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Biomedical subjects

E Byrne

Publications and source records attributed to E Byrne.

At least 91 records · Page 5Linked to original sources
PubMed1992

A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and strokelike episodes (MELAS) syndrome affects the ND4 subunit of the respiratory complex I.

The molecular lesions in two patients exhibiting classical clinical manifestations of MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) syndrome have been investigated. A recently reported disease-related A----G base substitution at nt 3243 of the mtDNA, in the DHU loop of tRNA(Leu), was detected by restriction-enzyme analysis of the relevant PCR-amplified segment of the mtDNA of one patient but was not observed, by either restriction-enzyme analysis or nucleotide sequencing, in the other. To define the molecular lesion in the patient who does not have the A----G base substitution at nt 3243, the total mitochondrial genome of the patient has been sequenced. An A----G base substitution at nt 11084, leading to a Thr-to-Ala amino acid replacement in the ND4 subunit of the respiratory complex I, is suggested to be a disease-related mutation.

Acidosis, Lactic↗
PubMed1992

The molecular genetics of mitochondrial cytopathies: the Melbourne experience.

Mitochondrial DNA is a unique, maternally inherited molecule encoding several subunits of the respiratory enzyme chain. In several mitochondrial cytopathies mutations have been described in this genome viz. large-scale heteroplasmic deletions in syndromes with progressive external ophthalmoplegia and point mutations in MELAS and MERRF encephalomyopathies. We here report Southern blot analyses in the cases of CPEO we have seen and describe the search for point mutations in MELAS and MERRF. Mitochondrial genetic sequencing in normal and disease controls as well as in patients has confirmed the pathogenic nature of a tRNA Lys point mutation in MERRF. We propose a novel mitochondrial structural gene mutation in a MELAS--like encephalomyopathy: an A-->G substitution at position 11084 leading to a Thr to Ala replacement in the ND4 subunit of complex I.

Base Sequence↗
PubMed1992

Hydroxyurea-induced HbF production in anemic primates: augmentation by erythropoietin, hematopoietic growth factors, and sodium butyrate.

Hydroxyurea, a cell-cycle-specific cytotoxic agent, has been shown to increase fetal hemoglobin (HbF) production. This property makes it an attractive drug for treatment of sickle cell disease and severe beta thalassemia. Its potential efficacy is limited because of a variable and often suboptimal response. Combinations of hydroxyurea and other drugs may induce more clinically significant increases in HbF. We have utilized chronically phlebotomized rhesus monkeys, treated with oral hydroxyurea, to investigate the capacity of several other agents to further augment HbF synthesis. Recombinant human erythropoietin, in super-pharmacologic doses, increased F-reticulocyte production when given on a weekly sequential schedule (3 of 7 days) with hydroxyurea (4 of 7 days), but it was less effective on an alternate day schedule when hydroxyurea was given daily. Neither recombinant human interleukin 3 (IL-3) nor recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), when infused individually, increased F-reticulocytes in animals receiving daily hydroxyurea. Sequential, overlapping infusions of IL-3 and GM-CSF produced a small but statistically significant increase in F-reticulocytes in one of two hydroxyurea-treated animals. Infusions of sodium butyrate produced a substantial augmentation in F-reticulocyte production in animals chronically treated with hydroxyurea. Thus, our studies have identified several agents that may prove useful in combination with hydroxyurea to achieve clinically beneficial levels of HbF.

Administration, Oral↗
PubMed1992

Alcohol and drug abuse.

Neurological complications are well recognized with alcohol abuse, and an increasing amount of literature is emerging describing neurological disease as a complication of other drugs of addiction (recreational drugs). This review covers recent papers related to alcohol and drug abuse.

Alcoholism↗
PubMed1991

Mitochondrial genome distribution in histochemically cytochrome c oxidase-negative muscle fibres in patients with a mixture of deleted and wild type mitochondrial DNA.

In situ hybridization studies were performed on a series of chronic progressive external ophthalmoplegia patients harbouring large mitochondrial DNA deletions, using intra- and extra-deletional probes. Clear differences in the distribution of wild type and deleted mitochondrial genomes were seen in both ragged-red and non-ragged red, cytochrome c oxidase-negative fibres, with an accumulation of deleted genomes in the subsarcolemmal zone. Wild type genome content was normal or decreased in the cytochrome c oxidase-negative regions of one case, but in two patients, wild type mtDNA content in cytochrome c oxidase-negative regions was either normal (most fibres) or increased (occasional fibres). The latter observation suggests there may be a stage in the natural history of ragged-red fibre evolution where wild type genomes are transiently increased. The significance of this finding is discussed.

Base Sequence↗
PubMed1991

Mitochondrial theory of senescence: respiratory chain protein studies in human skeletal muscle.

