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S DiMauro

Publications and source records attributed to S DiMauro.

At least 217 records · Page 12Linked to original sources
PubMed1993

Cytochrome C oxidase deficiency and neuronal involvement in Menkes' kinky hair disease: immunohistochemical study.

Antibodies against subunits II and IV of cytochrome c oxidase (COX) and against complex III of the respiratory chain were used to study the expression of these proteins in the cerebellum, spinal cord, and other regions of the central nervous system in an autoptic case of Menkes' kinky hair disease (MKHD). We found a reduced expression of COX subunits in all examined areas whereas staining for complex III appeared normal. Immunostaining was altered in morphologically well-preserved neurons, suggesting that COX deficiency may have a pathogenetic role in the neuronal degeneration of MKHD.

Antibodies, Monoclonal↗
PubMed1993

Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot?

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease.

Adult↗
PubMed1993

Valproic acid impairs carnitine uptake in cultured human skin fibroblasts. An in vitro model for the pathogenesis of valproic acid-associated carnitine deficiency.

The mechanisms of valproate-associated carnitine deficiency are controversial. The urinary excretion of valproylcarnitine is insufficient to account for tissue carnitine depletion. To explore this mechanism, we studied the effects of valproic acid (VPA) on carnitine uptake in cultured human skin fibroblasts by the method of Tein et al. (Pediatr Res 28:247-255, 1990). Fibroblasts were preincubated with varying concentrations (0-2000 microM) of VPA for 1, 3, 5, 7, 10, 14, 21, and 28 d and then incubated with fixed carnitine concentrations of 50 microM (normal physiologic concentration), 20 microM (as seen in secondary carnitine deficiency disorders), or 5 microM (as seen in the plasma membrane carnitine transport defect). There was an exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations, and the relative inhibitory effect was the same for all three carnitine concentrations. The mean percentages +/- SD (n-1) of residual carnitine uptake for all combined preincubation periods (1-28 d) and combined carnitine concentrations (5, 20, and 50 mumol/L) with increasing concentrations of VPA varied from 83.4 +/- 2.6% (10 microM VPA) to 56.7 +/- 0.1% (500 microM) to 19.8 +/- 1.3% (2000 microM). The degree of inhibition was directly proportional to the time of VPA preincubation and parallel for all three carnitine concentrations; the longer the preincubation period, the lower the toxic dose of VPA (to a minimum of 450 microM), resulting in a 50% suppression of carnitine uptake (TD50).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1993

Phosphoglycerate kinase deficiency: biochemical and molecular genetic studies in a new myopathic variant (PGK Alberta)

Biochemical analysis of muscle in a 37-year-old man with exercise intolerance, myalgia, recurrent myoglobinuria, and retinitis pigmentosa showed phosphoglycerate kinase (PGK) deficiency. Kinetic and physical characteristics of the mutant enzyme differed from those of two previously reported cases, suggesting a distinct mutation. Southern blot analysis showed similar bands in patient and control, but Northern blot analysis of muscle mRNA showed an abnormally large message. These data demonstrate that PGK deficiency is clinically, biochemically, and genetically heterogeneous.

Adult↗
PubMed1993

Polyglucosan body disease simulating amyotrophic lateral sclerosis.

We describe two patients with polyglucosan body disease (PBD) with the clinical features of atypical amyotrophic lateral sclerosis (ALS). Patient 1 was demented, and patient 2, of Ashkenazi background, was incontinent of urine. Autopsy of patient 1 revealed diffuse CNS accumulations of polyglucosan bodies (PB) localized primarily in neuronal and astrocytic processes and rarely in neuronal perikarya. PB were present in peripheral nerve and myocardium. Brancher enzyme analysis of nerve and muscle was normal. Patient 2's sural nerve biopsy showed PB. Brancher activity was markedly reduced in nerve but not in leukocytes. Previous reports have shown reduced leukocyte brancher activity in Ashkenazi patients with PBD. Clinically, pathologically, and biochemically, PBD is heterogeneous and may include patients presenting with ALS. Cases in which typical pathologic features of PBD are combined with findings of rare PB in neural perikarya may represent a pathologic variant of PBD. Brancher enzyme activity may be normal or only mildly reduced in leukocytes in Ashkenazi patients with PBD, implying genetic heterogeneity.

