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S DiMauro

Publications and source records attributed to S DiMauro.

At least 127 records · Page 7Linked to original sources
PubMed1998

Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy.

A patient with progressive exercise intolerance, proximal weakness, and complex III deficiency in skeletal muscle had a missense mutation in the cytochrome b gene of mitochondrial DNA (G15762A). The mutation, which leads to the substitution of a highly conserved amino acid (G339E), was heteroplasmic (85%) in the patient's muscle and was not present in 100 individuals of different ethnic backgrounds. These data strongly suggest that this molecular defect is the primary cause of the myopathy.

Adult↗
PubMed1998

Mitochondria and heart disease.

Because the myocardium depends heavily on oxidative metabolism, it is not surprising that genetic errors of mitochondrial function often result in cardiomyopathies. The emphasis of this review is on disorders of the respiratory chain, the only area of cell metabolism that is under dual genetic control: 1) the mitochondrial genome (mtDNA) encodes 13 subunits of respiratory chain complexes, and 2) the nuclear genome not only encodes all other respiratory chain proteins, but also mitochondrial translocases, components of the mitochondrial protein transport machinery, and factors that are essential for mtDNA transcription, translation, and replication. Mitochondrial cardiomyopathies due to mutations in the nuclear DNA are inherited as mendelian traits involving structural or enzyme proteins of the respiratory chain, mitochondrial protein importation, or the dialogue between the two genomes. Mitochondrial cardiomyopathies due to mtDNA mutations can be sporadic or inherited as maternal traits and follow the rules of "mitochondrial genetics," which are outlined briefly. MtDNA mutations can cause isolated cardiomyopathies or, more often, multisystem disorders of which cardiac involvement is a major component. We review recent advances in this rapidly expanding field and briefly discuss pathogenetic problems and the mitochondrial theory of presbycardia.

Age Factors↗
PubMed1997

Apparent mtDNA heteroplasmy in Alzheimer's disease patients and in normals due to PCR amplification of nucleus-embedded mtDNA pseudogenes.

In an unprecedented finding, Davis et al. [Davis, R. E., Miller, S., Herrnstadt, C., Ghosh, S. S., Fahy, E., Shinobu, L. A., Galasko, D., Thal, L. J., Beal, M. F., Howell, N. & Parker, W. D., Jr. (1997) Proc. Natl. Acad. Sci. USA 94, 4526-4531] used an unusual DNA isolation method to show that healthy adults harbor a specific population of mutated mitochondrial cytochrome c oxidase (COX) genes that coexist with normal mtDNAs. They reported that this heteroplasmic population was present at a level of 10-15% in the blood of normal individuals and at a significantly higher level (20-30%) in patients with sporadic Alzheimer's disease. We provide compelling evidence that the DNA isolation method employed resulted in the coamplification of authentic mtDNA-encoded COX genes together with highly similar COX-like sequences embedded in nuclear DNA ("mtDNA pseudogenes"). We conclude that the observed heteroplasmy is an artifact.

Adult↗
PubMed1997

Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS.

We report a novel G13513A mutation in the mitochondrial ND5 gene in a patient who had morphologically and biochemically abnormal muscle mitochondria and died at age 45 with a diagnosis of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The mutation affects an evolutionarily conserved nucleotide and was heteroplasmic in muscle, leukocytes, and several autopsy tissues, including brain. The mutation was less abundant (<5%) in leukocytes from an asymptomatic sister and was not found in over 100 controls, thus satisfying accepted criteria for pathogenicity. Our report reinforces the concept of genetic heterogeneity in MELAS and confirms that MELAS can be due to mutations in polypeptide-coding mtDNA genes.

Amino Acid Sequence↗
PubMed1997

Biochemical and genetic studies in a family with mitochondrial myopathy.

We present a family with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. Fifteen of 24 family members in five generations were affected. Since the affected males do not have offspring at this time, the family pedigree is consistent with either maternal or autosomal dominant inheritance. Muscle histochemistry showed ragged-red fibers and electron microscopy showed globular mitochondrial inclusions. Biochemical analysis showed reduced muscle activities of mitochondrial NADH-cytochrome c reductase (1 of 2 patients), succinate-cytochrome c reductase (2 patients), and cytochrome c oxidase (2 patients). For 1 patient, sequence analysis of 44% of the muscle mitochondrial DNA including all 22 transfer RNA regions showed no point mutation with pathogenic significance. Southern blot analysis showed no deletion. Six affected members of the family were treated with methylprednisolone (0.25 mg/kg) for 3 months. Muscle strength, serum lactate, and energy metabolism at rest (measured by 31P magnetic resonance spectroscopy) significantly improved with treatment.

