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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Identical twins developed myoclonic epilepsy in their teens. One twin remained mildly affected but the other went on to develop sensorineural deafness and ataxia with lactic acidosis and ragged red fibres leading to a diagnosis of mitochondrial encephalopathy. Multiple stroke-like episodes with hemiparesis followed, indicating progression from a MERRF to a MELAS phenotype. Biochemical studies revealed a severe deficiency of mitochondrial NADH-ubiquinone reductase and a moderate deficiency of cytochrome aa3. Western immunoblotting experiments using polyclonal antibodies raised against human placental cytochrome oxidase identified a similar profile of bands to those seen in controls, supporting the view that cytochrome aa3 deficiency in this case may be a secondary consequence of a failure of assembly related to a severe proximal respiratory chain defect.
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PMID:Progression from MERRF to MELAS phenotype in a patient with combined respiratory complex I and IV deficiencies. 285 17

We describe on a 3-year-old child referred for evaluation and therapy of a cerebral vascular accident with residual hemiplegia and partial epilepsy. Metabolic investigations initially showed normal urinary organic acids as well as normal blood and urinary amino acids. Blood carnitine fractions had been pathological and a secondary carnitine deficiency was diagnosed and treated by oral L-carnitine supplementation. During carnitine treatment, abnormal urinary acylcarnitine profiles were noticed with excessive amounts of several carnitine esters including propionylcarnitine, butyryl- and/or isobutyryl-carnitine, isovaleryl- and/or 2-methylbutyryl-carnitine, hexanoylcarnitine and octanoylcarnitine. Subsequently, an urinary organic acid profile suggestive of glutaric aciduria type II was recorded during a clinical decompensation crisis. Morphological and biochemical studies on skeletal muscle and skin fibroblasts were performed and confirmed the existence of a defect of the mitochondrial beta-oxidation pathways with lipidic myopathy, reduced palmitate and octanoate oxidation rates in cultured fibroblasts. Glutaric aciduria type II increases the list of metabolic disorders characterized by hemiplegia and other sequelae of brain ischaemia such as stroke-like episode, seizures, aphasia, ataxia and myoclonia, similar to those seen in MELAS.
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PMID:Stroke, hemiparesis and deficient mitochondrial beta-oxidation. 795 9

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

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

We describe a 42-year-old woman with overlapping syndrome of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonus epilepsy and ragged-red fibers). Clinically, she had episodic headache, stroke-like episode with left hemiparesis and lactic acidosis commonly found in MELAS syndrome. However, myoclonus seizure, and ataxia with dyssynergic gait characteristic of MERRF were also noted. Computed tomographic scans showed a right temporo-parietal hypodense lesion. The lesion disappeared 20 months later, even magnetic resonance images also failed to reveal this abnormality. A molecular analysis of mitochondrial DNA was conducted by using restriction endonucleases ApaI and NaeI. A transition from A to G was found at the nucleotide position 3243, but not found at the 8344th nucleotide pair. In this report, we document the fluctuating CT changes and emphasize the importance of molecular analysis in patients with overlapping syndrome of mitochondrial encephalomyopathies.
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PMID:Overlapping syndrome of MERRF and MELAS: molecular and neuroradiological studies. 835 81

We studied cerebral oxygen and glucose metabolism as well as cerebral blood flow using positron emission tomography (PET) in a case with MELAS showing dementia, diabetes mellitus, ataxia and lactic acidosis without any signs of stroke. This case, confirmed to have a point mutation at position 3243 in the transfer RNA gene of mitochondrial DNA, developed a stroke-like episode 8 months after the PET study. Uncoupling was observed between cerebral oxygen metabolism and cerebral blood flow with reduced fractional oxygen extraction ratio, indicating "hyperemia", not ischemia. The "hyperemia" may be closely related to the malfunction of mitochondria in aerobic energy production. A drastic decrease in cerebral oxygen metabolism (CMRO2) was found globally in contrast to preserved cerebral glucose metabolism (CMRglu), resulting in a remarkable decrease in the metabolic ratio (CMRO2/CMRglu). The dissociation between cerebral glucose and oxygen metabolism may be characteristic of MELAS.
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PMID:Cerebral metabolism of oxygen and glucose in a patient with MELAS syndrome. 875 Jan 17

