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Biomedical subjects

H Carrier

Publications and source records attributed to H Carrier.

At least 19 recordsLinked to original sources
PubMed2000

Immunolabelling of mitochondrial superoxide dismutase and of Hsp60 in muscles harbouring a respiratory chain deficiency.

In mitochondrial encephalomyopathies, impairment of the electron transfer chain may lead to overproduction of reduced oxygen species because oxygen consumption is decreased. Whether heat shock proteins (Hsp) are induced or not in mitochondria against oxidative stress is questionable. Muscle ragged-red fibres are the histological hallmark of most respiratory chain deficiencies in humans. They exhibit abnormal mitochondria which accumulate mainly under their sarcolemma. Within these fibres, immunolabelling demonstrated strong expression of mitochondrial manganese-dependent superoxide dismutase and a lack of expression of mitochondrial Hsp60 within the subsarcolemmal spaces. In contrast, Hsp60 was overexpressed within the intermyofibrillar mitochondria. These findings suggest enhanced generation and dismutation of superoxide anions and that processing and integration of imported precursor proteins is impaired within the subsarcolemmal mitochondrial aggregates of ragged-red fibres, whereas protein import and assembly may still be efficient in the intermyofibrillar mitochondria of these fibres.

Adolescent↗
PubMed2000

[Mitochondrial diabetes complicated by or associated with "MELAS" syndrome?].

We report the case of fifty-two year-old mentally deficient female who presented with diabetes mellitus, deafness, stroke-like episodes, cardiomyopathy, and macular pattern dystrophy of the retina. Her brain exhibited calcification within basal ganglia, lactacidaemia was not increased. Although her skeletal muscles had never been clinically impaired, a quadriceps biopsy led to the diagnosis of mitochondrial disease because it exhibited ragged red fibers and heteroplasmic point-mutation at position 3243 of the mitochondrial DNA, although not any detectable respiratory chain complex deficiency was found. The mutant percentage in muscle was 70 p.100 and 5 to 10 p.100 in leukocytes. The question of whether a diabetic microangiopathy may be responsible stroke-like episodes is discussed. We suggest it was rather a complicated form of diabetes-deafness than a incomplete MELAS syndrome associated with mitochondrial diabetes.

Brain↗
PubMed1998

Selective neurotomy of the tibial nerve in the spastic hemiplegic child: an explanation of the recurrence.

A series including 13 unilateral selective tibial neurotomies for spastic foot in hemiplegic children is reported. The results were considered excellent in three cases. Two cases needed additional corrective casts postoperatively. Eight cases had poor result with recurrence of the same deformity. The authors conclude that the effect of tibial neurotomy for spastic foot in hemiplegic children is transient in 61% of cases with a recurrence of the same deformity. Four of the patients with failed treatment underwent orthopedic surgery with muscle biopsies. Histologic data clearly demonstrate that previously denervated muscle fibers were reinnervated carrying into extensive motor units. This finding can explain the recurrence of the foot spasticity and deformity in neurotomized children.

Adolescent↗
PubMed1997

Increase in oxidative key enzymes in a case of muscle ubiquinol-cytochrome c reductase deficiency.

In a 29-year-old patient suffering from exertional muscle intolerance with a ubiquinol-cytochrome c reductase deficiency related to a cytochrome b gene point mutation of the mitochondrial DNA, we conducted a study of the aims of which were: (1) to test whether changes in the maximum activities of muscle key enzymes of the main energy-producing pathways occur, (2) to address the issue of whether fibers of different types are equally affected in their enzymatic machinery involved in energy production, and (3) to correlate the results obtained with histochemical and 31P NMR spectroscopy data. When compared to results obtained in six normal subjects, our study clearly shows that the type I fibers of the patient virtually all contained subsarcolemmal mitochondrial aggregates and increased activities of succinate dehydrogenase and cytochrome c oxidase; microdissected type I fibers also displayed a significant increase in both citrate synthase and beta-hydroxyacyl-CoA dehydrogenase, two key enzymes of mitochondrial oxidative metabolism. Despite these changes in the patient's muscle, its whole energy-producing machinery remained impaired as revealed by a slowed post-exercise recovery of phosphocreatine.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Identification of a large-scale mitochondrial deoxyribonucleic acid deletion in endocrinopathies and deafness: report of two unrelated cases with diabetes mellitus and adrenal insufficiency, respectively.

