Search request: F KW LEIGH AND DATE 1993
Search result: 33 citations in the Medline database
1. Santorelli FM; Shanske S; Macaya A; DeVivo DC; DiMauro S. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Annals of Neurology, 1993 Dec, 34(6):827-34. (UI: 94071416)
Abstract: Twelve patients with Leigh's syndrome from 10 families harbored a T > G point mutation at nt 8993 of mtDNA. This mutation, initially associated with neurogenic weakness, ataxia, and retinitis pigmentosa, was later found to result in the Leigh phenotype when present in a high percentage. In our patients, the mutation was heteroplasmic, maternally inherited, and appeared to segregate rapidly within the pedigrees. Quantitative analysis revealed a good correlation between percentage of mutant mitochondrial genomes and severity of the clinical phenotype. The mutation was not found in > 200 patients with other mitochondrial encephalomyopathies or in controls. Mitochondrial enzyme activities were normal in all but 1 patient, and there were no ragged-red fibers in the muscle biopsy. Lactic acidosis was present in 92% of patients. Our findings suggest that the mtDNA nt 8993 mutation is a relatively common cause of Leigh's syndrome.
2. Cavanagh JB. Selective vulnerability in acute energy deprivation syndromes. Neuropathology and Applied Neurobiology, 1993 Dec, 19(6):461-70. (UI: 94166936) Pub type: Journal Article; Review; Review, Tutorial.
Abstract: The topography and cellular events in the experimental lesions caused by chlorosugars, 6-aminonicotinamide, dinitrobenzene and tribromoimidazole in animals are considered in relation to those features in human acute thiamine deficiency (Wernicke's) encephalopathy and for comparison in Leigh's disease. The topography and cellular changes when closely examined are different and particular to each condition, although there is a basic cellular process common to all. The pathogenesis of each condition must be considered as multifactorial and a search for the factors responsible for the neuronal and cellular selective vulnerability of different regions of the neuraxis will lead us to understanding the pathogenesis of the disease process in each instance. The experimental models offer much for the understanding of the human conditions, particularly in the search for satisfactory therapeutic strategies.
3. Cavanagh JB; Nolan CC. The neurotoxicity of alpha-chlorohydrin in rats and mice: II. Lesion topography and factors in selective vulnerability in acute energy deprivation syndromes. Neuropathology and Applied Neurobiology, 1993 Dec, 19(6):471-9. (UI: 94166937)
Abstract: Mice and rats have been found almost equally susceptible to (R, S)-alpha-chlorohydrin neurotoxicity, but in rats the distribution of lesions in the neuraxis is less widespread. The topography of the brain lesions shows an incomplete relationship to the regional hierarchy of local glucose utilization in rats and local cerebral blood flow in mice, suggesting that other, unknown, factors also play roles in determining this. Evidence suggesting progressive tonotopic selective vulnerability was found in inferior colliculi in rats given five doses of 50 mg/kg/day. Distinct differences in the patterns of damage to brain stem centres found with chlorohydrin by comparison with other acute energy deprivation syndromes, despite the proximity of the metabolic lesions along the energy generation pathway, suggests there are other unrecognized factors that play a role in determining whether a neuronal centre is at risk or not.
4. Ortiz RG; Newman NJ; Shoffner JM; Kaufman AE; Koontz DA; Wallace DC. Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation. Archives of Ophthalmology, 1993 Nov, 111(11):1525-30. (UI: 94058837)
Abstract: OBJECTIVE: Ophthalmologic and neurologic manifestations of the mitochondrial DNA mutation at position 8993 (MTATP*NARP8993) are reported and compared with previously published reports of patients with the 8993 mutation and other mitochondrial disorders. DESIGN: Pedigree analysis. SETTING: University referral center. PATIENTS: Eight subjects from two unrelated pedigrees that were positive for the mitochondrial DNA replacement mutation at nucleotide position 8993 were evaluated ophthalmologically and neurologically. RESULTS: Retinal abnormalities ranged from mild salt-and-pepper changes to severe retinitis pigmentosa-like changes with maculopathy. Neurologic manifestations were also highly variable and ranged from migraine headaches to severe dementia and Leigh's disease. CONCLUSIONS: The type and extent of retinal pigmentary changes and neurologic findings varied substantially, even among members of the same family. These changes, although not specific for the MTATP*NARP8993 mutation, are highly suggestive of mitochondrial disease.
