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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.
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PMID:Mitochondrial DNA alterations and genetic diseases: a review. 799 80

Fourteen patients (10 boys, 4 girls) aged from 4 months to 14 years old were diagnosed with mitochondrial disease based on the clinical manifestations together with abnormal muscle mitochondrial morphologies. Their clinical diagnoses included Leigh syndrome, three; Menkes' syndrome, three; Kearns-Sayre syndrome, two; myoclonic epilepsy with ragged fibres, one; and infant-onset progressive myoclonic epilepsy, one; fatal infantile mitochondrial myopathy, one; fatty acid oxidation defect, two; and myopathy with cardiopathy, one. Organs involved other than muscles included central nervous system, ten; heart, six; eye, two; liver, two; and kidney, two. Clinical manifestations varied to include hypotonia, seizures, myoclonus, mental retardation, nystagmus, ataxia, ptosis, ophthalmoplegia, retinal degeneration, muscle atrophy, spasticity etc. Nine had an abnormal rise in lactate after glucose loading. Ragged-red fibres were found in four patients. Abnormal mitochondrial morphology included abnormal accumulation, abnormal cristae pattern of tubular, concentric, or parallel form, some contained osmiophilic inclusion bodies. One patient of Leigh syndrome had had brain necropsy which showed intramyelin splitting of myelinated axons.
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PMID:Clinical manifestation of mitochondrial diseases in children. 821 54

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

To obtain a better molecular definition of patients with syndromic retinitis pigmentosa, we screened for mitochondrial DNA (mtDNA) alterations of the two ATPase genes and 22 tRNA-coding sequences in 10 patients whose features resembled NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. In two patients, one of whom showed features mimicking Kearns-Sayre syndrome, we identified a heteroplasmic T8993G mutation (average 80%) in the mitochondrial ATPase 6 gene. There was no mutated mtDNA in muscle and leukocytes from the mother of one patient or in leukocytes from his brother, suggesting a rapid segregation of the mutated nucleotide. MtDNA analysis should be considered in the differential diagnosis of patients with syndromic retinitis pigmentosa.
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PMID:Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation. 922 7

A 32-year-old woman developed chronic progressive hearing impairment, trunkal ataxia, bilateral ptosis and external ophthalmoplegia. She also showed slowly progressive mild to moderate proximal dominant muscle weakness and atrophy. ECG showed incomplete right bundle branch block. An aerobic exercise test showed abnormal blood lactate elevation and muscle biopsy revealed ragged-red fibers in addition to the myopathic change. Analysis of mitochondrial DNA extracted from biopsied muscle and fibroblast samples revealed a 1,758bp deletion from the cytochrome b to ND6 coding regions. Common mutations in tRNALeu(UUR) coding region to the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) were not present. She was diagnosed as having incomplete Kearns-Sayre syndrome (KSS). Since the age of 35, she developed complex partial seizure attacks with secondary generalization frequently and at the age of 42, she had a severe generalized seizure with delayed consciousness loss followed by left hemiplegia. MRI showed wide T2-high signal lesions in the right temporo-parieto-occipital area. The proton MR-spectroscopy showed prominent increase of lactate beyond the lesions detected by MRI, indicating diffuse aerobic metabolic dysfunction in the central nervous system. We reviewed two other KSS cases with a stroke like episode, who also had epilepsy and large deletion but no tRNALeu(UUR) mutation, in mitochondrial DNA. Patients with KSS who have seizure may develop the stroke-like episode as seen in MELAS patients.
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PMID:[A case of incomplete Kearns-Sayre syndrome with a stroke like episode]. 940 43