Adolescent↗
PubMed1997

Association of myopathy with large-scale mitochondrial DNA duplications and deletions: which is pathogenic?

We identified large-scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50-year-old woman with an adult-onset progressive myopathy. The predominant mtDNA abnormality was a 21.2-kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6-kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA-encoded COX subunits. By single-fiber polymerase chain reaction analysis, COX-negative fibers contained a low number of wild-type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.

Base Sequence↗
PubMed1997

Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.

We identified a single thymidine insertion at nucleotide position 5537 (T5537i) in the mitochondrial DNA transfer RNA gene for tryptophan in a family in which the proband had a progressive neurological disorder and his brother died in infancy of Leigh syndrome. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. Complex IV was also severely reduced in autopsy tissues, including heart and brain tissues, from the Leigh syndrome infant. The novel T5537i mutation was very abundant in tissues from the proband and the infant (>92%) and less abundant (range, 42-89%) in blood, hair follicles, and skin fibroblasts from 4 maternal relatives, 3 of whom showed a neuropsychiatric disturbance. The mutation was not found in more than 100 control subjects. The degree of heteroplasmy in blood correlated well with the severity of the clinical presentation, suggesting specific segregation with the disease.

Adult↗
PubMed1997

Mitochondrial disorders.

In this minireview, we attempt to survey the three main group of mitochondrial disorders, defects of nuclear DNA, defects of mitochondrial DNA, and defects of intergenomic signaling, with emphasis on recent contributions and pathogenetic mechanisms. In so doing, we have tried to point out some of the numerous unsolved problems in genotype/phenotype correlation and to indicate future directions of research.

Central Nervous System Diseases↗
PubMed1997

Infantile phosphofructokinase deficiency with arthrogryposis: clinical benefit of a ketogenic diet.

We report a 2-year-old boy with phosphofructokinase deficiency presenting in the newborn period with congenital arthrogryposis and severe myopathy, who has had significant improvement on a ketogenic diet since its institution at 4 months of age. We provide a rationale for use of this treatment and hypothesize it may be beneficial in other patients with phosphofructokinase deficiency and progressive muscular involvement. Confirmation awaits further clinical trials in carefully selected patients.

Arthrogryposis↗
PubMed1997

Oculopharyngeal muscular dystrophy, other ocular myopathies, and progressive external ophthalmoplegia.

Progressive external ophthalmoplegia comprises many different disorders. Those of childhood onset can be separated from juvenile or adult onset. Among those of later onset the most common causes are oculopharyngeal muscular dystrophy, oculopharyngodistal muscular dystrophy and the several mitochondrial disorders, especially those with large deletions of mitochondrial DNA (mtDNA) (sporadic), those with maternal inheritance (point mutations), or the autosomal dominant forms with multiple deletions of mtDNA. Ophthalmoplegia of presumably neurogenic origin is seen in some of the familial spinocerebellar ataxias. Advances in molecular genetics should provide information about affected gene products and, therefore, pathogenesis.

Adult↗
PubMed1997

Sudden infant death syndrome (SIDS) in a family with myophosphorylase deficiency.

A previously healthy girl died suddenly and unexpectedly at three months of age in her sleep and an autopsy failed to reveal an adequate cause of death. As the father was known to have myophosphorylase (PPL) deficiency (McArdle's disease), we performed molecular genetic analysis of the PPL gene in autopsy muscle of the proposita. The girl was homozygous for the nonsense mutation at codon 49 most commonly associated with typical McArdle's disease. This report suggests that among children presenting as Sudden Infant Death Syndrome (SIDS) there may be cases associated with myophosphorylase deficiency.

Adult↗
PubMed1997

Mitochondrial tRNA(Cys) gene mutation (A5814G): a second family with mitochondrial encephalopathy.

We report an Italian family with maternally inherited encephalomyopathy including progressive external ophthalmoplegia, seizures, and neurophysiological evidence of brainstem dysfunction. Mitochondrial DNA analysis showed a heteroplasmic point mutation at position 5814 in the tRNA gene for cysteine (A5814G), previously reported in a 5-year-old girl of Portuguese origin. The mutation was very abundant (> 95%) in both muscle and blood from the proposita and was present in lower proportions (average 85 +/- 6%) in blood from three less severely affected maternal relatives. This observation confirms pathogenicity for the A5814G mutation.