5. Zeman J; Klement P; Houst'kova H; Hrebicek M; Hansikova H; Richterova I; Velenska Z; Houstek J. [Metabolic study in a child with Leigh's syndrome and deficient activity in complex I of the respiratory chain]. Ceskoslovenska Pediatrie, 1993 Oct, 48(10):586-9. Language: Czech. (UI: 94094346)
Abstract: Leigh's syndrome--subacute necrotizing encephalomyopathy--is a serious disease of child age manifested by severe psychomotor retardation, a varied neurological symptomatology, a typically symmetrical neuropathological affection of the central nervous system in the area of the basal ganglia and a metabolic disorder affecting the energy system of cells. The authors describe the clinical course of the disease and the results of metabolic and neuropathological investigations in an infant with Leigh's syndrome and severe lactate acidosis based on deficiency of complex I activity of the respiratory chain.
6. Morris SA; Harbord MG. Infant onset subacute necrotizing encephalomyelopathy (Leigh's disease). Journal of Paediatrics and Child Health, 1993 Oct, 29(5):363-7. (UI: 94059633)
Abstract: We reviewed six cases of proven or probable subacute necrotizing encephalomyelopathy with an onset under 12 months of age. All children had been investigated at the Adelaide Children's Hospital in the period 1975-90. Seizures (five of six) and cortical blindness (five of six) were more prominent clinical features at presentation than the literature would suggest, while respiratory abnormalities and developmental delay were also frequent. Flash visual evoked responses, brain-stem auditory evoked responses, and the interictal electroencephalogram did not contributed to diagnosis. Computerized tomography brain scans were abnormal in three of four cases with typical basal ganglia lesions in one case and brain atrophy in two cases. The diagnosis was suspected in four cases with raised blood or cerebrospinal fluid lactate concentrations. The importance of obtaining a blood or cerebrospinal fluid lactate in all infants with unexplained seizures, cortical blindness or apnoea is emphasized.
7. Bornemann A; Schmalbruch H. Anti-vimentin staining in muscle pathology. Neuropathology and Applied Neurobiology, 1993 Oct, 19(5):414-9. (UI: 94104740)
Abstract: The intermediate filaments of immature muscle fibres contain desmin and vimentin; vimentin is lacking in mature fibres. Regenerating fibres react with anti-vimentin antibodies and more intensely for desmin than mature fibres. The aim of the present study was to evaluate anti-vimentin staining for muscle pathology. Anti-vimentin-reactive fibres were found in 40 of 89 biopsies assessed. Fifteen patients with progressive destructive myopathy, infantile spinal muscular atrophy, clinically suspected Leigh's disease or unclassifiable congenital myopathy had between 1% and 95% vimentin-positive fibres. Less than 1% positive fibres were found in 25 patients with neuropathy with secondary myopathy or chronic myopathic conditions. Vimentin-positive fibres were lacking in 20 normal biopsies, in eight biopsies with neuropathic and in 21 biopsies with mild or non-destructive myopathic changes. We conclude that staining with anti-vimentin antibodies is a useful indicator for muscle fibre regeneration; it may help establish the diagnosis in infantile spinal muscular atrophy when the histopathology is non-characteristic. The high incidence of reactive fibres in some congenital or early-onset disorders may indicate developmental arrest.