In view of a previously demonstrated negative correlation between stage III respiratory activity in human mitochondria and increasing age, the relationship between human respiratory chain complex protein content and age was investigated. Quantitative immunoblot studies were carried out using holo complex I, III and IV antibody probes in human skeletal muscle mitochondrial homogenate from patients of varying ages. No significant negative correlation between increased age and respiratory complex chain protein content was seen for either total complex activity or for any of the subunits which could be reliably identified. As respiratory complex protein content is preserved with ageing, the decrease in respiratory efficiency is likely to follow aggregation of mutations in structural mitochondrial (mt) DNA genes which do not interfere with mt DNA transcription and protein translation rather than mutations in mt tRNA or ribosomal RNA genes. This is consistent with the fact that mt genes involved in protein translation only occupy a fairly small percentage of the mitochondrial genome.

Aging↗
PubMed1991

Mitochondrial DNA sequence analysis in congenital myotonic dystrophy.

Mitochondrial genetic modifying factors have been suspected in several autosomally inherited diseases. The congenital variant of myotonic dystrophy, in which there is striking maternal inheritance pattern, is a likely candidate disease. To investigate this possibility, we sequenced completely the mitochondrial genome in 2 patients with congenital myotonic dystrophy. Comparison of the two sequences with control data failed to reveal a specific nucleotide variant or length variant in this disease. We conclude that a mitochondrial genetic modifying factor is not present in congenital myotonic dystrophy.

Adult↗
PubMed1991

Normal variants of human mitochondrial DNA and translation products: the building of a reference data base.

A good standard reference for the highly polymorphic human mitochondrial DNA (mtDNA) sequence is essential for studies of normal and disease-related nucleotide variants in the mitochondrial genome. A consensus sequence for the human mitochondrial genome has been derived from thirteen unrelated mtDNA sequences. We report 128 nucleotide variants of the human mtDNA sequence, and 62 amino acid variants of the human mitochondrial translation products, observed in the coding region of these mtDNA sequences.

Amino Acid Sequence↗
PubMed1991

Chronic progressive external ophthalmoplegia in patients with large heteroplasmic mitochondrial DNA deletions: an immunocytochemical study.

Immunocytochemical studies with a holocomplex antibody battery in patients with chronic progressive external ophthalmoplegia, with and without large mitochondrial DNA deletions, revealed positive (and often increased) immunoreactivity for all complexes studied in histochemically cytochrome oxidase (COX)-negative areas, suggesting a compensatory up-regulation of these components. Similar findings were observed with subunit-specific probes directed against both nuclear- and mitochondrially encoded gene products. Comparison of staining intensities between the different complexes revealed significantly more variability in COX-negative than COX-positive fibres, suggesting disordered stoichiometric control during up-regulation. These differences were confirmed using statistical models. This data challenges the view that COX-negative fibre segments have little or no mitochondrially coded protein translation.

Adult↗
PubMed1991

Functional respiratory chain studies in mitochondrial cytopathies. Support for mitochondrial DNA heteroplasmy in myoclonus epilepsy and ragged red fibers (MERRF) syndrome.

Mitochondrial respiratory chain function was investigated with polarographic and enzymatic studies, and correlated with immunoblot studies using a battery of probes against respiratory chain holocomplexes in a series of patients with myoclonus epilepsy and ragged red fibers (MERRF) syndrome. State III respiration rates in intact skeletal muscle mitochondria were normal in two cases, suggested site I deficiency in one case and a mid-respiratory defect in another. Immunological studies of complex I showed reduced levels of several subunits with the apparent absence of two bands (which at 45 and 42 kDa, coincide with the predicted electrophoretic mobility of the ND5 gene product) in one case. Complex I, III and IV composition was normal in the other three cases indicating no major disruption of complex assembly. A differing severity of skeletal muscle respiratory chain impairment in a group of unrelated patients with severe cerebral clinical involvement is best explained by uneven tissue distribution between brain and muscle of a heteroplasmic mtDNA mutation. The relationship between MERRF and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) encephalopathies is reappraised by extension of this hypothesis.

Adult↗
PubMed1991

Mitochondrial encephalomyopathies: a correlation between neuropathological findings and defects in mitochondrial DNA.

Neuropathological studies were carried out in two patients with mitochondrial encephalomyopathies in whom the underlying lesions in muscle mitochondrial DNA (mtDNA) and respiratory enzyme complexes have been investigated. The first, a man with Kearns-Sayre syndrome, died at the age of 49 years. Autopsy showed an old parietal lobe infarct, diffuse spongiform leukoencephalopathy of cerebral and cerebellar white matter and mild spongiform change in deep grey matter and brainstem nuclei. Heteroplasmy of skeletal muscle mitochondrial DNA with a 3.5 kb mtDNA deletion in one of two mtDNA populations was found. The second case, a woman, suffering from myoclonic epilepsy, cerebellar ataxia, bilateral sensorineural deafness, several 'stroke-like' episodes died at age 52. At autopsy, an old infarct was seen in the L internal capsule. Severe loss of neurons and gliosis were found in the dentate nuclei, moderate changes in the red nuclei and inferior olivary nuclei and mild changes in the substantial nigra and locus coeruleus. In both patients, skeletal muscle biopsy showed numbers of ragged-red fibres and intramitochondrial paracrystalline inclusions at electron microscopy. A defect in the synthesis of the ND5 subunit of the respiratory complex I was suggested in the second patient in whom a diagnosis of MELAS was made.