In recent years, a broad variety of chronic diseases have been related to different mitochondrial DNA (mtDNA) rearrangements. We have investigated two 16-yr-old unrelated girls with unexplained endocrine disorders for a mtDNA mutation. One initially presented with an adrenal crisis at the age of 4 yr. Complete adrenal insufficiency for nearly 15 yr was the main clinical manifestation, along with insiduous growth retardation and sensorineural hearing loss since age 6. The other girl presented with ketoacidosis at the age of 15 yr. She exhibited incomplete deafness since age 6 and poor growth. In both patients, brain magnetic resonance imaging abnormalities and raised cerebrospinal fluid protein concentration indicated mild leucodystrophy. Biopsy of skeletal muscle showed a mitochondrial dysfunction; molecular analysis using a PCR screening procedure revealed a 7.4 kb deletion of the mtDNA in skeletal muscle but not in leucocytes. Direct sequence analysis of the junctional regions showed that the deletion spanned 7.436 kb (nucleotide 8649 to nucleotide 16084). The relative amount of deleted mtDNA estimated by Southern blot analysis was 25 and 15%, respectively. No deletion was present in leukocytes obtained from the asymptomatic mothers. The presence of the same mutation in different patients with various endocrine conditions supports the view that the 7.4 kb mtDNA deletion should be considered as one of the candidate causes for phenotypically uncommon cases of endocrinopathies, specially in children with deafness. This is the first report of a mitochondrial disease with primary adrenocortical insufficiency as the clinical onset.

Adolescent↗
PubMed1997

[Dropped head syndrome: diagnostic discussion apropos of 3 cases].

We report three cases presenting mainly with neck extensor weakness, or dropped head syndrome, revealing respectively myasthenia gravis, amyotrophic lateral sclerosis and non-inflammatory neck extensors myopathy. We discuss the different diagnosis of this rare syndrome and this late onset localized myopathy of unknown etiology.

Aged↗
PubMed1997

[MELAS syndrome with pure vascular manifestation?].

Two stroke-like episodes then a grand mal seizure occurred within nine years in a 42-year-old patient. Neuroradiological findings (CT-scan and MRI) led to the diagnosis of incomplete MELAS syndrome. MRI with T2-weighted images (TR: 1000ms; TE: 35ms) showed two small asignal lesions possibly resulting from hemosiderine. Metabolic studies are required to help decide on muscular biopsies. Histological findings are needed for diagnosis of this form of mitochondrial cytopathy with only stroke-like manifestations.

Adult↗
PubMed1996

Antimycin resistance and ubiquinol cytochrome c reductase instability associated with a human cytochrome b mutation.

Progressive exercise intolerance was associated with a decreased maximal rate of ubiquinol cytochrome c reductase (complex III) activity in the muscle mitochondria of the studied patient and with a thirty five-fold increase in the I50 for antimycin A. In contrast, myxothiazol sensitivity was not altered. Complex III activity was stable at 37 degrees C, but progressively decreased at 4 degrees C. An heteroplasmic G to A mutation at position 15615 of the mitochondrial DNA, resulting in the replacement of the highly conserved Gly290 in cytochrome b by Asp, was identified. Histochemical studies showed increased cytochrome oxidase and succinate dehydrogenase activities under the sarcolemma of type I fibres. After partial extraction of mitochondria from the muscle, the residual pellet contained a lower percentage of the mutation than did whole muscle, suggesting that the percentage of mutation is higher in the most readily extracted mitochondria, most probably present under the sarcolemma. In the current 8 transmembrane helix model of cytochrome b, Gly290 lies at the end of the sixth transmembrane helix, facing the intermembrane space and close to the presumed sites of interaction between cytochrome b, the iron-sulfur protein and the 9.5 kDa protein. Since immunoblotting experiments showed a relative decrease in the proportions of these three subunits in the patient's mitochondria compared with the other complex III subunits, it is probable that the complex III instability and the relative decrease in these subunits are related to the mutation. The relationship between the decrease in the apparent affinity for antimycin A and the instability of complex III are discussed.

Amino Acid Sequence↗
PubMed1996

Variations of muscle mitochondrial creatine kinase activity in mitochondrial diseases.

Mitochondrial creatine kinase (mtCK) activity has been measured in the mitochondria isolated from the muscle of 69 patients suspected of mitochondrial diseases. The isolated mitochondria did not contain significant amounts of the muscle isoform of creatine kinase, as checked by an immunoassay performed after electrophoretic separation of the various isoforms. Hence, the enzyme assay reliably represented the mtCK activity. Therefore, a simple measurement of CK activity in isolated mitochondria permitted the measurement of mtCK activity. An absence of mtCK activity in muscle was never observed. The lowest activities were not associated to defined mitochondrial diseases linked to defects of respiratory chain complexes or to defects of citric cycle enzymes. On the contrary, mtCK activity was significantly increased in the muscle of patients exhibiting ragged red fibers. This increase was generally associated to an increase of citrate synthase activity. Since ragged-red fibers and elevated mtCK activities were generally not found in children younger than 3 years, even in cases of characteristic oxidative phosphorylation deficiency, it is suggested that the increase in mtCK activity as well as the appearance of ragged-red fibers are not the first events which occur during the evolution of mitochondrial diseases but would rather be long-term secondary processes which slowly develop in deficient mitochondria.

