Biomedical subjects

S DiMauro

Publications and source records attributed to S DiMauro.

At least 253 records · Page 14Linked to original sources

PubMed1990

Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA.

Large-scale deletions of mitochondrial DNA (mtDNA) have been described in patients with progressive external ophthalmoplegia (PEO) and ragged red fibers. We have determined the exact deletion breakpoint in 28 cases with PEO, including 12 patients already shown to harbor an identical deletion; the other patients had 16 different deletions. The deletions fell into two classes. In Class I (9 deletions; 71% of the patients), the deletion was flanked by perfect direct repeats, located (in normal mtDNA) at the edges of the deletion. In Class II (8 deletions; 29% of patients), the deletions were not flanked by any obviously unique repeat element, or they were flanked by repeat elements which were located imprecisely relative to the breakpoints. Computer analysis showed a correlation between the location of the deletion breakpoints and sequences in human mtDNA similar to the target sequence for Drosophila topoisomerase II. It is not known how these deletions originate, but both slipped mispairing and legitimate recombination could be mechanisms playing a major role in the generation of the large mtDNA deletions found in PEO.

Base Sequence↗

PubMed1990

Metabolic causes of myoglobinuria.

To evaluate the proportion of cases of myoglobinuria that can be ascribed to specific metabolic defects, we have studied eight enzymes--phosphorylase, phosphorylase kinase, phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), lactate dehydrogenase (LDH), carnitine palmitoyltransferase (CPT), and myoadenylate deaminase (MAD)--in muscle biopsy specimens from 77 consecutive patients with myoglobinuria (documented in 44, suspected in 33). Enzyme defects were found in 36 patients: CPT deficiency in 17, phosphorylase deficiency in 10, phosphorylase kinase deficiency in 4, MAD deficiency in 3, PGK deficiency in 1, and a combined defect of CPT and MAD in 1. Exercise was the main precipitating factor, both in patients with and in those without detectable enzymopathies. Thirty patients had specific enzymopathies without myoglobinuria: 14 had phosphorylase deficiency, 9 had MAD deficiency, 3 had phosphorylase kinase deficiency, 3 had PFK deficiency, and 1 had PGAM deficiency. Systematic biochemical evaluation of muscle biopsy specimens revealed specific enzymopathies in about half of the patients with idiopathic myoglobinuria. The rest may have blocks of metabolic pathways not yet studied routinely, such as beta oxidation, or genetic defects of the sarcolemma, such as Becker's muscular dystrophy.

AMP Deaminase↗

PubMed1990

Rare McArdle disease locus polymorphic site on 11q13 contains CpG sequence.

When probes throughout the McArdle disease (myophosphorylase) gene region were used to search for DNA polymorphisms, only an MspI polymorphism was found in 94 enzyme-probe combinations. Along with an insertion/deletion polymorphism more 3' to the gene locus, these polymorphisms will be informative in 75% of at-risk patients. These results contrast strikingly to the six polymorphic sites detected in 15 enzyme-probe combinations in the homologous Her's disease (liver phosphorylase) gene region. This single MspI polymorphic site includes a CpG sequence of known increased mutability suggesting that DNA regions with rare polymorphisms will have most polymorphic sites at sequences with enhanced mutability. Fluorescence in situ hybridization sublocalized this gene to proximal band 11q13, establishing a point of cross-reference between the physical and genetic maps.

Base Sequence↗

PubMed1990

Progressive cytochrome c oxidase deficiency in a case of Leigh's encephalomyelopathy.

We report the morphological, biochemical, immunological, and genetic findings in a patient with the clinical characteristics of Leigh's disease due to multisystemic cytochrome c oxidase (CCO) deficiency. Muscle biopsy at 2 years and 5 months of age showed markedly decreased CCO and cytochrome a + a3, moderately decreased NADH-cytochrome c reductase to 46.3%, and generalized loss of immunologically detectable CCO subunits, but other respiratory chain enzyme proteins were normal. All the tissues examined at autopsy showed decreased activity of all respiratory chain enzymes except complex II. The decrease in cytochromes b and a + a3 were in harmony with decreased enzyme activities in complex III and IV (CCO), respectively. All immunologically detectable subunits of CCO in immunoprecipitation were uniformly decreased in the cardiac and skeletal muscles, but subunits 1 and 4 were selectively decreased in other organs except liver. No large deletion could be detected in the cardiac muscle mtDNA after digestion with restriction enzymes. These results suggest that the respiratory chain enzymes are variable in their activity and the amount of enzyme proteins decreases as the disease progresses.

Brain↗

PubMed1990

Mitochondrial defects of brain and muscle.

