Biomedical subjects

S DiMauro

Publications and source records attributed to S DiMauro.

At least 325 records · Page 18Linked to original sources

PubMed1985

Fatal infantile cytochrome c oxidase deficiency: decrease of immunologically detectable enzyme in muscle.

A 2-month-old boy had progressive generalized weakness, hypotonia, and respiratory insufficiency requiring assisted ventilation. At age 3 1/2 months, he started having seizures and recurrent pulmonary infections; he died at age 7 months. Serum lactate was chronically elevated, but there was no aminoaciduria. Histochemical and ultrastructural studies of muscle biopsies at ages 2 and 3 months showed excessive mitochondria, lipid, and glycogen; a third biopsy at 6 months showed marked increase in perimysial fibrous and fat tissue. Cytochrome c oxidase activity was 7% of normal in the first biopsy and undetectable in the others. Cytochrome spectra of mitochondria isolated from postmortem muscle showed complete lack of cytochrome aa3. Antibodies were obtained against cytochrome c oxidase purified from normal human heart. Immunotitration and enzyme-linked immunosorbent assay (ELISA) showed decreased immunologically reactive enzyme protein in the patient's muscle, but SDS-PAGE electrophoresis of immunoprecipitates of muscle mitochondrial extracts showed the presence of all cytochrome c oxidase subunits. These data suggest that decreased synthesis of one or more subunits may result in markedly decreased concentration of electrophoretically normal complex IV in skeletal muscle.

Cytochrome-c Oxidase Deficiency↗

PubMed1985

Physiologic assessment of phosphoglycerate mutase deficiency: incremental exercise test.

A third case of phosphoglycerate mutase (PGAM) deficiency, a metabolic myopathy involving terminal glycolysis, was identified in a 24-year-old black man with episodic, exercise-induced myoglobinuria since age 13. To better understand the physiologic consequences of PGAM deficiency, incremental exercise testing was performed. Results were compared with those of two patients having myophosphorylase deficiency and five normals. In contrast to the patients with phosphorylase deficiency, the PGAM-deficient patient achieved near-normal levels of maximal exercise and produced a normal peak lactate after exercise. The mechanisms underlying the asymptomatic performance of such strenuous exercise in this case are uncertain, but the data suggest that unidentified factors are operative in precipitating attacks of myoglobinuria in patients with some metabolic myopathies. Despite similar clinical histories, patients with different glycolytic enzyme deficiencies can have striking differences in exercise tolerance.

Adult↗

PubMed1984

Clinical varieties of neuromuscular disease in debrancher deficiency.

Two men and one woman with debrancher deficiency had symptoms and signs of neuromuscular disease. The two men had adult-onset and slowly progressive weakness, distal muscle wasting, "mixed" electromyographic patterns, and slow nerve conduction velocities; the initial diagnosis was Charcot-Marie-Tooth disease in one patient and motor neuron disease in the other. The woman had stunted growth, delayed motor milestones, and lifelong nonprogressive weakness. A muscle biopsy specimen showed severe vacuolar myopathy in all three cases. The glycogen concentration was increased threefold to sixfold and had an abnormal iodine spectrum. Anaerobic glycolysis in vitro showed impaired use of endogenous and exogenous glycogen but normal use of hexose-phosphate glycolytic intermediates. These three cases illustrated the clinical variety of neuromuscular disease in debrancher deficiency. In patients with weakness of adult onset, the diagnosis is impossible to make without performing a muscle biopsy.

Adult↗

PubMed1984

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome.

We report on two patients who have a mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent cerebral insults that resemble strokes (MELAS). These two and nine other reported patients share the following features: ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness. Lactic acidemia is a common finding. We believe that MELAS represents a distinctive syndrome and that it can be differentiated from two other clinical disorders that also are associated with mitochondrial myopathy and cerebral disease: Kearns-Sayre syndrome and the myoclonus epilepsy ragged red fiber syndrome. Existing information suggests that MELAS is transmitted by maternal inheritance. The ragged red fibers suggest an abnormality of the electron transport system, but the precise biochemical disorders in these three clinical syndromes remain to be elucidated.

Acidosis↗

PubMed1984

Phosphoglycerate kinase deficiency myopathy: biochemical and immunological studies of the mutant enzyme.

