corresponding genes in the control population. The extent to which the increased variation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding specific to cytopathies cannot be stated with certainty given the small control group. Regardless as to which of these suggestions is correct, the possibility exists that increased nucleotide variation in certain mitochondrial ND subunits may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor individual mutagenic potential.

DNA, Mitochondrial↗
PubMed2002

Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients harboring the A3243G point mutation or large-scale deletions of mitochondrial DNA.

To assess the detailed expression pattern of mitochondrial-encoded proteins in skeletal muscle of patients with mitochondrial diseases we performed determinations of cytochrome content and enzyme activities of respiratory chain complexes of 12 patients harboring large-scale deletions and of 10 patients harboring the A3243G mutation. For large-scale deletions we observed a mutation gene dose-dependent linear decline of cytochrome aa3 content, cytochrome c oxidase (COX) activity, and complex I activity. The content of cytochromes b and the complex III activity was either not affected or only weakly affected by the deletion mutation and did not correlate to the degree of heteroplasmy. In contrast, in skeletal muscle harboring the A3243G mutation all investigated enzymes containing mitochondrial-encoded subunits were equally affected by the mutation, but we observed milder enzyme deficiencies at a comparable mutation gene dose. The results of single fiber analysis of selected biopsies supported these findings but revealed differences in the distribution of COX deficiency. Whereas predominantly type I fibers were affected in A3243G and deletion CPEO biopsies, we observed in MELAS and KSS biopsies higher quantities of COX-deficient type 2 fibers. Our findings indicate different pathomechanisms of deletion and A3243G mutations.

Base Sequence↗
PubMed1991

Mutations in mitochondrial tRNA genes: a frequent cause of neuromuscular diseases.

We have sequenced the tRNA genes of mtDNA from patients with chronic progressive external ophthalmoplegia (CPEO) without detectable mtDNA deletions. Four point mutations were identified, located within highly conserved regions of mitochondrial tRNA genes, namely tRNA(Leu)(UAG), tRNA(Ser)(GCU), tRNA(Gly) and tRNA(Lys). One of these mutations (tRNA(Leu)(UAG)) was found in four patients with different forms of mitochondrial myopathy. An accumulation of three different tRNA point mutations (tRNA(Leu)(UAG)), tRNA(Ser)(GCU) and tRNA(Gly) was observed in a single patient, suggesting that mitochondrial tRNA genes represent hotspots for point mutations causing neuromuscular diseases.

Adult↗
PubMed2005

Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study.

The purpose of our randomized, double-blind, placebo-controlled crossover study in 15 patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) because of single large-scale mitochondrial (mt) DNA deletions was to determine whether oral creatine (Cr) monohydrate can improve skeletal muscle energy metabolism in vivo. Each treatment phase with Cr in a dosage of 150 mg/kg body weight/day or placebo lasted 6 weeks. The effect of Cr was estimated by phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS), clinical and laboratory tests. (31)P-MRS analysis prior to treatment showed clear evidence of severe mitochondrial dysfunction. However, there were no relevant changes in (31)P-MRS parameters under Cr. In particular, phosphocreatine (PCr)/ATP at rest did not increase, and there was no facilitation of post-exercise PCr recovery. Clinical scores and laboratory tests did not alter significantly under Cr, which was tolerated without major side-effects in all patients. Cr supplementation did not improve skeletal muscle oxidative phosphorylation in our series of patients. However, one explanation for our negative findings may be the short study duration or the limited number of patients included.

Adult↗
PubMed1996

Tandem duplications and large-scale deletions of mitochondrial DNA are early molecular events of human aging process.