The brain and muscle are particularly vulnerable to mitochondrial defects as are the heart, kidney and liver. This hierarchy of organ involvement is reflected in the clinical signs and symptoms associated with these diverse encephalomyopathic syndromes. The biochemical correlates involve pyruvate metabolism, the citric acid cycle and the respiratory chain. Lactic acidosis is the metabolic signature in these diseases although not present in all syndromes, witness Leber hereditary optic neuropathy. Ragged-red fibers are equally distinctive in biopsied skeletal muscle but are present only with biochemical defects involving the respiratory chain. Defects of pyruvate metabolism and the citric acid cycle are inherited as autosomal or x-linked Mendelian traits. Respiratory chain defects may be inherited as Mendelian or maternal (non-Mendelian) traits. All mitochondria of the progeny are inherited from the mother; and all 13 polypeptides encoded by the mitochondrial genome are located in the respiratory chain (complexes I, III, IV and V). These biological principles are helpful in understanding the clinical syndromes and patterns of inheritance associated with the mitochondrial myopathies and encephalomyopathies.

Brain Diseases↗

PubMed1990

Cytochrome c oxidase deficiency in muscle with dicarboxylic aciduria and renal tubular acidosis.

A patient with deficient activity of cytochrome c oxidase in muscle presented at 1 year of age with extreme failure to thrive. He was found to have dicarboxylic aciduria, renal tubular acidosis, and deficiency of carnitine. Treatment with sodium bicarbonate, riboflavin, and carnitine led to considerable improvement in growth and a significant reduction in the dicarboxylic aciduria.

Acidosis, Renal Tubular↗

PubMed1990

Cytochrome c oxidase deficiency.

Cytochrome c oxidase (COX) is a complex enzyme composed of 13 subunits, three of which are encoded by the mitochondrial DNA (mtDNA). The other 10 subunits are encoded by the nuclear DNA, synthesized in the cytoplasm, and transported into the mitochondria. The complexity of the enzyme and its dual genetic control explain the heterogeneity of clinical phenotypes associated with COX deficiency. There are two major syndromes, one characterized by muscle involvement (fatal infantile or benign infantile myopathy), the other dominated by brain disease (Leigh syndrome, myoclonic epilepsy with ragged red fibers, Menkes' disease). Partial defects of COX have been shown in muscle of patients with progressive external ophthalmoplegia, either alone (ocular myopathy) or as part of Kearns-Sayre syndrome. Biochemical studies have documented either muscle-specific or generalized defects of COX; COX deficiency is reversible in the benign infantile myopathy. Immunologically detectable protein may be normal (benign myopathy) or variably decreased (fatal myopathy, Leigh syndrome). The subunit pattern of COX is normal by immunoblot in patients with fatal myopathy and Leigh syndrome; a disproportionate decrease of subunit II was seen in a patient with myoclonic epilepsy with ragged red fibers. Availability of the three mtDNA genes and of complementary DNA probes for eight of the 10 nuclear DNA-encoded subunits makes it possible to investigate the different diseases at the molecular level. Large deletions of mtDNA have been found in patients with ocular myopathy and Kearns-Sayre syndrome: the deleted mtDNA appear to be transcribed but not translated, thus explaining the partial COX deficiency.

Brain Diseases↗

PubMed1990

Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome.

We performed Southern analysis of mitochondrial DNA (mtDNA) in 6 tissues from a patient with Kearns-Sayre syndrome and found a single deletion of 4.9 kb in all tissues. The percentage of deleted mtDNAs varied widely between tissues, from only 4% in smooth muscle to approximately 50% in skeletal muscle. Samples of DNA obtained from 3 different skeletal muscles and from separate areas of individual tissues showed little variation in percentage of deleted mtDNA. Biochemical analysis showed no clear correlation between mitochondrial enzyme activity and deleted mtDNAs.

Blotting, Southern↗

PubMed1990

Kearns-Sayre syndrome presenting as renal tubular acidosis.

Renal tubular acidosis and tetany were the 1st manifestations of Kearns-Sayre syndrome in a 5-year-old child. Subsequently, he developed progressive external ophthalmoplegia, ptosis, retinopathy, heart block, and endocrinopathy. There was a 7.5-kb deletion of mitochondrial DNA documented in muscle, kidney, skin fibroblasts, and leukocytes, providing evidence for a multisystem mitochondrial cytopathy.

Acidosis, Renal Tubular↗

PubMed1990

Partial dystrophin deficiency in monozygous twin carriers of the Duchenne gene discordant for clinical myopathy.

We studied monozygous twin women, age 63. One, asymptomatic, had a serum creatine kinase (CK) level of 191 units (normal, 1 to 50); her son died of typical Duchenne muscular dystrophy (DMD) at age 18. Her twin sister had symptomatic limb weakness from about age 40. Her serum CK was 495 units. EMG and muscle biopsy were compatible with myopathy. In the asymptomatic twin, the peripheral blood lymphocyte karyotype was 46,XX. In the affected twin, 18% of cells were 45,X, and the others 46,XX, without X/autosome translocation. DNA analysis did not reveal a deletion at the DMD locus. Immunologic studies of dystrophin showed a partial deficiency of the protein that was more severe in the symptomatic twin. The clinical discordance and the different severity of dystrophin deficiency may have resulted from the effects of lyonization.