8. Barkovich AJ; Good WV; Koch TK; Berg BO. Mitochondrial disorders: analysis of their clinical and imaging characteristics. Ajnr. American Journal of Neuroradiology, 1993 Sep-Oct, 14(5):1119-37. (UI: 94056054)
Abstract: PURPOSE: Investigation of the clinical, imaging, and in vivo MR spectroscopy (MRS) characteristics of disorders of mitochondrial function. METHODS: Clinical, imaging (five CT and 20 MR examinations), and MRS (six studies in five patients) findings in 19 patients with mitochondrial disorders were retrospectively reviewed. Results were critically analyzed and, when applicable, compared with results in the literature. RESULTS: Patients included four with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), two with myoclonus, epilepsy, and ragged red fibers (MERRF), two with Kearns-Sayre syndrome, seven with Leigh syndrome, one with progressive cerebral poliodystrophy (Alpers syndrome), and three with trichopoliodystrophy (Menkes disease). MELAS, MERRF, and Kearns-Sayre tended to occur in older children and adults, whereas Leigh syndrome, Alpers syndrome, and Menkes disease occurred in infants and young children. All diseases involved gray matter early in their course, manifest primarily as T2 prolongation, with the deep cerebral nuclei being involved more often than the cerebral cortex. When T2 prolongation was seen in the white matter (MELAS, MERRF, Kearns-Sayre, Leigh), the peripheral and retrotrigonal white matter showed early involvement. Patients with Menkes disease showed rapidly progressive atrophy accompanied by large subdural hematomas. Proton MRS showed an elevated lactate level in involved regions of the brain; the lactate peak disappeared in old areas of T2 prolongation. CONCLUSIONS: Mitochondrial disorders have a wide range of both clinical and imaging findings. Although no one set of findings is diagnostic of these disorders, the combination of deep gray matter involvement and peripheral white matter involvement in young adults or children should suggest the diagnosis, especially when associated with an elevated lactate level on proton MRS.
9. Heckmann JM; Eastman R; Handler L; Wright M; Owen P. Leigh disease (subacute necrotizing encephalomyelopathy): MR documentation of the evolution of an acute attack. Ajnr. American Journal of Neuroradiology, 1993 Sep-Oct, 14(5):1157-9. (UI: 94056058)
Abstract: The radiologic evolution of Leigh disease is documented with sequential brain MR in the acute phase of the illness, at 3 weeks, and at 3 months. High-signal-intensity lesions seen on T2-weighted images in the first week resolved by 3 months, whereas new lesions appear during the chronic stage. Putamenal involvement is not a pathognomonic radiologic finding. Brain stem tegmentum, particularly the mesencephalon, is characteristically involved on MR in the early and late phases of the illness.
10. de Vries DD; van Engelen BG; Gabreels FJ; Ruitenbeek W; van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Annals of Neurology, 1993 Sep, 34(3):410-2. (UI: 93371018)
Abstract: By direct sequencing, we have discovered a novel heteroplasmic mutation (T-->C) at nucleotide position 8993 in the mitochondrial ATPase 6 gene in a family with Leigh's syndrome. Another mutation in the same codon (T8993G) has been reported before in Leigh's syndrome. As these two mutations led to different amino acid substitutions, it provides strong evidence for the relevance of ATP synthase dysfunction in maternally inherited Leigh's syndrome.
11. Krageloh-Mann I; Grodd W; Schoning M; Marquard K; Nagele T; Ruitenbeek W. Proton spectroscopy in five patients with Leigh's disease and mitochondrial enzyme deficiency. Developmental Medicine and Child Neurology, 1993 Sep, 35(9):769-76. (UI: 93359091)
Abstract: Five children with Leigh's disease and progressive neurological symptoms were compared with 14 control children. In all patients, MRI showed bilateral lesions of the putamina and caudate heads. Serum lactate was normal for four of the children, and CSF lactate slightly elevated for three. Volume-selective proton MR spectroscopy (1H-MRS) of the basal ganglia in the Leigh patients revealed elevated lactate, giving further evidence for a defect of energy metabolism in the brain. 1H-MRS is an important tool for non-invasive brain tissue analysis in Leigh's disease, particularly in the absence of peripheral lactate elevation.
12. Nakao E; Suga T; Endoh M; Nomoto Y; Sakai H. Glomerulocystic kidney--report of an adult case. Internal Medicine, 1993 Sep, 32(9):742-4. (UI: 94191292) Pub type: Journal Article; Review; Review of Reported Cases.
Abstract: A 32-year-old adult case of glomerulocystic kidney disease (GCK) is reported. He had brain and muscle atrophy, probably due to congenital malformation. Progressive renal failure developed and he died. Autopsy disclosed multiple tiny cysts exclusively in the renal cortices. Microscopic study revealed that the cysts were dilated Bowman's spaces. This case is the 12th adult case reported in the world.
13. Nakase H. [Leigh's syndrome and mitochondrial myopathy]. Nippon Rinsho. Japanese Journal of Clinical Medicine, 1993 Sep, 51(9):2403-8. Language: Japanese. (UI: 94017257) Pub type: Journal Article; Review; Review Literature.
