A defect in pyruvate decarboxylase in a child with an intermittent movement disorder
01 Mar 1970-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 49, Iss: 3, pp 423-432
TL;DR: Kinetic data suggested the posibility of several forms of pyruvate decarboxylase in this family, and possible mechanisms relating the chemical abnormality and the clinical symptoms in this patient are discussed.
Abstract: A patient with an intermittent movement disorder has been found to have an inherited defect in pyruvate decarboxylase ((2-oxo-acid carboxy-lyase, E.C. 4.1.1.1.). The patient is a 9 yr old boy who since infancy has had repeated episodes of a combined cerebellar and choreoathetoid movement disorder. He has an elevated level of pyruvic acid in his blood, an elevated urinary alanine content, and less marked elevations in blood alanine and lactate. Methods were developed to study his metabolic abnormality in dilute suspensions of white blood cells and cultured skin fibroblasts, as well as in cell-free sonicates of fibroblasts. Oxidation of pyruvic acid-1-(14)C and pyruvic acid-2-(14)C by his cells and pyruvate decarboxylase activity in sonicates of his cells were less than 20% of those in cells from control subjects. Oxidation of glutamic acid-U-(14)C, acetate-1-(14)C, and palmitate-1-(14)C was normal, as was incorporation of alanine-U-(14)C into protein. The rate of oxidation of pyruvic acid by the father's cells and the activity of pyruvate decarboxylase in the father's sonicated fibroblasts were intermediate between those of the patient and those of controls. Values for the mother were at or just below the lower limits of the ranges in controls. Kinetic data suggested the posibility of several forms of pyruvate decarboxylase in this family. Possible mechanisms relating the chemical abnormality and the clinical symptoms in this patient are discussed.
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TL;DR: A glucose-alanine cycle in which alanine is formed peripherally by transamination of glucose-derived pyruvate and transported to the liver where its carbon skeleton is reconverted to glucose is suggested.
Abstract: Alanine is quantitatively the primary amino acid released by muscle and extracted by the splanchnic bed in postabsorptive as well as prolonged fasted man. The hepatic capacity for conversion of alanine to glucose exceeds that of all other amino acids. Insulin inhibits gluconeogenesis by reducing hepatic alanine uptake. In contrast, in diabetes, an increase in hepatic alanine extraction is observed in the face of diminished circulating substrate. In prolonged fasting, diminished alanine release is the mechanism whereby gluconeogenesis is reduced. In circumstances in which alanine is deficient, such as pregnancy and ketotic hypoglycemia of infancy, fasting hypoglycemia is accentuated. Augmented glucose utilization in exercise and hyperpyruvicemia consequent to inborn enzymatic defects are accompanied by increased circulating levels of alanine. These data thus suggest the existence of a glucose-alanine cycle in which alanine is formed peripherally by transamination of glucose-derived pyruvate and transported to the liver where its carbon skeleton is reconverted to glucose. The rate of recycling of glucose carbon skeletons in this pathway appears to occur at approximately 50% of that observed for the Cori (lactate) cycle.
694 citations
Book•
01 Apr 1991
TL;DR: This booklet discusses Vestibular Nerve and Labyrinthine Disorders and Vertigo in Childhood, as well as non-Vestibular Vertigo Syndromes, and discusses the role of drugs and psychogenic Vertigo.
Abstract: Contents: Vestibular Nerve and Labyrinthine Disorders.- Central Vestibular Disorders.- Positional Vertigo.- Vascular Vertigo.- Traumatic Vertigo.- Familial Vertigo and Vertigo in Childhood.- Drugs and Vertigo.- Non-Vestibular Vertigo Syndromes.- Psychogenic Vertigo.- Physiological Vertigo.- Subject Index.
381 citations
TL;DR: The first myopathy was demonstrated only 35 years ago as discussed by the authors, and the list continues to grow, and the field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA.
Abstract: Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.
292 citations
TL;DR: The findings suggest that the mtDNA nt 8993 mutation is a relatively common cause of Leigh's syndrome, and a good correlation between percentage of mutant mitochondrial genomes and severity of the clinical phenotype is revealed.
Abstract: Twelve patients with Leigh's syndrome from 10 families harbored a T > G point mutation at nt 8993 of mtDNA. This mutation, initially associated with neurogenic weakness, ataxia, and retinitis pigmentosa, was later found to result in the Leigh phenotype when present in a high percentage. In our patients, the mutation was heteroplasmic, maternally inherited, and appeared to segregate rapidly within the pedigrees. Quantitative analysis revealed a good correlation between percentage of mutant mitochondrial genomes and severity of the clinical phenotype. The mutation was not found in > 200 patients with other mitochondrial encephalomyopathies or in controls. Mitochondrial enzyme activities were normal in all but 1 patient, and there were no ragged-red fibers in the muscle biopsy. Lactic acidosis was present in 92% of patients. Our findings suggest that the mtDNA nt 8993 mutation is a relatively common cause of Leigh's syndrome.
243 citations
TL;DR: Although the clinical spectrum of PDC deficiency is broad, the dominant clinical phenotype includes presentation during the first year of life; neurological and neuromuscular degeneration; lactic acidosis and a blood lactate:pyruvate ratio ≤20.
226 citations
Cites background from "A defect in pyruvate decarboxylase ..."
...A few papers reported complimentary details of the same patient [6,24,32,38,40,41,45,47,49,66,69,75,77,80,83,84,96,97,103,105, 112,114,129]....
[...]
...Although over 40 years have elapsed since the first description of a congenital deficiency of the PDC [6], the incidence and prevalence of this life-threatening condition remain unknown....
[...]
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TL;DR: The measurement of SGP-T alterations has been found to be a useful tool in the diagnosis and study of acute hepatic disease and appears to be more sensitive than SGO-T in depicting acute hepatocellular damage.
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753 citations
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