A new phosphoglycerate kinase variant (PGK New Jersey) has been purified from muscle and cultured fibroblasts of a patient with recurrent myoglobinuria. The mutant enzyme had higher than normal affinity for adenosine triphosphate (ATP) and 3-phosphoglycerate, and a shift of the pH optimum towards the acidic side. Antibodies raised against PGK purified from normal muscle were used to evaluate the presence of immunologically cross-reacting enzyme protein in tissues from the patient. Immunodiffusion and an antibody consumption test showed the presence of reduced amounts of cross-reacting material in the patient's muscle. Several PGK variants have been characterized in asymptomatic individuals or in patients with hemolytic anemia. The biochemical features of PGK New Jersey, the only known variant associated with recurrent myoglobinuria, distinguish this mutant enzyme from others.

Adolescent↗

PubMed1984

Multiple neutral maltase activities in normal and acid maltase-deficient human muscle.

The subcellular distribution and isoelectric focusing profile of neutral maltase were investigated in human skeletal muscle from controls and patients with acid maltase deficiency. After subcellular fractionation of normal muscle by differential centrifugation, 75% of the neutral maltase activity was soluble and 13% sedimented with a "microsomal" fraction; the relative specific activity was highest in this latter fraction. After isoelectric focusing (pH gradient 3.5 to 10) of a soluble fraction from control muscle, three peaks of activity were observed: peak 1 had exclusively neutral maltase activity; peak 2 had predominantly neutral maltase activity; and peak 3 had acid maltase activity predominating. The soluble fraction of muscle from a patient with infantile acid maltase deficiency showed no detectable activity at acid pH in any of the peaks and the neutral maltase peaks were unaltered. In muscle from a patient with late-onset acid maltase deficiency the focusing pattern for neutral maltase was similar to controls; the small amount of residual activity at acid pH was found in peak 3.

Adult↗

PubMed1984

Myoadenylate deaminase deficiency. Functional and metabolic abnormalities associated with disruption of the purine nucleotide cycle.

To assess the role of the purine nucleotide cycle in human skeletal muscle function, we evaluated 10 patients with AMP deaminase deficiency (myoadenylate deaminase deficiency; MDD). 4 MDD and 19 non-MDD controls participated in an exercise protocol. The latter group was composed of a patient cohort (n = 8) exhibiting a constellation of symptoms similar to those of the MDD patients, i.e., postexertional aches, cramps, and pains; as well as a cohort of normal, unconditioned volunteers (n = 11). The individuals with MDD fatigued after performing only 28% as much work as their non-MDD counterparts. Muscle biopsies were obtained from the four MDD patients and the eight non-MDD patients at rest and following exercise to the point of fatigue. Creatine phosphate content fell to a comparable extent in the MDD (69%) and non-MDD (52%) patients at the onset of fatigue. Following exercise the 34% decrease in ATP content of muscle from the non-MDD subjects was significantly greater than the 6% decrease in ATP noted in muscle from the MDD patients (P = 0.048). Only one of four MDD patients had a measurable drop in ATP compared with seven of eight non-MDD patients. At end-exercise the muscle content of inosine 5'-monophosphate (IMP), a product of AMP deaminase, was 13-fold greater in the non-MDD patients than that observed in the MDD group (P = 0.008). Adenosine content of muscle from the MDD patients increased 16-fold following exercise, while there was only a twofold increase in adenosine content of muscle from the non-MDD patients (P = 0.028). Those non-MDD patients in whom the decrease in ATP content following exercise was measurable exhibited a stoichiometric increase in IMP, and total purine content of the muscle did not change significantly. The one MDD patient in whom the decrease in ATP was measurable, did not exhibit a stoichiometric increase in IMP. Although the adenosine content increased 13-fold in this patient, only 48% of the ATP catabolized could be accounted for by the combined increases of adenosine, inosine, hypoxanthine, and IMP. Studies performed in vitro with muscle samples from seven MDD and seven non-MDD subjects demonstrated that ATP catabolism was associated with a fivefold greater increase in IMP in non-MDD muscle. There were significant increases in AMP and ADP content of the muscle from MDD patients following ATP catabolism in vitro, while there was no detectable increase in AMP or ADP in non-MDD muscle. Adenosine content of MDD muscle increased following ATP catabolism, but there was no detectable increase in adenosine content of non-MDD muscle following ATP catabolism in vitro. These studies demonstrate that AMP deaminase deficiency leads to reduced entry of adenine nucleotides into the purine nucleotide cycle during exercise. We postulate that the resultant disruption of the purine nucleotide cycle accounts for the muscle dysfunction observed in these patients.