1,4-alpha-Glucan Branching Enzyme↗
PubMed1993

Clinical features associated with the A-->G transition at nucleotide 8344 of mtDNA ("MERRF mutation").

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.

Adult↗
PubMed1993

The molecular genetic basis of muscle phosphoglycerate mutase (PGAM) deficiency.

The glycolytic enzyme phosphoglycerate mutase (PGAM) is a dimer, and mature human skeletal muscle contains almost exclusively the MM form of the enzyme, PGAM-M. In 1981, we identified a patient with PGAM-M deficiency, and three additional patients have since been described. All presented with exercise intolerance, cramps, and myoglobinuria. We report two new patients with PGAM-M deficiency and describe the molecular lesions in five patients--four African-Americans and one Caucasian. Three patients were homozygous for an identical G-to-A transition converting an encoded Trp to an in-frame stop codon (codon 78). A fourth patient was heterozygous for this mutation and also carried an A-to-C mutation converting Glu to Ala (codon 89). The fifth patient, the only Caucasian, was homozygous for a different point mutation, a C-to-T mutation, converting Arg to Trp (codon 90).

Adolescent↗
PubMed1992

Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR.

We have developed a quantitative PCR technique to measure the amount of a specific mitochondrial DNA deletion (delta mtDNA), the so-called 'common deletion', in human tissues. Using this method, we estimate that there is a 10,000-fold increase in this delta mtDNA species in muscle during the course of the normal human lifespan. The maximum amount of common deletion observed in aged muscle was approx. 0.1%. Tissues that turn-over slowly, such as skeletal muscle and heart, contained more delta mtDNA than more rapidly dividing tissues, such as liver, in agreement with studies performed by others.

Aging↗
PubMed1992

Use of single strand conformation polymorphism analysis to detect point mutations in human mitochondrial DNA.

Myoclonus epilepsy with ragged-red fibers (MERRF) has been shown to be associated with a specific point mutation at the nucleotide 8344 in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). We screened 6 patients with clinically diagnosed MERRF and 1 patient with ocular myopathy for point mutations in the tRNA(Lys) gene, using single strand conformation polymorphism (SSCP) analysis, which can detect even a 1-basepair difference between 2 DNA sequences. Using SSCP and consequent DNA sequencing, we identified the known MERRF mutation in 4 out of 6 MERRF patients, as well as in 1 patient with a new clinical phenotype associated with this mutation: progressive external ophthalmoplegia, muscle weakness and a lipoma, but no myoclonus or epilepsy. Two of the patients with clinical MERRF had neither the MERRF-mutation nor any other mutations in the tRNA(Lys) gene. Using SSCP analysis, we also detected a new polymorphism in 1 patient. Thus, SSCP analysis can be applied to search effectively and rapidly for point mutations or polymorphisms in mitochondrial DNA.

Adolescent↗
PubMed1992

Correlation between clinical and molecular features in two MELAS families.

We describe the clinical, morphological, biochemical presentation in two MELAS families, and correlate it with the distribution and proportion of mitochondrial DNA carrying the A to G transition at nt 3243. Family A was characterized by late onset MELAS in two members, CPEO in one, and mild CNS involvement in another. 20-61% of mtDNA of affected and unaffected individuals was mutated in muscle, 2-18% in blood. There was no obvious correlation between clinical picture and proportion of mutated mtDNA. In family B full MELAS syndrome appeared only in the third generation, but the mutation was also detected in muscle of asymptomatic individuals of the first and second generation. The proportion of mutated mtDNA in blood, and to a lesser extent in muscle, correlated with the severity of the clinical presentation. The MELAS mutation is consistently detected in all asymptomatic maternal relatives of MELAS patients. We conclude that different clinical presentations of mitochondrial encephalomyopathy may coexist in the same family, and correlation between clinical severity and molecular abnormality is not always recognizable. Presence of the MELAS mutation in muscle and blood is a necessary but not sufficient condition for the expression of the typical MELAS phenotype.