Rapid progress has been made in the identification of mitochondrial DNA mutations which are typically associated with diseases of the nervous system and muscle. The well established mitochondrial disorders are maternally inherited and males and females are equally affected. An exception is Leber's hereditary optic atrophy (LHON) which is observed much more frequently in males than in females. There are three common point mutations in LHON which can be homoplasmic or heteroplasmic. In mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) most mutations are single base changes and lie within the tRNA-Leu gene. Point mutations in myoclonic epilepsy with ragged red fibres (MERRF) usually occur within the tRNA-Lys gene but mutations of the tRNA-Leu gene are also observed. MELAS and MERRF mutations are heteroplasmic and there is considerable clinical overlap between these diseases. Point mutations within the ATPase6 gene result in either neuropathy, ataxia and retinitis pigmentosa (NARP) or in Leigh's syndrome. The latter occurs if the mutation is present in the majority of mitochondria (extreme heteroplasmy). Finally, mitochondrial DNA deletions are the cause underlying Kearns-Sayre syndrome (KSS). Apart from the well-established mitochondrial diseases, there is increasing evidence that mitochondrial mutations may also play a role in the neurodegenerative disorders Parkinson, Alzheimer and Huntington disease. The complex I defect found in Parkinson disease is especially interesting in this respect. However, no causative mitochondrial mutation has as yet been established in any of these three common disorders.
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PMID:Recent developments in the molecular genetics of mitochondrial disorders. 951 82

Since the first identification in 1988 of pathogenic mitochondrial DNA (mtDNA) mutations, the mitochondrial diseases have emerged as a major clinical entity. The most striking feature of these disorders is their marked heterogeneity, which extends to their clinical, biochemical, and genetic characteristics. The major mitochondrial encephalomyopathies include MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), KSS/CPEO (Kearns-Sayre syndrome/chronic progressive external ophthalmoplegia), and NARP/MILS (neuropathy, ataxia, and retinitis pigmentosum/maternally inherited Leigh syndrome) and they typically present highly variable multisystem defects that usually involve abnormalities of skeletal muscle and/or the CNS. The primary emphasis here is to review recent investigations of these mitochondrial diseases from the standpoint of how the complexities of mitochondrial genetics and biogenesis might determine their varied features. In addition, the mitochondrial encephalomyopathies are compared and contrasted to Leber hereditary optic neuropathy, a mitochondrial disease in which the pathogenic mtDNA mutations produce a more uniform and focal neuropathology. All of these disorders involve, at some level, a mitochondrial respiratory chain dysfunction. Because mitochondrial genetics differs so strikingly from the Mendelian inheritance of chromosomes, recent research on the origin and subsequent segregation and transmission of mtDNA mutations is reviewed.
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PMID:Human mitochondrial diseases: answering questions and questioning answers. 977 Feb 97

Kearns-Sayre syndrome (KSS) and Pearson's marrow-pancreas syndrome (PMPS) are rare disorders caused by the same molecular defect, one of several deletion mutations in mitochondrial DNA (mtDNA). KSS is an encephalomyopathy with ophthalmoplegia, retinal degeneration, ataxia, and endocrine abnormalities. PMPS is a disorder of childhood characterized by refractory anemia, vacuolization of bone marrow cells, and exocrine pancreas dysfunction. Children with PMPS that have a mild phenotype, or are supported through bone marrow failure, often develop the encephalomyopathic features of KSS. The subject of numerous reports in the neuromuscular, genetic, and pediatric literature in recent years, very few cases of either disorder have ever been studied at autopsy. We report the results of our studies of a patient with clinically documented KSS who presented with renal dysfunction and was found to have a novel mtDNA deletion and degenerative changes in the central nervous system, retina, skeletal muscle, and pancreas.
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PMID:Kearns-Sayre syndrome with features of Pearson's marrow-pancreas syndrome and a novel 2905-base pair mitochondrial DNA deletion. 1033 30

Congenital glaucoma and insulin-dependent diabetes mellitus were the predominant presenting signs in a patient with Kearns-Sayre syndrome. Thereafter, he developed short stature, pigmentary retinopathy, progressive external ophthalmoplegia, and ataxia. The diagnosis was confirmed by detecting a deletion of mitochondrial DNA in muscle, thus demonstrating that Kearns-Sayre syndrome can have the unusual presenting signs described above.
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PMID:Unusual presentation of Kearns-Sayre syndrome in early childhood. 1059 76

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.
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PMID:[Eye diseases in mitochondrial encephalomyopathies]. 1121 87


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