AMP Deaminase↗

PubMed1984

Mitochondrial encephalomyopathy with decreased succinate-cytochrome c reductase activity.

We report two siblings with a mitochondrial encephalomyopathy. The syndrome was characterized by ataxia, intellectual impairment, myoclonic jerks, rare seizures, and small stature. Muscle biopsy specimens showed abnormal accumulations of mitochondria and lipid droplets. Biochemical studies on muscle demonstrated decreased succinate-cytochrome c reductase activity in the mitochondrial respiratory chain.

Brain Diseases↗

PubMed1984

Disorders of glycogen metabolism of muscle.

This review will briefly outline the major steps of glycogen metabolism in muscle and the role of glycogen as a source of energy in different types of exercise. There are nine specific enzyme defects of glycogen metabolism or glycolysis affecting muscle. Each of the nine glycogenoses will be discussed in terms of typical and variant clinical presentation, genetic transmission, muscle biopsy and biochemical findings. The proposed pathophysiology of the various symptoms and signs will be presented and the many unsolved problems in this area will be discussed.

Biopsy↗

PubMed1983

[Muscular carnitine-palmityl-transferase deficiency].

Deficiency in carnitine-palmityl-transferase (CPT) was demonstrated in a 20-year-old man with paroxysmal myoglobinuria, after failure to discover another cause. It is concluded that muscular CPT deficiency must be excluded before a recurrent myoglobinuria is classified as "idiopathic".

Acyltransferases↗

PubMed1983

Phosphoglycerate kinase deficiency: another cause of recurrent myoglobinuria.

A 14-year-old boy had myoglobinuria and renal failure after intense exercise; a year earlier he had experienced a milder episode. There was no consanguinity and no family history of neuromuscular diseases or hemolytic anemia. Strength was normal. Forearm ischemic exercise caused prolonged contracture with no rise of venous lactate. Muscle morphology showed only a mild increase of lipid droplets. Glycogen concentration was normal. Muscle phosphoglycerate kinase (PGK) activity was 5% of the normal mean, and all other glycolytic enzymes were normal. The residual PGK activity of muscle was heat stable but showed slower than normal electrophoretic mobility and decreased Michaelis constants for 3-phosphoglycerate and adenosine triphosphate. The enzyme defect was also expressed in erythrocytes and in fibroblast and muscle cultures. PGK activity was decreased in tissues from the patient's mother but normal in the father. PGK deficiency is an X-linked recessive trait usually associated with hemolytic anemia, mental retardation, and seizures; myopathy had not been recognized previously. Muscle PGK deficiency is now added to two other newly recognized glycolytic defects, phosphoglycerate mutase and lactate dehydrogenase deficiencies, as a cause of recurrent myoglobinuria.

Acute Kidney Injury↗

PubMed1983

Kearns-Sayre syndrome with reduced plasma and cerebrospinal fluid folate.

A young woman with Kearns-Sayre syndrome and progressive central nervous system deterioration over 15 years had decreased plasma and cerebrospinal fluid folate levels while receiving phenytoin for a seizure disorder. A muscle biopsy showed a "ragged red fiber" myopathy with reduced muscle carnitine and mitochondrial enzymes. Computed tomographic brain scans showed cerebral white matter hypodensities and bilateral calcification of the basal ganglia. The mechanism for the folate deficiency and altered ratio of plasma to cerebrospinal fluid folate is unknown, but the deficiency may be responsive to replacement therapy.

Adolescent↗

PubMed1983

Benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency.

A 2-week-old boy had profound generalized weakness, hypotonia, hyporeflexia, macroglossia, and severe lactic acidosis. The infant improved spontaneously: he held his head at 4 1/2 months, rolled over at 7 months, and walked by 16 months. At 33 months of age, he had mild proximal weakness. Macroglossia disappeared by age 4 months. Blood lactic acid declined steadily and was normal by 14 months of age. Histochemical and ultrastructural studies of muscle biopsy specimens obtained at 1 and 7 months of age showed excessive mitochondria, lipid, and glycogen; a third biopsy at age 36 months showed only atrophy of scattered fibers. Cytochrome c oxidase stain was positive in fewer than 5% of fibers in the first biopsy, in approximately 60% of fibers in the second biopsy, and in all fibers in the third biopsy. Biochemical analysis showed an isolated defect of cytochrome c oxidase activity, which was only 8% of the lowest control level in the first biopsy; the activity increased to 47% in the second biopsy and was higher than normal in the third. In contrast to that in the fatal infantile form of cytochrome c oxidase deficiency, the enzyme defect in this condition is reversible. The biochemical basis for this difference remains to be explained.