Abstract: Leigh's syndrome is a subacute encephalopathy with characteristic pathological features and lactic acidosis. This syndrome is due to the disturbance of aerobic metabolism. Pyruvate dehydrogenase deficiency and cytochrome c oxidase deficiency are common metabolic disturbances in this syndrome. Complex I or II deficiency has also been claimed. Recently, mutations of mitochondrial genome have been also identified in some cases with Leigh's syndrome: np 3243 T to C, np 8344 G to A and np 8993 T to G. The possible correlation between phenotype and genotype in this heterogeneous syndrome was discussed.
14. Nitschke W; Jubault-Bregler M; Rutherford AW. The reaction center associated tetraheme cytochrome subunit from Chromatium vinosum revisited: a reexamination of its EPR properties. Biochemistry, 1993 Aug 31, 32(34):8871-9. (UI: 93372093)
Abstract: The heme components of chromatophore membranes from the purple bacterium Chromatium vinosum have been studied by EPR. Five different heme species could be distinguished on the basis of their g values, redox midpoint potentials, and orientations of heme planes with respect to the membrane plane: gz = 2.94, Em = +10 mV, 40 degrees-50 degrees; gz = 2.94, Em = +10 mV, 0 degree; gz = 3.1, Em = +330 mV, 90 degrees; gz = 3.3, Em = 360 mV, 30 degrees; gz = 3.4, Em = 0 mV, no detectable orientation. Four of these five hemes (gz = 3.3, gz = 3.1, and 2x gz = 2.94) were ascribed to the tetraheme cytochrome subunit associated with the photosynthetic reaction center of this bacterium. Some of the results obtained have already been reported previously [Tiede, D.M., Leigh, J.S., & Dutton, P.L. (1978) Biochim. Biophys. Acta 503, 524-544] and have led to a model for the tetraheme cytochrome subunit in Chromatium which is significantly different from the three-dimensional structure of the reaction center associated subunit in the purple bacterium Rhodopseudomonas viridis. The additional data obtained in our work, however, require a reinterpretation of the previously published results. The model arrived at is in general agreement with the X-ray structure from Rhodopseudomonas viridis. A model rationalizing the detailed differences between the structure of the Rhodopseudomonas viridis cytochrome subunit and the data obtained on tetraheme subunits from other photosynthetic bacteria is presented.
15. Merante F; Petrova-Benedict R; MacKay N; Mitchell G; Lambert M; Morin C; De Braekeleer M; Laframboise R; Gagne R; Robinson BH. A biochemically distinct form of cytochrome oxidase (COX) deficiency in the Saguenay-Lac-Saint-Jean region of Quebec. American Journal of Human Genetics, 1993 Aug, 53(2):481-7. (UI: 93318848)
Abstract: We report the results of biochemical and molecular investigations on a group of patients from the Saguenay-Lac-Saint-Jean region of Quebec who have an unusual form of cytochrome oxidase deficiency and Leigh disease. This group can be distinguished from the classical presentation of cytochrome oxidase deficiency with Leigh disease, by the severity of the biochemical defect in different tissues. The activity in skin fibroblasts, amniocytes, and skeletal muscle of cytochrome oxidase is 50% of normal, while in kidney and heart it is close to normal values. Brain and liver, on the other hand, have very low activities. The defect in activity appears to result from a failure of assembly of the cytochrome oxidase complex in liver, but levels of mRNA for both mitochondrially encoded and nuclear-encoded subunits in liver and skin fibroblasts were found to be the same as those in controls. The cDNA sequence of the liver-specific cytochrome oxidase subunits VIa and VIIa were determined in samples from patient liver and skin fibroblasts and showed normal coding sequence.