Adult↗
PubMed1991

Functional respiratory chain studies in subjects with chronic progressive external ophthalmoplegia and large heteroplasmic mitochondrial DNA deletions.

The functional consequences of large heteroplasmic mtDNA deletions were investigated in a group of 6 patients with chronic progressive external ophthalmoplegia (CPEO) syndromes. State III respiration rates corrected for age were low with site I and II substrates in all cases and cytochrome oxidase activity was depressed. The severity of impairment varied and is consistent with inclusion of a variable percentage of non-functioning mitochondria (with deleted mtDNA) in the pellet. Western blot studies with a holocomplex antibody battery revealed no abnormalities in subunit content of complexes III and IV. A deficiency of several complex I subunits in 3 cases suggests that abnormal nuclear-mitochondrial regulation of complex I assembly may follow large mtDNA deletions.

Adult↗
PubMed1991

Affinity chromatography isolation of human cytochrome oxidase and small-scale Western immunoblot probing of the enzyme complex in mitochondrial cytopathy patients.

Isolation of human cytochrome oxidase by a one-step affinity chromatography procedure on a Sepharose 4B-ferrocytochrome c matrix following solubilization with the nonionic detergent laurylmaltoside yields an enzyme isolate of adequate purity for producing polyclonal antisera. Such an antiserum produced a distinctive immunoreactive profile in Western immunoblot studies to that reported using the enzyme isolated with ionic detergents. A sensitive and highly reproducible Western immunoblotting method is described for probing mitochondrial fractions prepared from small frozen skeletal muscle biopsies with an antiserum against the human placenta cytochrome oxidase. Application of this method to mitochondrial cytopathy patients with partial cytochrome oxidase deficiency shows that the detected subunits are synthesized in these patients.

Blotting, Western↗
PubMed1991

Painful sciatic neuropathy following cardiac surgery.

Ten patients developed bilateral asymmetrical lower limb sensori-motor or motor deficits associated with prominent causalgic pain after cardiac surgery. The clinical and electrophysiological abnormalities indicated bilateral proximal sciatic nerve lesions, although in several cases the distinction from a diffuse ischaemic axonopathy was difficult to make. This pattern of postcardiac surgery peripheral neurological dysfunction has not been previously described but is likely to relate either to the intra-operative posturing technique for access to the saphenous veins and/or the upright posture used to nurse patients in the immediate post-operative period and is in keeping with the previously demonstrated susceptibility of peripheral nerves to pressure palsy during cardiac surgical procedures.

Adult↗
PubMed1991

Biochemical and molecular investigation of mitochondrial disease: an illustrative case showing the value of a multifaceted approach.

Detailed biochemical and molecular investigations in a patient with Kearns-Sayre syndrome are presented. Polarographic studies in isolated mitochondria revealed a global impairment in respiratory capacity consistent with an admixture of functional and non-functional mitochondria. Cytochrome difference spectra revealed a selective deficiency in cytochrome aa3. Western immunoblot studies revealed normal subunit content of Complexes I, III and IV. Southern blot studies of mtDNA showed a deletion of approximately 5 Kb coexisting with wild type DNA. PCR analysis confirmed that this deletion lies between the ATPase8 and NAD coenzyme Q oxidoreductase subunit 5 (ND5) genes. Breakpoint sequencing revealed a 13 nucleotide direct repeat flanking sequence (ACCTCCCTCACCA) consistent with slippage in mtDNA during replication as the mechanism of deletion. Histochemical studies of skeletal muscle revealed many cytochrome oxidase negative fibres and immunocytochemical studies showed cytochrome oxidase negative areas with abundant respiratory complex protein suggesting upregulation. The value of a multifaceted approach in unravelling the pathophysiology of mitochondrial diseases is emphasised.

Adolescent↗
PubMed1991

Hemitonic seizures: etiological and diagnostic considerations.

Intermittent unilateral tonic posturing of the limbs may relate to focal motor epilepsy, intermittent dystonia or hysteria, and diagnosis may be difficult. Five patients are presented who illustrate two distinct hemitonic syndromes which we believe to be epileptic, namely forced elevation of one arm and paroxysmal hemispasm. It is suggested that these attacks follow an irritative lesion involving the supplementary motor cortex and a deep lesion involving striatothalamic projections respectively. Brevity of episodes, their stereotyped nature and rapid response to anticonvulsant drugs supports an epileptic etiology. The term paroxysmal hemidystonia may not be appropriate for patients with intermittent stereotyped disorders of limb posture, where the clinical features support an epileptic basis and we suggest the designation hemitonic seizures.

Adult↗
PubMed1991

Familial dystonic choreoathetosis with myokymia; a sleep responsive disorder.

A family is presented with paroxysmal dystonic choreoathetosis transmitted as a dominant trait over five generations. The family is unusual in the marked responsiveness of the episodes to short periods of sleep in several members, in the very variable age of onset, and in the association with prominent myokymia in some cases. These overlap features suggest a link between paroxysmal dystonic choreoathetosis and familial paroxysmal ataxia with myokymia.

Adolescent↗