Creatine Kinase↗

PubMed1990

Mitochondrial myopathy and myoclonic epilepsy.

The authors describe a family (mother, son and two daughters) with mitochondrial myopathy. The mother was asymptomatic. Two daughters had lactic acidosis and myoclonic epilepsy, mild dementia, ataxia, weakness and sensory neuropathy. The son suffered one acute hemiplegic episode due to an ischemic infarct in the right temporal region. All the patients studied had hypertension. EEG disclosed photomyoclonic response in the proband patient. Muscle biopsy disclosed ragged-red fibers and abnormal mitochondria by electron microscopy. Biochemical analysis showed a defect of cytochrome C oxidase in mitochondria isolated from skeletal muscle. Several clinical and genetic aspects of the mitochondrial encephalomyopathies are discussed.

Acidosis, Lactic↗

PubMed1990

Transcription and translation of deleted mitochondrial genomes in Kearns-Sayre syndrome: implications for pathogenesis.

Large-scale deletions of human mitochondrial DNA (mtDNA) have been described in a clinical subgroup of mitochondrial encephalomyopathies associated with progressive external ophthalmoplegia and ragged-red fibers in skeletal muscle, including cases of Kearns-Sayre syndrome (KSS). Since the decrease in the activities of mtDNA-encoded respiratory-chain enzymes did not seem to be correlated to the sites of the deletions, the role played by the mtDNA deletions in the pathogenesis of these disorders has been unclear. To address this issue, we studied transcription and translation of deleted mtDNA in two patients with KSS harboring two different deletions. We found that the deleted genomes were transcriptionally active in both cases. Analysis of translation in one of the patients showed that the "fusion" mRNA derived from the region spanning the deletion did not seem to be translated. Thus, the biochemical defects in KSS can be explained by a lack of translation of mtDNA-encoded respiratory-chain polypeptides in some mitochondria, which, in turn, is probably due to the lack of indispensable mtDNA-encoded tRNAs in these organelles. These results imply that deleted mtDNAs may be segregated from normal genomes in this group of diseases. It seems likely that the absence of translation in proliferating mitochondria containing partially deleted genomes plays a major role in the pathogenesis of these disorders.

Base Sequence↗

PubMed1990

Mitochondrial encephalomyopathies.

The mitochondrial diseases present with great heterogeneity. They are often multisystemic and vary considerably in age at onset, distribution of weakness, severity, and course. Only nonthyroidal hypermetabolism has a distinctive clinical presentation. Therefore, attempts at classification have generated some controversy. This article discusses the general classification that takes into account genetic and biochemical features, which has resulted from the fast pace of biochemical and molecular genetic investigations.

Brain↗

PubMed1990

Recurrent childhood myoglobinuria.

Recurrent heritable childhood myoglobinuria is a potentially fatal entity (mortality up to 35%) in which prompt diagnosis and treatment are critical. Sixty childhood cases have been reported between 1910 to 1988, most with undiagnosed etiologies. We have studied an additional 40 cases referred to CPMC (1980-1988), suggesting that this condition is largely underdiagnosed or unreported. We have found important differences between the childhood and adult-onset cases. Of 77 cases of adult-onset recurrent myoglobinuria, 45% have been diagnosed biochemically. In contrast, only 30% of the 60 childhood cases from the literature have been diagnosed; 11 with CPT deficiency and 7 with various glycolytic defects, and only 5 of our 40 childhood cases have been diagnosed, all with CPT deficiency. The 100 combined childhood cases can be divided into an exertional group (type I) with exertion as the leading precipitating factor (46 literature and 10 CPMC cases), a toxic group (type II) with infection and/or fever as the primary precipitant (14 literature and 23 CPMC cases), and 7 undefined cases. The type I group resembles the adult-onset group in which exercise is also the leading precipitating factor. There is a slight female predominance (male/female = 1:1.3) in the toxic group vs. a marked male predominance in the exertional and adult groups (4:1). Only 4 of 37 cases (11%) of the toxic group are diagnosed (all with CPT deficiency) vs. 19 of 56 cases (34%) of the exertional group (12 CPT, 7 glycolytic) and 45% of the adult group. The toxic group is also differentiated by a higher mortality rate and by the presence of additional clinical features, including ictal bulbar signs (8 of 18), encephalopathy (4 of 19), and seizures (2 of 7), as well as persistent cardiac abnormalities, developmental delay (4 of 17), and dysmorphic features (2 of 9). These clinical characteristics clearly differentiate the childhood from the adult cases and suggest the presence of more generalized disease processes and different biochemical etiologies. A study of the heritable causes of myoglobinuria is important because identification of the biochemical defect may elucidate the pathogenetic mechanism of the myoglobinuria and facilitate the development of rational treatment strategies aimed at circumventing or correcting the metabolic block.