16. Morin C; Mitchell G; Larochelle J; Lambert M; Ogier H; Robinson BH; De Braekeleer M. Clinical, metabolic, and genetic aspects of cytochrome C oxidase deficiency in Saguenay-Lac-Saint-Jean. American Journal of Human Genetics, 1993 Aug, 53(2):488-96. (UI: 93318849)
Abstract: Thirty-four children with lactic acidosis and Leigh encephalopathy due to cytochrome C oxidase (COX) deficiency distributed in 28 families have recently been identified in northeastern Quebec, particularly in the Saguenay-Lac-Saint-Jean (SLSJ) region. The segregation analysis was consistent with an autosomal recessive mode of inheritance. The incidence was estimated at 1/2,063 live births between 1979 and 1990, and the carrier rate was estimated at 1/23 inhabitants in SLSJ. In SLSJ, the places of origin of the COX-deficient children and their parents did not show a clustered nonuniform distribution. The genealogical reconstruction of 54 obligate carriers identified 26 ancestors common to all of them. Twenty-two were 17th-century Europeans, suggesting that the COX-deficient gene was introduced in the French-Canadian population by early settlers. These results support the hypothesis of a founder effect for COX deficiency in northeastern Quebec. Clinical findings are reported for 15 of these COX-deficient patients, age 6 mo to 11 years. Moderate developmental delay, hypotonia, ataxia, strabismus, and mild facial dysmorphism were frequent. Eleven children died in episodes of fulminant metabolic acidosis. The patients had elevated blood and cerebrospinal fluid lactate levels, decreased blood bicarbonate levels, and normal blood pH. Leigh disease and microvesicular steatosis of the liver were present in all affected patients for whom postmortem examination was performed. This biochemically uniform group of patients showed a wide range of clinical severity.
17. Mak SC; Chi CS; Chen CH; Shian WJ. Clinical manifestation of mitochondrial diseases in children. Acta Paediatrica Sinica, 1993 Jul-Aug, 34(4):247-56. (UI: 94026276)
Abstract: 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.
18. Wu TS; Lee CC; Lin JT; Hsu HH; Lin ST; Jong YJ; Shen EY. Leigh disease (subacute necrotizing encephalomyelopathy): report of one case. Acta Paediatrica Sinica, 1993 Jul-Aug, 34(4):301-7. (UI: 94026283)
Abstract: A case is reported of a 16-month-old girl who presented with generalized hypotonia, ptosis and persistent low grade fever after a previous pneumonia. Brain CT and MRI showed symmetric necrotizing lesions in the basal ganglia, substantia nigra and periaqueduct area. Lactate and pyruvate levels were elevated in both the blood and cerebrospinal fluid. Biopsy of the rectus femoris muscle for electron microscopic examination revealed some distortion of the mitochondrial cristae. Biochemical study showed normal respiratory chain enzymes. Leigh disease was considered from the neuroradiological findings and morphological investigations.
19. Shian WJ; Chi CS; Mak SC. Intramyelin splitting in the spongiform lesions of Leigh syndrome. Acta Paediatrica Sinica, 1993 Jul-Aug, 34(4):308-13. (UI: 94026284)
Abstract: A 5-month-old male infant, diagnosed as Leigh syndrome, presented with developmental delay, episodic apnea, metabolic acidosis, and myoclonic seizures. The magnetic resonance image of brain showed multiple symmetric low signals over the putamen in the T1-weighted axial view and linear high signal over the brainstem in the T2-weighted sagittal view. On electron microscopy, subsarcolemmal aggregation of abnormal mitochondria in muscle cells were found via biopsy. Small samples of myocardium, liver and brainstem, obtained via necropsy, were subjected to pathological examinations. On light microscopy, vacuoles were found in the myocardium and hepatocytes, while spongiform lesions in the neuropils, round cell infiltration, and vascular proliferation were observed in the brainstem. On electron microscopy, intramyelin splittings were observed in the spongiform lesions. We believe that intramyelin splitting must play an important role in the pathogenesis of spongiform lesions in Leigh syndrome.
20. Matthews PM; Marchington DR; Squier M; Land J; Brown RM; Brown GK. Molecular genetic characterization of an X-linked form of Leigh's syndrome. Annals of Neurology, 1993 Jun, 33(6):652-5. (UI: 93270474)
Abstract: We report a patient with necrotizing encephalomyelopathy (Leigh's syndrome) associated with a deficiency of pyruvate dehydrogenase complex activity. The underlying mutation is an A to C transversion in the pyruvate dehydrogenase complex E1 alpha subunit gene. As the E1 alpha subunit is encoded on the X chromosome, this observation confirms that some patients with Leigh's syndrome may potentially exhibit X-linked inheritance.
