1/89. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.- - - - - - - - - - ranking = 1keywords = myopathy (Clic here for more details about this article) |
2/89. lipomatosis, proximal myopathy, and the mitochondrial 8344 mutation. A lipid storage myopathy?Multiple symmetric lipomatosis (MSL) has been related in some cases to the 8344 point mutation of the tRNA-lysine gene of the mitochondrial DNA, mainly in the context of families with classic myoclonic epilepsy with ragged-red fibers (MERRF) and exceptionally in patients with proximal myopathy as the only manifestation of mitochondrial disease. We report on two families harboring the 8344 mutation. The patients presented with MSL and myopathy, expressed as limb girdle weakness in index cases and as exercise intolerance in the others. All muscle biopsies performed showed lipid storage apart from RRF and respiratory chain complexes deficiency. A possible explanation for both adipose proliferation and lipid storage myopathy in these cases is a disturbance in intermediary lipid metabolism secondary to mitochondrial respiratory chain deficiency that could be related via carnitine deficiency.- - - - - - - - - - ranking = 2.2keywords = myopathy (Clic here for more details about this article) |
3/89. A new mtDNA mutation associated with a progressive encephalopathy and cytochrome c oxidase deficiency.The authors describe a novel pathogenic G5540A transition in the mitochondrial transfer rna (tRNA)Trp gene of a sporadic encephalomyopathy characterized by spinocerebellar ataxia. Clinical features also included neurosensorial deafness, peripheral neuropathy, and dementia. biochemistry revealed a severe reduction of cytochrome c oxidase (COX) activity. Single-fiber PCR demonstrated higher levels of mutant genomes in COX-negative ragged red fibers than in normal fibers. These findings confirm that COX is more susceptible than other respiratory chain complexes to mutations in the mitochondrial tRNATrp gene.- - - - - - - - - - ranking = 0.2keywords = myopathy (Clic here for more details about this article) |
4/89. pregnancy with cytochrome oxidase-deficient mitochondrial myopathy.BACKGROUND: Cytochrome oxidase-deficient mitochondrial myopathies represent a heterogeneous group of muscle disorders. Physical stress can cause life-threatening risks related to rhabdomyolysis or respiratory compromise. CASE: A 21-year-old primigravida with cytochrome C oxidase-deficient mitochondrial myopathy who presented for obstetric care at 8 weeks' gestation complained of muscle fatigue and spasm after exertion. The increased metabolic demands of pregnancy led to worsening pain, muscle fatigue, and ultimately complete immobility. CONCLUSION: Cytochrome oxidase-deficient mitochondrial myopathies are rare but serious complications of pregnancy.- - - - - - - - - - ranking = 1keywords = myopathy (Clic here for more details about this article) |
5/89. Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease.BACKGROUND: Mutations in the SCO2 gene have been associated with fatal cardioencephalomyopathy. OBJECTIVE: To report a novel SCO2 mutation with prominent spinal cord involvement mimicking spinal muscular atrophy (Werdnig-Hoffmann disease). PATIENT AND methods: An infant girl presented at birth with generalized weakness, hypotonia, and lactic acidosis. At 1 month of age she developed hypertrophic cardiomyopathy and died of heart failure 1 month later. Neuroradiological studies were unremarkable. Muscle biopsy specimens showed groups of atrophic and hypertrophic fibers, but mutation screening of the SMN gene was negative. Histochemical and biochemical studies of respiratory chain complexes were performed, and the whole coding region of the SCO2 gene was sequenced. RESULTS: Findings from muscle histochemistry studies showed virtually undetectable cytochrome c oxidase activity, but normal succinate dehydrogenase reaction. Biochemical analysis in muscle confirmed a severe isolated cytochrome c oxidase deficiency. Pathologic findings of the brain were unremarkable, but the ventral horns of the spinal cord showed moderate-to-severe loss of motor neurons and astrocytosis. Sequencing of the SCO2 gene showed the common E140K mutation, and a novel 10 base-pair duplication of nucleotides 1302 to 1311, which disrupts the reading frame of the messenger rna and gives rise to a truncated protein. CONCLUSION: The SCO2 mutations should be considered in the differential diagnosis of children with spinal muscular atrophy without mutations in the SMN gene.- - - - - - - - - - ranking = 0.4keywords = myopathy (Clic here for more details about this article) |
6/89. Severe mitochondrial cytopathy with complete A-V block, PEO, and mtDNA deletions.We describe a 17-year-old male with neurologic and cardiovascular disorders characterized by complete atrioventricular block and a mitochondrial cytopathy with clinical, structural, biochemical, and molecular features shared by chronic progressive external ophthalmoplegia and kearns-sayre syndrome. The patient's manifestations included progressive external ophthalmoplegia, bilateral ptosis, muscle weakness, delayed development, and progressive hearing loss with multiple mitochondrial DNA deletions, including an abundant 11-kb novel deletion and reduced specific activities of respiratory complexes I, III, and IV present in skeletal muscle. Ultrastructural analysis of biopsied muscle revealed a heterogenous mixture of normal and abnormal mitochondria with unusual cristae. This unique mitochondrial DNA deletion, which eliminates the origin of mitochondrial dna replication for the light strand, may be responsible for generating an intermediate clinical phenotype.- - - - - - - - - - ranking = 0.46204059232403keywords = ophthalmoplegia (Clic here for more details about this article) |