Adolescent↗
PubMed1996

Molecular histology of mitochondrial and nuclear transcripts in the muscle of patients harbouring a single mitochondrial DNA deletion.

The distribution of transcripts of mitochondrial and nuclear genes involved in oxidative phosphorylation and of the mitochondrial creatine kinase nuclear gene was examined, using in situ hybridisation, in the skeletal muscle of 11 patients harbouring a heteroplasmic mitochondrial DNA (mtDNA) single deletion. Levels of mRNAs transcribed from genes located within the deletions were not decreased, suggesting that the remaining wild-type mtDNA was still transcribed. Those muscle fibres with characteristic abnormal mitochondrial proliferation always showed overexpression of mRNAs and rRNAs transcribed from mitochondrial genes located outside the deletions. Interestingly, they also showed overexpression of the nuclear-encoded ATP synthase beta subunit mRNA, but not of mitochondrial creatine kinase mRNA. These observations lead to three proposals: (1) overexpression of mitochondrial transcripts within fibres harbouring mitochondrial proliferation, together with the apparently normal expression of the remaining wild-type mtDNA, is not related to decreased mitochondrial translation; (2) it is more probably related to an up-regulation mechanism which co-ordinates both mitochondrial and nuclear expression; and (3) this mechanism is restricted to transcripts directly involved in oxidative phosphorylation and to fibres with mitochondrial accumulation.

Adolescent↗
PubMed1995

Fine mapping of randomly distributed multiple deletions of mitochondrial DNA in a case of chronic progressive external ophthalmoplegia.

Multiple deletions of mitochondrial DNA have been detected by Southern blotting in the skeletal muscle of a 42-year-old woman with chronic progressive external ophthalmoplegia. A PCR method, using several combinations of primers covering the whole mtDNA as well as sequence analysis, disclosed the wide spectrum of these multiple deletions differing in size, location and sequence at the breakpoint junction. Most involved the major region between the two replication origins. However, three deletions affected the minor region and lacked either the light strand origin of replication or the heavy strand promoter. These data suggest an impairment of mtDNA replication leading to illegitimate recombination and extensive damage of mtDNA.

Adolescent↗
PubMed1995

An abnormal exercise test response revealing a respiratory chain complex III deficiency.

A 29-year-old man with a progressive exertional muscle intolerance since childhood was referred for incremental exercise test on a bicycle ergometer. The response pattern suggested a mitochondrial myopathy: that is, a greatly reduced maximum oxygen consumption with appropriate heart rate increase and an anaerobic threshold point reached early. The metabolic investigation in plasma revealed an abnormal oxidoreduction status (hyperlactataemia and high lactate/pyruvate ratio) at rest and after a carbohydrate rich meal. The histochemical examination of a muscle biopsy revealed red granular deposits under the sarcolemma for all type 1 fibers. Oxypolarographic and enzymological studies of the mitochondrial respiratory chain in both isolated mitochondria and muscle homogenate demonstrated a marked deficiency of ubiquinol cytochrome c reductase (complex III) activity.

Adult↗
PubMed1995

Effects of chronic renal failure on enzymes of energy metabolism in individual human muscle fibers.

In order to improve knowledge about the mechanisms underlying the alterations of energy metabolism recently observed in the skeletal muscle of patients suffering from chronic renal failure, this study was designed to test (1) whether changes in the activity of key enzymes of energy metabolism occur in the muscle of these patients, and if so (2) whether the different muscle fiber types are equally altered in their metabolic machinery. For this, the maximum activities of 14 enzymes were measured in individual muscle fibers microdissected from biopsies of rectus abdominis muscle obtained from seven normal subjects and seven patients with end-stage renal failure before renal replacement therapy. A large decrease in the activities of beta-hydroxyacyl-coenzyme A dehydrogenase, a key enzyme of the beta-oxidation pathway, of citrate synthase, which initiates the tricarboxylic acid cycle, and of fructose-1,6-bisphosphatase, which contributes to the synthesis of glycogen from lactate, was observed in the three fiber types (slow-twitch oxidative, fast-twitch oxidative-glycolytic, and fast-twitch glycolytic). A smaller reduction of the activities of phosphofructokinase and/or pyruvate kinase, two key enzymes of glycolysis, was also observed in slow-twitch oxidative and/or fast-twitch oxidative-glycolytic fibers. These results demonstrate that the abnormalities of muscle energy metabolism observed in patients with chronic renal failure are due, at least in part, to intrinsic changes in the key enzymes of major energy-providing pathways; they also offer a satisfactory explanation for the defect of oxidative metabolism recently demonstrated in the muscle of these patients.