21. Hammans SR; Sweeney MG; Brockington M; Lennox GG; Lawton NF; Kennedy CR; Morgan-Hughes JA; Harding AE. The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain, 1993 Jun, 116 ( Pt 3):617-32. (UI: 93291955)
Abstract: The mitochondrial DNA (mtDNA) transfer RNA (tRNA)Lys A-->G(8344) mutation was identified in seven patients. These patients and their relatives were assessed clinically; in one family the mutation was deduced to be present in four generations. The phenotype in index cases was consistent with the syndrome of myoclonic epilepsy with ragged red fibres, with the core clinical features of myoclonus, ataxia and seizures. Amongst other features, progressive external ophthalmoplegia, Leigh's syndrome and stroke-like episodes were observed, well recognized in mitochondrial myopathies but novel manifestations of this genotype. Samples of blood and muscle were analysed for the proportion of mutant mtDNA using an oligonucleotide hybridization technique. The proportion of mutant mtDNA in blood was significantly greater in symptomatic than asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. Study of disease associated with the tRNA(Lys) A-->G(8344) mutation provides further insight into the pathogenesis and transmission of mitochondrial diseases. Quantification of the proportion of mtDNA in tissues demonstrates that this is a major factor determining the course of disease, but other, as yet unidentified factors are also likely to play a role.
22. Jung KC; Myong NH; Chi JG; Choi HR; Lee HS; Ahn YM. Leigh's disease involving multiple organs. Journal of Korean Medical Science, 1993 Jun, 8(3):214-20. (UI: 94059456)
Abstract: Leigh's disease is a rare progressive neurological disorder that is characterized light microscopically by focal spongy necrosis in the brain and electron microscopically by mitochondriopathy. We report an autopsy case of Leigh's disease that showed abnormalities in the liver, kidney and skeletal muscle as well as the central nervous system. The patient was an 18-month-old girl who has carried a diagnosis of cerebral palsy ever since her birth to a 20-year-old mother. The baby was generally hypertonic and mentally retarded. She died of severe metabolic acidosis. Postmortem examination showed growth retardation, fatty liver, fatty kidney and soft brain. Brain section showed multifocal softenings in the brainstem, basal ganglia and periventricular areas. Microscopically increased capillaries with endothelial proliferation, vacuolar degeneration and mild gliosis were seen in the brain. The axons were relatively preserved. Liver and kidneys showed microvesicular fatty change. Myofiber degeneration of the skeletal muscle was also noted. Electron microscopic examination showed markedly increased mitochondria in the parenchymal cells of the brain, liver and kidney. The mitochondria showed round to ovoid ballooned appearance including electron-dense core-like structures and pseudoinclusions of glycogen granules.
23. Silvestri G; Ciafaloni E; Santorelli FM; Shanske S; Servidei S; Graf WD; Sumi M; DiMauro S. Clinical features associated with the A-->G transition at nucleotide 8344 of mtDNA ("MERRF mutation"). Neurology, 1993 Jun, 43(6):1200-6. (UI: 94224350)
Abstract: We looked for the A-->G transition at position 8344 of mtDNA in 150 patients, most of them with diagnosed or suspected mitochondrial disease, to assess the specificity of this mutation for the MERRF phenotype, to define the clinical spectrum associated with the mutation, and to study the relationship between percentage of mutation in muscle and clinical severity. Our results confirm the high correlation between the A-->G transition at position 8344 and the MERRF syndrome, but they also show that this mutation can be associated with other phenotypes, including Leigh's syndrome, myoclonus or myopathy with truncal lipomas, and proximal myopathy. The absence of the mutation in four typical MERRF patients suggests that other mutations in the tRNA(Lys) gene, or elsewhere in the mitochondrial DNA, can produce the same phenotype.
24. Tatuch Y; Robinson BH. The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria. Biochemical and Biophysical Research Communications, 1993 Apr 15, 192(1):124-8. (UI: 93236562)
Abstract: Mitochondria were prepared from three lymphoblast cell lines from patients with high percentage copy numbers of the human mtDNA 8993 mutation and compared to those prepared from related and non-related control cell lines. Rates of ATP synthesis with pyruvate/malate, succinate/rotenone, ascorbate/N'N'N'N' tetramethyl phenylene diamine were reduced to 67%, 58% and 54% of the control rates, respectively. The backward reaction measured as oligomycin sensitive ATPase was reduced to an average of 42% of that in controls. This mutation which changes a conserved leucine to an arginine in the putative membrane proton channel of mitochondrial ATPase effectively reduces the overall rate of oxidative phosphorylation.