Acidosis↗

PubMed1983

Activation of free fatty acids in subcellular fractions of human skeletal muscle.

In human pathology little is known about the activating enzymes for fatty acids of different carbon chain length. In order to have a better insight into disorders of lipid metabolism in human skeletal muscle, we studied the distribution of acyl-CoA synthetases in muscular subcellular fractions. We find that in muscle mainly long chain fatty acids are activated to CoA esters. Distribution of palmityl-CoA synthetase in subcellular fractions compared with marker enzymes suggested that this enzymatic activity is located only in the outer mitochondrial membrane, in contrast to human liver, where this enzyme is also located in the microsomes. In human skeletal muscle we also found low butyryl-CoA formation, which was limited to the mitochondrial matrix. This site of activation implies that short chain fatty acids may not depend on carnitine for their oxidation in the mitochondrial matrix, in contrast to long chain fatty acids activated in the outer mitochondrial membrane.

Coenzyme A Ligases↗

PubMed1983

Muscle phosphofructokinase deficiency. Biochemical and immunological studies of phosphofructokinase isozymes in muscle culture.

Muscle cultures from three unrelated patients with muscle phosphofructokinase (PFK; EC 2.7.1.11) deficiency (Glycogenosis type VII; Tarui disease) had normal PFK activity and normal morphology. Chromatographic and immunological studies showed that normal muscle cultures express all three PFK subunits, M (muscle-type), L (liver-type), and P (platelet-type) and contain multiple homotetrameric and heterotetrameric isozymes. Muscle cultures from patients lack catalytically active M subunit-containing isozymes, but this is compensated for by the presence of P- and L-containing isozymes. Despite the lack of muscle-type PFK activity, presence of immunoreactive M subunit was demonstrable by indirect immunofluorescence, suggesting a mutation of the structural gene coding for the M-subunit of PFK.

Adult↗

PubMed1983

Congenital myopathy due to phosphorylase deficiency.

A 4-year-old boy had delayed psychomotor development, proximal weakness, increased serum CK, and myopathic EMG. Muscle biopsy was normal, but histochemical stain for phosphorylase showed no reaction. The enzyme defect was confirmed biochemically and in studies of anaerobic glycolysis in vitro. Glycogen concentration was twice normal. Atypical presentations of myophosphorylase deficiency have included progressive weakness of late onset and fatal infantile myopathy. This patient represents another example of clinical heterogeneity.

Child, Preschool↗

PubMed1983

Lysosomal glycogen storage disease without acid maltase deficiency.

We studied two brothers with lysosomal glycogen storage disease without acid maltase deficiency in skeletal muscle. Although no specific biochemical defect was identified, a characteristic clinical picture emerged from evaluation of these siblings and two other previously reported patients. The syndrome is manifested by proximal muscle weakness, hypertrophic cardiomyopathy, probable intellectual impairment, and possible liver involvement.

Adolescent↗

PubMed1983

Muscle phosphoglycerate mutase (PGAM) deficiency: a second case.

Muscle phosphoglycerate mutase (PGAM) activity was markedly decreased (6% of the normal mean) in a 17-year-old girl with recurrent myoglobinuria after intense exercise. Muscle biopsy showed increased PAS stain; glycogen concentration was twice normal. Studies of anaerobic glycolysis in vitro showed decreased lactate production with glycogen, and with all hexose phosphate glycolytic intermediates, which was corrected by addition of purified PGAM to the reaction mixtures. A defect of the M subunit of PGAM was documented by electrophoretic, heat lability, and mercury inhibition studies. Intermediate PGAM activities (39 and 50% of normal) were found in muscle biopsies from the patient's asymptomatic parents. These data confirm the clinical, morphologic, and biochemical features described in the first patient with PGAM deficiency and suggest autosomal-recessive transmission of the trait.

Adolescent↗