7/89. The length of cytochrome c oxidase-negative segments in muscle fibres in patients with mtDNA myopathy.Heteroplasmic mitochondrial DNA mutations often cause a skeletal myopathy associated with a mosaic distribution of cytochrome c oxidase-deficient muscle fibres. The function of an individual muscle fibre is dependent upon the metabolic activity throughout its length, but little is known about the length of cytochrome c oxidase-deficient segments in human skeletal muscle in patients with mitochondrial disease. We studied cytochrome c oxidase activity by serial section analysis of quadriceps muscle from two patients. We observed a striking variation in the length of the cytochrome c oxidase-negative segments. The shortest segments were 10 microm long, and the longest segment was the entire length of the larger biopsy (> or =1.2 mm). The lengths of the cytochrome c oxidase-negative segments were generally shorter in the less severely affected biopsy, and we frequently observed non-contiguous segments of cytochrome c oxidase deficiency within the same muscle fibre. The findings have important implications for our understanding of the pathogenesis and progression of mitochondrial DNA myopathy.- - - - - - - - - - ranking = 1.2keywords = myopathy (Clic here for more details about this article) |
8/89. The A8344G mutation in mitochondrial DNA associated with stroke-like episodes and gastrointestinal dysfunction.We report an unusual case of encephalo-entero-myopathy associated with the A8344G mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). This patient had mitochondrial myopathy, multiple lipomatosis, mild hearing loss, stroke-like episodes, and paralytic ileus, but she lacked the canonical clinical features of MERRF, myoclonus, epilepsy, or ataxia. We conducted genetic, biochemical, histochemical, and immunohistochemical studies in skeletal muscle, brain, intestine, and lipoma tissue. The mutation was abundant in all tissues, and cytochrome c oxidase (COX) activity was selectively decreased in brain and small intestine. COX deficiency was also documented histochemically and immunohistochemically in the small intestine, suggesting that mitochondrial dysfunction played a role in the pathogenesis of paralytic ileus. This case illustrates an unusual and dramatic clinical phenotype of the A8344G mutation, characterized by stroke-like episodes and acute ileus.- - - - - - - - - - ranking = 0.4keywords = myopathy (Clic here for more details about this article) |
9/89. Cytochrome C oxidase-deficient mitochondria in mitochondrial myopathy.Electron microscopic cytochemistry was used to evaluate the behavior of cytochrome c oxidase (COX) in cultured skin fibroblasts from 4 patients with decreased COX activity (Leigh encephalopathy, fatal infantile COX deficiency). In patients with Leigh encephalopathy, all mitochondria reacted to COX staining either equivocally or negatively, indicating that all mitochondria were abnormal in these patients. In 1 patient with fatal infantile COX deficiency, intercellular heterogeneity of mitochondria was observed by COX staining. In another patient with fatal infantile COX deficiency, intracellular heterogeneity of mitochondria was observed. patients with Leigh encephalopathy appeared to have a different type of mitochondrial COX deficiency than those with fatal infantile COX deficiency. Our result suggest that these 2 diseases may result from different genetic mechanisms.- - - - - - - - - - ranking = 0.8keywords = myopathy (Clic here for more details about this article) |
10/89. Defects of the mitochondrial respiratory chain complexes in three pediatric cases with hypotonia and cardiac involvement.Three children displaying hypotonia, cardiac involvement and defects of the mitochondrial respiratory chain complexes are reported. The first case showed severe neonatal hypotonia, failure to thrive, hepatomegaly, dilation of the right cardiac cavities, profound lactic acidosis and amino aciduria. The boy died at the age of 7 weeks. In the second case hypotonia, severe cardiomyopathy, cyclic neutropenia, lactic acidosis and 3-methylglutaconic aciduria occurred. The boy died at the age of 27 months. The third case presented at the age of 16 months as an acute hypokinetic hypertrophic cardiomyopathy with transient hypotonia and mild lactic acidosis. Spontaneous clinical remission occurred. In all cases muscle biopsy was performed. Morphological studies failed to show ragged-red fibers but there was lipid storage myopathy and decreased cytochrome c oxidase activity. Biochemical studies confirmed the cytochrome c oxidase deficiency in muscle in all cases. It was associated with complex I III deficiency in case 1 and with severe deficits of all respiratory chain complexes in case 2. Post-mortem studies in case 1 indicated that complex IV was reduced in the liver but not in the heart and quantitative analysis of mtDNA revealed a depletion in muscle. Cases 1 and 2 shared some clinical features with fatal infantile myopathy associated with cytochrome c oxidase deficiency, while case 3 displayed a very unusual clinical presentation. The histochemical enzyme reaction of cytochrome c oxidase is useful for the diagnosis of mitochondrial myopathy because ragged-red fibers may be lacking. Finally, biochemical measurement of the different mitochondrial respiratory chain complexes is required because multiple defects are frequent and occasionally related to mtDNA depletion.- - - - - - - - - - ranking = 1keywords = myopathy (Clic here for more details about this article) |
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