25. Munoz Hiraldo ME; Martinez Bermejo A; Gutierrez Molina M; Garcia Melian RM; Arcas Martinez J; Pascual-Castroviejo I. [Dystonia as a principal manifestation of Leigh syndrome in an infant]. Anales Espanoles de Pediatria, 1993 Apr, 38(4):348-50. Language: Spanish. (UI: 93243597)
26. Yoshinaga H; Ogino T; Ohtahara S; Sakuta R; Nonaka I; Horai S. A T-to-G mutation at nucleotide pair 8993 in mitochondrial DNA in a patient with Leigh's syndrome. Journal of Child Neurology, 1993 Apr, 8(2):129-33. (UI: 93280396)
Abstract: We studied a patient with Leigh's syndrome using neurophysiologic, radiologic, enzymatic, biochemical, and molecular analysis. Her clinical course had started with acute encephalopathic symptoms at 7 months of age. With repeated remission and exacerbation, she developed hypotonia and symptoms of brainstem dysfunction, such as irregular respiration and swallowing difficulty. These symptoms were followed by epileptic seizures, including simple partial seizures and tonic spasms. Both serum lactate and serum pyruvate levels were elevated, and deficient activity was detected in cytochrome c oxidase in her quadriceps femoris muscle. From the early stages, we noted an abnormality in the auditory brainstem response and visual evoked potentials, and an abnormal symmetrical low-density area in the basal ganglia on the computed tomographic scan. We found a mitochondrial DNA point mutation at 8993 in blood samples from both the patient and her mother using a simple polymerase chain reaction method. The ratio of wild and mutant mitochondrial DNA calculated densitometrically on polymerase chain reaction products was 56.6% in the patient's blood cells and 8.4% in her mother's. This patient's disorder was thought to be maternally inherited Leigh's syndrome. Her brother had died of the identical clinical features at 1 year 9 months of age.
27. Macaya A; Munell F; Burke RE; De Vivo DC. Disorders of movement in Leigh syndrome. Neuropediatrics, 1993 Apr, 24(2):60-7. (UI: 93317103)
Abstract: Leigh syndrome (LS) is the clinical prototype of a genetically-determined mitochondrial encephalopathy. Twenty-two of 34 patients with LS had evidence of a movement disorder (MD). Dystonia, the most common MD, was present in 19 cases, rigidity in 4, tremor in 2, chorea in 2, hypokinesia in 2, myoclonus in 1, and tics in 1. Dystonia was most commonly multifocal at onset and showed progression in six patients. In half of the cases an enzymatic defect was detected, most commonly cytochrome C oxidase. The neuroradiologic findings showed prominent basal ganglia lesions in 20/21 patients. Putamen, caudate, substantia nigra and globus pallidus were involved in this order of frequency. This experience was reflected in a literature review encompassing 284 cases of LS. However, only 26.4% had MD. Eleven patients, including one of our cases, presented as the primary torsion dystonia phenotype. There are clinical and pathological similarities between LS and other metabolic diseases affecting the central nervous system. The enhanced vulnerability of the nervous system to metabolic stress and the resemblance in the distribution of the pathology of these diverse conditions suggests a common pathogenetic mechanism. An excitotoxin-mediated mechanism is favored, one which might account for the frequent involvement of the basal ganglia in LS.
28. Cassedy KJ; Edwards MK. Metabolic and degenerative diseases of childhood. Topics in Magnetic Resonance Imaging, 1993 Spring, 5(2):73-95. (UI: 93349504) Pub type: Journal Article; Review; Review, Tutorial.
Abstract: The metabolic and degenerative diseases of childhood are a diverse group of disorders with varied imaging features. Some of the disease processes have characteristic findings and some have no findings at all, but most present with nonspecific abnormalities in white matter. These patchy lesions, seen best on magnetic resonance scanning with T2 weighting, require a good history and a dialogue with the referring physicians to help in narrowing the differential possibilities. The major disease processes involving white matter are the dysmyelinating diseases, in which the abnormal white matter is the result of an inherited enzyme deficiency, and the demyelinating diseases, in which an acquired process such as infection destroys white matter. Several diseases result in gray matter abnormalities, including central pontine myelinolysis, MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like symptoms), Batten's disease, Leigh disease, and Wilson's disease.