Adolescent↗

PubMed1989

Structure of the gene encoding the muscle-specific subunit of human phosphoglycerate mutase.

We report the isolation and analysis of genomic clones containing the entire gene encoding the muscle-specific subunit of human phosphoglycerate mutase. The gene spans 2.83 kilobase pairs and has a three-exon/two-intron structure that is similar to the organization of the human 2,3-bisphosphoglycerate mutase gene (Joulin, V., Garel, M.-C., LeBoulch, P., Valentin, C., Rosa, R., Rosa, J., and Cohen-Solal, M. (1988) J. Biol. Chem. 263, 15785-15790), in that the second introns of both genes are localized precisely at the same position. A canonical TATA box and an inverted CCAAT box are present immediately upstream of this gene. Comparison with other muscle-specific enzyme genes reveals a conserved 9-base pair element (GGGGCTGGG) in the 5'-flanking region that may be associated with the expression of genes encoding muscle-specific enzymes.

Amino Acid Sequence↗

PubMed1989

A gene specifying subunit VIII of human cytochrome c oxidase is localized to chromosome 11 and is expressed in both muscle and non-muscle tissues.

Subunit VIII of mammalian cytochrome c oxidase (COX; EC 1.9.3.1) exists in at least two isoforms, because different but related polypeptides have been identified in COX isolated from liver and heart of both beef and pig. We have isolated a full length cDNA specifying subunit VIII of human COX from a human liver cDNA library. Sequences hybridizing to this cDNA are present at only one site, the COX8 locus, on human chromosome 11q12-q13. The deduced human polypeptide is 58% identical with COX VIII isolated from beef liver, but only 38% identical with COX VIII isolated from beef heart. Transcriptional analysis shows that an mRNA identical with the isolated cDNA is present in abundant amounts not only in human and monkey liver tissue, but in heart and skeletal muscle as well, tissues not known previously to contain this isoform. Since the only COX VIII subunit found in human heart agrees 100% with the polypeptide deduced from this coxVIII cDNA, it may well be that, in distinction to other mammals, only one form of COX VIII exists in primates.

Amino Acid Sequence↗

PubMed1989

An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region.

Deletions of muscle mitochondrial DNA (mtDNA) have recently been found in patients with mitochondrial myopathy. However, as most of the described cases were sporadic, and individual deletions involved different portions of mtDNA, the mechanism(s) producing the molecular lesions, as well as their mode of transmission, remain unclear. By studying families with mtDNA heteroplasmy, valuable information can be obtained about the role of inheritable factors in the pathogenesis of these disorders. We have studied four members of a family with autosomal dominant mitochondrial myopathy. Multiple deletions, involving the same portion of muscle mtDNA, were identified in all patients. Sequence analysis of the mutant mtDNAs, performed after DNA amplification by the polymerase-chain reaction showed that all the deletions start within a 12-nucleotide stretch at the 5' end of the D-loop region, a site of active communication between the nucleus and the mtDNA. The data indicate that a mutation of a nuclear-coded protein can destroy the integrity of the mitochondrial genome in a specific, heritable way.

Base Sequence↗

PubMed1989

Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome.

We investigated the correlations of deletions of mitochondrial DNA in skeletal muscle with clinical manifestations of mitochondrial myopathies, a group of disorders defined either by biochemical abnormalities of mitochondria or by morphologic changes causing a ragged red appearance of the muscle fibers histochemically. We performed genomic Southern blot analysis of muscle mitochondrial DNA from 123 patients with different mitochondrial myopathies or encephalomyopathies. Deletions were found in the mitochondrial DNA of 32 patients, all of whom had progressive external ophthalmoplegia. Some patients had only ocular myopathy, whereas others had Kearns-Sayre syndrome, a multisystem disorder characterized by ophthalmoplegia, pigmentary retinopathy, heart block, and cerebellar ataxia. The deletions ranged in size from 1.3 to 7.6 kilobases and were mapped to different sites in the mitochondrial DNA, but an identical 4.9-kilobase deletion was found in the same location in 11 patients. Biochemical analysis showed decreased activities of NADH dehydrogenase, rotenone-sensitive NADH-cytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase, four enzymes of the mitochondrial respiratory chain containing subunits encoded by mitochondrial DNA. We conclude that deletions of muscle mitochondrial DNA are associated with ophthalmoplegia and may result in impaired mitochondrial function. However, the precise relation between clinical and biochemical phenotypes and deletions remains to be defined.

Blotting, Southern↗