Large-scale deletions and tandem duplications of mtDNA, which were originally identified in the patients with KSS or CPEO, have recently been found, although with lower abundance, in various tissues of aged individuals. By use of PCR techniques with back-to-back primers, we demonstrated for the first time that small tandem duplications occur in the D-loop of mtDNA in an age-dependent manner in human tissues. A total of 10 types of such tandem duplications were identified and confirmed by primer-shift PCR and DNA sequencing. Based on the sequence characteristics of the junction sites, we classified these small tandem duplications into 3 groups. Most of the tandem duplications were found to occur at hot spots containing poly C runs, and the number of C residues exhibited wide variations in type I, II, V, VI, VII, and VIII duplications. These observations suggest that these tandem duplications may be generated through similar recombination mechanisms. Among them, type I, II, III, IV and IX duplications were found to occur more frequently and abundantly in aging human tissues. They were not detectable in muscle, testis or skin tissues of young subjects or blood cells from subjects of any age. On the other hand, we also analyzed the samples for the aging-associated 4,977-bp and 7,436-bp mtDNA deletions. The results showed that these two deletions and some of the small tandem duplications could occur alone or in different combinations in human tissues in the aging process. From our data, no clear association between tandem duplications and large-scale deletions of mtDNA could be established. However, one common and important observation is that the incidence and abundance of some of the tandem duplications as well as the large-scale deletions were increased in an age-dependent manner. On the basis of these findings and data reported from this and other laboratories, we propose that tandem duplications and large-scale deletions of mtDNA are early molecular events of the human aging process.

Adolescent↗
PubMed1992

Defects of mitochondrial DNA.

In the past few years several syndromes have been associated with lesions of the human mitochondrial DNA. MtDNA is a small, circular extra-nuclear chromosome encoding essential components of the respiratory chain. MtDNA-related syndromes can be divided into two groups: mitochondrial encephalomyopathies, characterized by the presence of ragged-red fibres (RRF) as the morphological hallmark, or "pure" encephalopathies with no gross morphological abnormalities in muscle. The first group includes myoclonic epilepsy with ragged-red fibres (MERRF), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO) and a new entity, maternally inherited myopathy and cardiomyopathy. The second group includes Leber's Hereditary Optic Neuroretinopathy (LHON) and the newly described ataxia-retinitis pigmentosa-dementia complex. Three kinds of molecular lesions have been identified: point mutations of protein encoding mtDNA-genes (similar to yeast mit- mutations); point mutations of mtDNA-tRNA genes (similar to yeast syn- mutations); and large-scale rearrangements of mtDNA (similar to yeast rho- mutations). In general, "mit-" mutations are responsible for non-RRF encephalopathies, while "syn-" and "rho-" mutations are associated with mitochondrial encephalomyopathies with RRF. Furthermore, point mutations (mit- and syn-) are usually maternally- inherited, while large-scale mtDNA rearrangements are either sporadic or inherited as mendelian traits. In most cases, the molecular detection of the known defects of mtDNA can be carried out by non-invasive techniques, thus making it an easy and relatively inexpensive procedure in the differential diagnosis of the mitochondrial disorders, a rapidly expanding area of clinical neurology.

DNA, Mitochondrial↗
PubMed2001

Elevated visual motion detection thresholds in adults with acquired ophthalmoplegia.

AIMS: To test the hypothesis that in patients with acquired chronic bilateral ophthalmoplegia, abnormal retinal image slippage during head movements would result in abnormal thresholds for visual perception of motion. METHODS: Five patients (two males and three females) with ophthalmoplegia were included in the study. The average age was 44 years (range 30-69 years). The aetiology of ophthalmoplegia was myasthenia gravis (MG; n=2), chronic progressive external ophthalmoplegia (CPEO; n=2), and chronic idiopathic orbital inflammation. Visual motion detection thresholds were assessed using horizontal and vertical gratings (spatial frequency) set at thresholds for visibility. The grating was then accelerated at 0.09 deg/s(2). The subject's task was to detect the drift direction of the stimulus. RESULTS: Visual motion detection thresholds were raised to a mean of 0.434 deg/s (SD 0.09) (mean normal value 0.287 deg/s (SD 0.08)) for horizontal motion; and to a mean of 0.425 deg/s (SD 0.1) (mean normal value 0.252 deg/s (SD 0.08)) for vertical motion. The difference in values for both horizontal and vertical motion detection were statistically significant when compared with age matched controls; p <0.023 for horizontal motion and p<0.07 for vertical motion (two tailed t test). CONCLUSION: Abnormally raised visual motion thresholds were found in patients with ophthalmoplegia. This may represent a centrally mediated adaptive mechanism to ignore excessive retinal slip and thus avoid oscillopsia during head movements.

Adult↗