29. Ciafaloni E; Santorelli FM; Shanske S; Deonna T; Roulet E; Janzer C; Pescia G; DiMauro S. Maternally inherited Leigh syndrome. Journal of Pediatrics, 1993 Mar, 122(3):419-22. (UI: 93180085)
Abstract: A 6 1/2-year-old girl had developmental regression, and Leigh syndrome was diagnosed. A second girl born to the same mother after heterologous artificial insemination also lost acquired skills and died at 2 1/2 years of age; neuropathologic examination confirmed the diagnosis of Leigh syndrome. Tissues from both children and from the mother had a point mutation at nucleotide 8993 in the adenosinetriphosphatase 6-gene of mitochondrial DNA. This family illustrates that Leigh syndrome can be transmitted by maternal inheritance.
30. Johnson MA; Bindoff LA; Turnbull DM. Cytochrome c oxidase activity in single muscle fibers: assay techniques and diagnostic applications. Annals of Neurology, 1993 Jan, 33(1):28-35. (UI: 93263587)
Abstract: Microphotometric enzyme assay was used to study cytochrome c oxidase activity in single human skeletal muscle fibers. The assay techniques combine the precise localization of enzyme activity provided by histochemical methodology with the precise quantitation of a sensitive assay system. Abnormalities of cytochrome c oxidase were investigated using microphotometric enzyme assay in 12 patients with Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, or Leigh's syndrome. Control values were obtained using muscle biopsy specimens from 20 juvenile and 18 adult subjects with no evidence of neuromuscular disease. In the patients with Leigh's syndrome due to cytochrome c oxidase deficiency, the abnormality was found to be expressed uniformly throughout the muscle fiber population. In contrast, patients with Kearns-Sayre syndrome or chronic progressive external ophthalmoplegia showed abnormal heterogeneity of cytochrome c oxidase activity. In many cases, extreme degrees of variability were seen, with fibers containing high activity adjacent to fibers with no detectable activity. Mitochondrial DNA analysis showed that most of the patients with Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia had major rearrangements of mitochondrial DNA. It was concluded that the extreme variability of cytochrome c oxidase activity detected using microphotometric enzyme assay was an indicator of a probable abnormality of mitochondrial DNA. Conversely, cytochrome c oxidase defects in muscle which show a homogeneous distribution are more likely to be associated with defects of the nuclear genome.
31. De Vivo DC. The expanding clinical spectrum of mitochondrial diseases. Brain and Development, 1993 Jan-Feb, 15(1):1-22. (UI: 93332219) Pub type: Journal Article; Review; Review, Academic.
Abstract: 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)
32. Coker SB. Leigh disease presenting as Guillain-Barre syndrome. Pediatric Neurology, 1993 Jan-Feb, 9(1):61-3. (UI: 93199604)
Abstract: A 4-year-old male evidenced the criteria for the diagnosis of Guillain-Barre syndrome. Eventually a diagnosis of Leigh disease was made based on magnetic resonance imaging and mitochondrial enzyme deficiencies. Although chronic neuropathy has been reported with Leigh disease, this is the first reported patient with acute symmetric motor polyneuropathy.
33. Haginoya K; Miyabayashi S; Iinuma K; Tada K. Quantitative evaluation of electron transport system proteins in mitochondrial encephalomyopathy. Acta Neuropathologica, 1993, 85(4):370-7. (UI: 93243109)
Abstract: The levels of mitochondrial electron transport system proteins cytochrome c oxidase (COX) and complex III were measured in muscle fibers of patients with mitochondrial encephalomyopathy using quantitative immunoelectron microscopy. In a patient with Leigh's encephalopathy, immunoreactive COX protein was decreased to 20% of the normal mean value in all muscle fibers examined, while the amount of complex III was within the normal range. In a patient with fatal infantile COX deficiency, the level of COX protein was found to be decreased to 27-40% of the normal value in all muscle fibers examined. In patients with mitochondrial myopathy, encephalopathy, lactic acidosis associated with stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), COX protein levels were decreased to 20% of normal in muscle fibers lacking COX activity. In normal fibers, however, COX protein levels were also normal. The amount of complex III protein was normal in COX-deficient muscle fibers. In two patients, in situ hybridization was performed for detection of mitochondrial mRNA. Mitochondrial mRNAs were found to be abundant in muscle fibers with decreased COX protein, suggesting a defect at the mitochondrial protein-synthesis level in a COX-deficient muscle fiber.
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