Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy.

Long-term zidovudine therapy in patients with human immunodeficiency virus (HIV) infection can cause a destructive mitochondrial myopathy with histological features of ragged-red fibres (RRF) and proliferation of abnormal mitochondria. In 9 zidovudine-treated patients with this myopathy we found severely reduced amounts (up to 78% reduction vs normal adult controls) of mitochondrial DNA (mtDNA) in muscle biopsy specimens by means of Southern blotting. In 2 HIV-positive patients who had not received zidovudine, muscle mtDNA content did not differ from that in the 4 controls.

mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases.

We studied two related infants with a fatal mitochondrial disease, affecting muscle in one and liver in the other. Quantitative analysis revealed a severe depletion of mtDNA in affected tissues. This genetic abnormality was also observed in muscle of an unrelated infant with myopathy and in muscle and kidney of a fourth child with myopathy and nephropathy.

Replication-competent human mitochondrial DNA lacking the heavy-strand promoter region.

We identified two patients with progressive external ophthalmoplegia, a mitochondrial disease, who harbored a population of partially deleted mitochondrial DNA (mtDNA) with unusual properties. These molecules were deleted from mtDNA positions 548 to 4,442 and encompassed not only rRNA sequences but the heavy-strand promoter region as well. A 13-bp direct repeat was found flanking the breakpoint precisely, with the repeat at positions 535 to 547 located within the binding site for mitochondrial transcription factor 1 (mtTF1).

Polyglucosan body disease.

Adult polyglucosan disease has been described in 15 cases. All had signs of peripheral neuropathy, upper motor neuron signs, and 12 of the 15 had sphincter problems. Dementia was prominent in 8 of 15 cases.

Differential diagnosis of fatal and benign cytochrome c oxidase-deficient myopathies of infancy: an immunohistochemical approach.

To differentiate the 2 major myopathies of infancy due to cytochrome c oxidase (COX) deficiency, we studied muscle biopsies from 4 patients with fatal myopathy and 4 with benign myopathy using biochemical, histochemical, and immunohistochemical techniques. Immunohistochemistry with antibodies directed against individual subunits of COX differentiated the 2 phenotypes: the fatal infantile myopathy was characterized by absence of the nuclear DNA (nDNA)-encoded subunit VIIa,b of COX, while in the benign myopathy both VIIa,b and the mitochondrial DNA (mtDNA)-encoded subunit II were absent. Early differential diagnosis between fatal and benign COX-deficient myopathies is of critical importance for prognosis and management of these infants, because the benign form is initially life-threatening but ultimately reversible.

[Clinical and biochemical heterogeneity of childhood cytochrome C deficiency. Review of the literature].

The detailed clinical history of a patient with a partial cytochrome c oxidase (COX) deficiency, which was demonstrated both in muscle and liver tissues, is presented. The review of the 27 pediatric cases published shows the multisystemic involvement of this enzyme deficiency and its vast clinical heterogeneity. In addition to the classical findings (myopathy, Debré-DeToni-Fanconi syndrome and lactic acidosis), our patient presented: Neurosensorial hearing loss, feeding problems, failure to thrive and hypertrophic myocardiopathy.

An adult-onset myopathy characterized by a double ring appearance of muscle fibers.

We report a 33-yr-old man with an unusual neuromuscular disorder characterized by progressive generalized weakness of 3 yr duration whose muscle biopsy showed a double ring appearance in most muscle fibers. This double ring appearance was due to a peripheral outer sarcoplasmic mass and an inner ring of annular myofibrils surrounding a core of normal longitudinally oriented myofibrils. Nerve conduction studies were normal.

Mitochondrial encephalomyopathies: biochemical approach.

Thanks to recent advances in the molecular genetics of mitochondrial encephalomyopathies, we can now begin to correlate genetic lesions with biochemical defects. In the fatal infantile myopathy due to cytochrome c oxidase (COX) deficiency, an autosomal recessive condition, immunocytochemical studies have shown an isolated defect of subunit VIIa, which is 1 of the only 2 tissue-specific subunits of human COX. In muscle biopsies from patients with Kearns-Sayre syndrome, a multisystem disorder characterized by deletions of the mitochondrial DNA (mtDNA), the activities of all mitochondrial enzymes containing mtDNA-encoded subunits are decreased.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

[Myopathy due to succinate cytochrome C oxidoreductase deficiency: possible defect of complex II of the respiratory chain].

The case of a 24 years-old woman with weakness since the teens and progressive loss of muscle strength is reported. The muscle biopsy showed increased number of mitochondria. In two occasions the respiratory chain enzymes showed important reduction of the succinate-cytochrome-C-reductase, suggesting a possible defect in the complex II of the respiratory chain.