Mitochondrial diseases are characterized by considerable clinical variability and are most often caused by mutations in mtDNA. Because of the phenotypic variability, epidemiological studies of the frequency of these disorders have been difficult to perform. We studied the prevalence of the mtDNA mutation at nucleotide 3243 in an adult population of 245,201 individuals. This mutation is the most common molecular etiology of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), one of the clinical entities among the mitochondrial disorders. Patients with diabetes mellitus, sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia were ascertained on the basis of defined clinical criteria and family-history data. A total of 615 patients were identified, and 480 samples were examined for the mutation. The mutation was found in 11 pedigrees, and its frequency was calculated to be >=16. 3/100,000 in the adult population (95% confidence interval 11.3-21. 4/100,000). The mutation had arisen in the population at least nine times, as determined by mtDNA haplotyping. Clinical evaluation of the probands revealed a syndrome that most frequently consisted of hearing impairment, cognitive decline, and short stature. The high prevalence of the common MELAS mutation in the adult population suggests that mitochondrial disorders constitute one of the largest diagnostic categories of neurogenetic diseases.
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PMID:Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. 968 91

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

A 55-year-old woman, who had two episodes of difficulty in putting a key into a keyhole probably due to optic ataxia at age 52 and 54 years old, developed speaking errors and was admitted to our hospital. She was 152.5 cm in height and 52.5 kg in weight. Neurological examination revealed right homonymous hemianopsia and sensory aphasia. A CSF examination revealed lymphocytic pleocytosis of 88/microliter. Serum lactate and pyruvate were remarkably increased after an aerobic exercise test. A few ragged-red fibers were present in the biopsied brachial biceps muscle. Brain MRI by FLAIR method showed scattered high signal lesions in the left temporal lobe, bilateral parieto-occipital lobes, left insular cortex and left thalamus. The left superficial temporal lesion was enhanced by gadolinium-DTPA. The proton MRS demonstrated the lactic acid peak as well as the decrease of NAA/choline ratio (0.38) in the left parieto-occipital region. Thus, she was diagnosed as a case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and successfully treated with ubidecarenone (150 mg/day). Six months later, she again developed seizure, right hemiparesis and deterioration of aphasia and presented again CSF lymphocytic pleocytoses of 15/microliter. Brain MRI demonstrated new lesions in the left temporoparietal lobes, left insular cortex and left corona radiata. Therefore, CSF pleocytosis appeared to be associated with stroke-like episodes in this case. Although the mechanism of CSF pleocytosis remains to be elucidated, it may involve the breakdown of blood-brain barrier caused by mitochondrial dysfunction. Otherwise, an inflammatory process similar to that in cases of Leber disease, who developed multiple sclerosis-like additional lesions in the central nervous system, may also take place in MELAS.
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PMID:[A case of MELAS showing CSF pleocytosis associated with stroke-like episodes]. 986 8

This mini-review summarizes our present view of the biochemical alterations associated with mitochondrial DNA (mtDNA) point mutations. Mitochondrial cytopathies caused by mutations of mtDNA are well-known genetic and clinical entities, but the biochemical pathogenic mechanisms are often obscure. Leber's hereditary optic neuropathy (LHON) is due to three main mutations in genes for complex I subunits. Even if the catalytic activity of complex I is maintained except in cells carrying the 3460/ND1 mutation, in all cases there is a change in sensitivity to complex I inhibitors and an impairment of mitochondrial respiration, eliciting the possibility of generation of reactive oxygen species (ROS) by the complex. Neurogenic muscle weakness, Ataxia and Retinitis Pigmentosa (NARP), is due to a mutation in the ATPase-6 gene. In NARP patients ATP synthesis is strongly depressed to an extent proportional to the mutation load; nevertheless, ATP hydrolysis and ATP-driven proton translocation are not affected. It is suggested that the NARP mutation affects the ability of the enzyme to couple proton transport to ATP synthesis. A point mutation in subunit III of cytochrome c oxidase is accompanied by a syndrome resembling MELAS: however, no major biochemical defect is found, if we except an enhanced production of ROS. The mechanism of such enhancement is at present unknown. In this review, we draw attention to a few examples in which the overproduction of ROS might represent a common step in the induction of clinical phenotypes and/or in the progression of several human pathologies associated with mtDNA point mutations.
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PMID:Bioenergetics of mitochondrial diseases associated with mtDNA mutations. 1528 79


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