Multiple genotypes, multiple phenotypes, and partial defects

Kark, Ruth; Becker, David M.

doi:10.1002/mus.880040107

Cited by 8 publications

(3 citation statements)

References 48 publications

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“…If there is still some residual enzyme activity, it may be sufficient to degrade most of the substrate, giving rise to a less severe form of the disease, with late onset and slow evolution. Clinical symptoms can also be linked to the speed with which the substrate enters the various organs or types of cells: low residual enzyme activity may suffice to prevent accumulation in one cell type whereas in another it is synthesized more quickly and the same residual activity may not be sufficient [27], This data suggests the existence of a complex system of biochemical and molecular regulation of enzyme ac tivity which may be impaired in different ways in earlyand late-onset disease. Enzyme activity may be impaired in many ways.…”

Section: Pathogenesis Of Latc-onset Genetic Encephaloneuromyopathiesmentioning

confidence: 93%

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Federico¹

1991

Dev Neurosci

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The strategy of clinical investigations for the diagnosis of the late-onset neurometabolic diseases is reported. The criteria for the diagnostic suspicion are inheritance and multisystem involvement. The different clinical signs that are the basis for further biological investigations are reviewed. The diagnostic confirmation will be obtained by laboratory analyses, some of which can be easily performed in all hospitals. The pathogenesis of late-onset neurometabolic encephaloneuromyopathies and the clinical consequences of heterozygosity are reported. Finally these disorders are discussed as a useful model for understanding the pathogenesis of some of the most common neurological diseases and of the normal functions of many molecules in the nervous system.

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Section: Pathogenesis Of Latc-onset Genetic Encephaloneuromyopathiesmentioning

confidence: 93%

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Federico¹

1991

Dev Neurosci

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“…The mother and daughter presented in this paper may Clark, Hayes, Morgan-Hughes and Byrne imply maternal inheritance, although two other sisters, whilst showing slight muscle weakness, have muscle carnitine levels within the normal range. However, the phenotypic expression of the defect may be dependent upon the number of mutant DNA molecules in anyone cell/tissue (see Howell, 1983) or the defect may give rise to an activity which, although impaired, is still sufficient to provide for the 'critical flux' of the pathway in question (Kark and Becte, 1981). Another consideration raised by the mother/daughter study presented in this paper is that if their defect is maternally inherited then some translation product essential for the functional integrity ofcomplex I (Ragan, 1976) and/or thefatty acylcarnitine system must be coded for by mt DNA.…”

Section: Defect Referencesmentioning

confidence: 99%

Mitochondrial myopathies: Disorders of the respiratory chain and oxidative phosphorylation

Clark

Hayes

Morgan‐Hughes

et al. 1984

J of Inher Metab Disea

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Mitochondrial myopathies are a clinical condition characterized by muscle weakness and fatigue in which the primary defect is localized at the level of the mitochondria. Microscopic examination shows accumulations of mitochondria at the fibre periphery (ragged red fibres) and in some cases mitochondrial paracrystalline inclusions. The spectrum of different mitochondrial defects so far described is reviewed and data from cases investigated in this laboratory are described. The first case was a 17-year-old boy with a multisystem disorder whose muscle mitochondria showed low respiratory activity with all substrates, which doubled in the presence of uncoupler. Further investigation showed that the mitochondrial ATPase activity was only 6% of normal. The next cases were a mother and daughter who showed a typical lipid storage myopathy. The latter was treated successfully with oral carnitine but the myopathy persisted. Mitochondrial investigations indicated a low respiratory activity with NAD-linked substrates but normal activity with succinate and ascorbate + TMPD. A defect in the NADH-CoQ reductase section of the respiratory chain was pinpointed possibly at an iron-sulphur centre. The fourth and fifth cases were two sisters who exhibited no lipid storage myopathy but whose mitochondrial activity was low with NAD-linked substrates but normal with succinate. Again a defect in the NADH-CoQ reductase (complex I) of the respiratory chain was determined. They were also investigated using 31P-NMR. It was found after exercise that their muscle creatine phosphate levels took seven times longer to return to pre-exercise concentrations than control subjects. These results are discussed with respect to the synthesis of mitochondrial proteins and the influence that both the mitochondrial and nuclear DNA have on this process.

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Section: Defect Referencesmentioning

confidence: 99%

Mitochondrial Myopathies: Disorders of the Respiratory Chain and Oxidative Phosphorylation

et al. 1984

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Mitochondrial myopathies are a clinical condition characterized by muscle weakness and fatigue in which the primary defect is localized at the level of the mitochondria. Microscopic examination shows accumulations of mitochondria at the fibre periphery (ragged red fibres) and in some cases mitochondrial paracrystalline inclusions. The spectrum of different mitochondrial defects so far described is reviewed and data from cases investigated in this laboratory are described. The first case was a 17-year-old boy with a multisystem disorder whose muscle mitochondria showed low respiratory activity with all substrates, which doubled in the presence of uncoupler. Further investigation showed that the mitochondrial ATPase activity was only 6 %of normal. The next cases were a mother and daughter who showed a typical lipid storage myopathy. The latter was treated successfully with oral carnitine but the myopathy persisted. Mitochondrial investigations indicated a low respiratory activity with NAD-linked substrates but normal activity with succinate and ascorbate + TMPD. A defect in the NADH-CoQ reductase section of the respiratory chain was pinpointed possibly at an iron-sulphur centre. The fourth and fifth cases were two sisters who exhibited no lipid storage myopathy but whose mitochondrial activity was low with NAD-linked substrates but normal with succinate. Again a defect in the NADH-CoQ reductase (complex I) ofthe respiratory chain was determined. They were also investigated using 31 P-NMR. It was found after exercise that their muscle creatine phosphate levels took seven times longer to return to pre-exercise concentrations than control subjects.These results are discussed with respect to the synthesis of mitochondrial proteins and the influence that both the mitochondrial and nuclear DNA have on this process.Journal ofInherited Metabolic Disease. ISSN 0141-8955.

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Multiple genotypes, multiple phenotypes, and partial defects

Cited by 8 publications

References 48 publications

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Diagnosis and Pathogenesis of Late-Onset Genetic Metabolic Encephaloneuromyopathies

Mitochondrial myopathies: Disorders of the respiratory chain and oxidative phosphorylation

Mitochondrial Myopathies: Disorders of the Respiratory Chain and Oxidative Phosphorylation

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