Adult↗
PubMed1993

2-Ketoglutarate dehydrogenase deficiency, a rare cause of primary hyperlactataemia: report of a new case.

Two new familial cases of 2-ketoglutarate dehydrogenase (2-KGD) deficiency are reported: a girl who died at 10 years and a boy, still alive at 4 years, born to consanguineous parents. The cases developed progressively severe encephalopathy with axial hypotonia, psychotic behaviour, pyramidal symptoms and failure to thrive. Both children exhibited permanent lactic acidosis with acute episodes during emotional stress and various infections, associated with elevated lactate/pyruvate (L/P) ratio and slightly decreased ketone body ratio in plasma. In fibroblasts, the L/P ratio was greatly increased in the boy. No respiratory chain complex deficiency could be demonstrated in cultured fibroblasts or in mitochondria isolated from a muscle biopsy performed on the boy. In muscle isolated mitochondria, a progressive decrease of the rate of glutamate oxidation was observed after ADP addition; the rate of 2-ketoglutarate oxidation was low in the absence of ADP and did not increase after ADP addition. 2-KGD deficiency was demonstrated in fibroblasts from both children and in the boy's muscle and myoblasts. The 2-KGD complex is composed of three separate enzymes: E1, E2 and E3. We could demonstrate in our patient that the E1 and E3 subunits were normal, suggesting that the E2 component could be responsible for the defect.

Acidosis, Lactic↗
PubMed1990

Myopathic evolution of an exertional muscle pain syndrome with phosphorylase b kinase deficiency.

The symptoms of a myopathy permanently affecting limb girdle muscles are reported in a 31-year-old woman who has been presenting an exertional muscle pain syndrome with myoglobinuria for 20 years. Investigations revealed a slightly decreased utilization of glycogen in muscle, while its storage affected only rare type 2 fibers. Active phosphorylase was undetectable and phosphorylase b kinase activity was clearly decreased in muscle cells, but normal in erythocytes, lymphocytes and cultured fibroblasts.

Adult↗
PubMed1987

Congenital Lambert-Eaton myasthenic syndrome.

A 4 year old girl had been hypotonic and areflexic since birth with delayed milestones in motor development. Repetitive stimulation at high rates performed at 3 years elicited an incremental response typical of the Lambert-Eaton Syndrome.

Action Potentials↗
PubMed1986

[A case of myopathy with carnitine deficiency].

Clinical and biological criteria of myopathies associated with carnitine deficiency allow to distinguish a muscular and a systemic form of the condition. In this report, the results of clinical, pathological and electrophysiological data obtained from a patient with carnitine deficiency-linked myopathy are described. The patient was a 23-year-old girl who was previously known to suffer from muscle weakness when suddenly acidosis associated with a severe drop in plasma carnitine appeared. In addition there were hypermetabolic symptoms similar to those described in Luft's syndrome. Biopsy from the quadriceps femoris muscle before treatment revealed that all type I fibers were either hypotrophic or atrophic. They showed lipid overloading manifested by triglyceride droplets adjacent to the mitochondrial membrane. Furthermore, the level of soluble muscle carnitine was 83 p. 100 less than in controls and membrane linked muscle carnitine was also 73.5 p. 100 less than in controls. The patient rapidly recovered after the initiation of daily treatment with 4.40 g carnitine chlorhydrate associated with 50 g Lipogram 20. Nine months later, lipid overloading completely disappeared and the level of plasma carnitine returned to near normal whereas the level of both soluble and linked carnitine remained very low. To provide more information on the origin of the myopathy (myogenic, neurogenic or humoral) we carried out an electrophysiological investigation of cultured skeletal muscle cells from the patient and from biopsies of patients not known to be suffering from myopathy. The electrophysiological data showed that the patient myotubes were less polarized than myotubes from control patients. Furthermore, the amplitude of the action potential was smaller than the amplitude of the action potential measured in control cells. Daily addition of 50 microM carnitine chlorhydrate to the cultured myotubes induced a recovery of the action potential amplitude. Taken together these results indicate that the carnitine deficiency reported here was probably of systemic origin in addition to a myogenic component. Muscle deficiency could be either linked to an alteration in the carnitine pathway or to overconsumption of carnitine by muscle. This latter point is discussed.

Action Potentials↗