Adult↗
PubMed1992

Melas: an original case and clinical criteria for diagnosis.

We describe the full history and postmortem findings in one of the first identified cases of mitochondrial encephalomyopathy with stroke-like episodes (MELAS). To clarify diagnostic criteria, we analyzed 69 reported cases. The syndrome should be suspected by the following three invariant criteria: (1) stroke-like episode before age 40 yr; (2) encephalopathy characterized by seizures, dementia, or both; and (3) lactic acidosis, ragged-red fibers (RRF), or both. The diagnosis may be considered secure if there are also at least two of the following: normal early development, recurrent headache, or recurrent vomiting. There are incomplete syndromes in relatives of patients with the full syndrome and incomplete syndromes might also be encountered in sporadic cases. Some MELAS patients have features of the Kearns-Sayre syndrome (KSS) or myoclonic epilepsy with ragged-red fibers (MERRF), but none had the full KSS syndrome. In partial or confusing cases, analysis of mitochondrial DNA (mtDNA) may point to the correct diagnosis; however, not all patients with clinical MELAS have had the typical mtDNA point mutation and some patients with the mutation have clinical syndromes other than MELAS.

Brain↗
PubMed1992

Polysaccharide storage myopathy associated with recurrent exertional rhabdomyolysis in horses.

A polysaccharide storage myopathy is described in nine Quarterhorses, Quarterhorse crossbreds, American Paints and Appaloosa horses which had a history of recurrent exertional rhabdomyolysis. Muscle biopsies were characterized by high muscle glycogen concentrations with up to 5% of type 2 muscle fibers containing inclusions which stained positively with the periodic acid Schiff (PAS) stain. The inclusions were classified as an acid mucopolysaccharide, based on their histochemical staining characteristics. Ultrastructural studies revealed that the inclusions were composed of beta glycogen particles interspersed among arrays of filamentous material. In addition, many type 2 fibers contained multiple subsarcolemmal vacuoles. These vacuoles stained lightly with eosin and did not stain positively with PAS. Centrofascicular atrophy and necrosis of scattered type 2 fibers were present in biopsies from some horses. No glyco(geno)lytic enzyme deficiencies were identified using a biochemical screening test for anaerobic glycolysis. Attempts to measure branching enzyme activities in both affected and control samples were unsuccessful, employing methods developed for human muscle. The polysaccharide accumulation in these horses may represent a hereto yet undefined metabolic disorder of skeletal muscle.

Animals↗
PubMed1992

Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions.

Large-scale deletions of mitochondrial DNA (mtDNA) are associated with a subgroup of mitochondrial encephalomyopathies. We studied seven patients with Kearns-Sayre syndrome or isolated ocular myopathy who harboured a sub-population of partially-deleted mitochondrial genomes in skeletal muscle. Variable cytochrome c oxidase (COX) deficiencies and reduction of mitochondrially-encoded polypeptides were found in affected muscle fibres, but while many COX-deficient fibres had increased levels of mutant mtDNA, they almost invariably had reduced levels of normal mtDNA. Our results suggest that a specific ratio between mutant and wild-type mitochondrial genomes is the most important determinant of a focal respiratory chain deficiency, even though absolute copy numbers may vary widely.

Blotting, Southern↗
PubMed1992

Disorders associated with depletion of mitochondrial DNA.

Quantitative defects of mtDNA have been recently described in patients with fatal mitochondrial disease of early infancy or mitochondrial myopathy of childhood. There was variable tissue expression and depletion of up to 98% of mtDNA in affected tissues. Pedigree analysis was compatible with mendelian inheritance, suggesting faulty communication between nuclear and mitochondrial genomes, but the primary molecular lesion is unknown. In muscle, morphological studies allowed to correlate mtDNA depletion, absence of mtDNA-encoded peptides, mitochondrial proliferation, and loss of cytochrome c oxidase (COX) activity in individual fibers.

Acquired Immunodeficiency Syndrome↗