Adult↗
PubMed1997

Mitochondrial DNA mutations and pathogenesis.

Approximately there years ago, this journal published a review on the clinical and molecular analysis of mitochondrial encephalomyopathies, with emphasis on defects in mitochondrial DNA (mtDNA). At the time, approximately 30 point mutations associated with a variety of maternally-inherited (or rarely, sporadic) disorders had been described. Since that time, almost twenty new pathogenic mtDNA point mutations have been described, and the pace of discovery of such mutations shows no signs of abating. This accumulating body of data has begun to reveal some patterns that may be relevant to pathogenesis.

Cardiomyopathies↗
PubMed1997

Diagnosis of the mitochondrial encephalomyopathies.

In few fields of medicine has recent progress been as fast and exciting as in the area of mitochondrial diseases. Although the clinical manifestations of mitochondrial dysfunction are extremely variable, biochemical and genetic classification of these disorders is now possible and recent advances in morphologic analysis and genetic testing aid in the identification of patients. What makes these diseases uniquely interesting from a genetic point of view is the fact that mitochondria contain their own DNA, which has distinct genetic properties. It is in the area of mitochondrial DNA defects that there has been extraordinary progress in the past few years, and a new chapter of human genetics, "mitochondrial genetics," has opened up and is becoming increasingly important in the differential diagnosis and in genetic counseling.

DNA, Mitochondrial↗
PubMed1997

The mitochondrial A3243G mutation presenting as severe cardiomyopathy.

A 6 year old Portuguese boy with dilated cardiomyopathy had abundant ragged red fibres in muscle (20% of total) and severe lactic acidosis. Molecular genetic analysis showed the A to G transition in the mitochondrial transfer RNALeu(UUR) gene at nt 3243 ("MELAS mutation"), which accounted for 88% and 68% of the total mtDNA in his muscle and blood, respectively. Molecular studies in blood from 16 maternal relatives identified lower percentages of the mutation only in the oligo-symptomatic mother and brother. This case reinforces the notion that cardiomyopathy can be the presenting and predominant clinical expression of the A3243G mutation.

Acidosis, Lactic↗
PubMed1997

A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy.

We describe a childhood mitochondrial disorder in which the clinical symptoms began and remained confined to the gastrointestinal (GI) system during the first 4 y. Seizures heralded the onset of progressive encephalopathy at age 7. Peripheral neuropathy, retinitis pigmentosa, and neural deafness developed subsequently. Laboratory investigations disclosed elevated levels of plasma lactate, and a muscle biopsy revealed ragged red fibers lacking cytochrome c oxidase activity and diminished levels of respiratory chain enzyme complexes. Molecular genetic tests failed to show any of the previously reported pathogenic mitochondrial DNA (mtDNA) mutations. We therefore screened the whole mitochondrial genome by coupling restriction digestions with single-strand conformational polymorphism (SSCP) patterns. We identified a unique SSCP in the segment that encompassed the tRNA(Lys) gene, and direct sequencing of this segment revealed a G-->A transition at an evolutionarily conserved nucleotide at mtDNA position 8313. This G8313A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in the white blood cells and platelets from his maternal relatives. This report illustrates how GI symptoms can be the initial manifestation in a mitochondrial disorder and suggests that mitochondrial dysfunction should be considered in differentials of unexplained chronic GI symptoms, especially when lactic acidosis or other unrelated clinical signs or symptoms are present.

Adolescent↗
PubMed1997

Two large Spanish pedigrees with nonsyndromic sensorineural deafness and the mtDNA mutation at nt 1555 in the 12s rRNA gene: evidence of heteroplasmy.

We describe two unrelated Spanish families with isolated sensorineural hearing loss. In both pedigrees, the deafness was transmitted maternally, which suggested a mitochondrial, DNA (mtDNA) defect. Within the same pedigree, some relatives showed aminoglycoside-induced deafness, whereas others were not exposed to aminoglycosides before the onset of hearing loss. Molecular genetic analysis in both families showed the A-to-G transition at nt 1555 (A1555G) in the mitochondrial 12S rRNA gene. In one pedigree, the mutation was homoplasmic; in the other, it was heteroplasmic. To assess the frequency of this mutation, we screened 42 patients of various ethnic backgrounds with isolated sensorineural hearing loss; none harbored the A1555G mutation. This is the first report of heteroplasmy in a family with isolated sensorineural deafness associated with the A1555G mutation.

Amino Acid Sequence↗