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A patient with neonatal expression of severe De Toni-Debré-Fanconi syndrome is presented. Because of early signs of renal tubulopathy together with a large urinary excretion of lactate, 3-hydroxybutyrate and citric acid cycle intermediates, a mitochondrial disorder was suspected and muscle and liver biopsies were performed. Biochemical investigations in both tissues revealed a defect in the respiratory chain at the level of complex III. In this patient renal dysfunction was the primary symptom, and hyperlactataemia, an important clue for a mitochondrial disorder, was lacking. CONCLUSION. Complex III deficiency should be included in the differential diagnosis of neonatal De Toni-Debré-Fanconi syndrome. [ABSTRACT FROM AUTHOR]

Patients suffering from a mitochondrial (encephalo-)myopathy have a remarkable clinical heterogeneity. A reliable and extensive investigation must be performed in order to obtain a correct diagnosis, but many factors may influence the ultimate results of these investigations leading, under certain circumstances, to an incorrect diagnosis. Patients selection is of crucial importance. Metabolic examination of body fluids, particularly with respect to lactate accumulation, is used as a selection criterion for further examinations. Numerous aspects associated with this metabolic examination have been critically evaluated, including the phenomenon of other causes of lactic acidaemia apart from mitochondrial disorders. Correct performance of in vivo function tests may contribute to a reduction of the number of missed diagnoses. Selection of the controls for biochemical investigations must be accurately be performed to obtain reliable reference values. Knowledge of the age-dependency of the biochemical parameters is necessary for a correct interpretation. It goes without saying that the choice of the tissue for biochemical investigations is of utmost importance. Knowledge of the tissue-specific occurrence of some defects in the mitochondrial respiratory chain is necessary. The biochemical examinations can be performed both in biopsy and autopsy material but only under certain conditions. Diagnostic approach requires application of reliable biochemical methods which are described. One of the most intriguing aspects in the diagnosis of mitochondrial disorders is the significance of a defect in relation to the residual enzyme activity found in the patient. Moreover, attention is paid to relevant items such as the occurrence of multiple and secondary defects.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

In six patients with mitochondrial (encephalo-) myopathy investigations of skeletal muscle revealed a defect of pyruvate dehydrogenase complex (PDHC) in combination with one or more respiratory chain complex deficiencies. A combination of defects of this kind has not been reported previously. Five of the six patients presented within the 1st year of life and had a severe clinical course. Intrafamilial variability of the clinical course in dizygotic twins both suffering from a cytochrome c oxidase deficiency and one of them also from a PDHC deficiency suggests an additional effect of PDHC deficiency on the clinical symptoms. Immunoblot studies of PDHC in five of the patients revealed no abnormalities in their subunit pattern, rendering a defect of mitochondrial protein import or assembly unlikely. The finding of a combined PDHC and respiratory chain deficiency has implications for the diagnostic approach, for therapy and genetic counselling. The exact pathogenetic mechanism of this combination of defects remains to be elucidated. [ABSTRACT FROM AUTHOR]

We describe eight children with complex I deficiency, four of them with an isolated, the other four with an additional deficiency of complex IV. Clinical, chemical and morphological findings were compared from patients with isolated and combined deficiency. In both groups, the age of onset of symptoms was between the 1st day and the 4th month of life. Clinical and biochemical heterogeneity were observed. We found no correlation between residual activity of complex I in muscle, blood lactate level, and severity of clinical symptoms. Newborns presenting with severe lactic acidosis and children with later onset myopathy were seen in both groups. The group with combined complex I deficiency showed a more severe clinical course. By light microscopy ragged red fibres were only found in two patients with combined deficiency. However, by electron microscopy structural alterations of the mitochondria were observed in six out of seven muscle specimens. [ABSTRACT FROM AUTHOR]

Three patients suffering from the neonatal form of a syndrome characterized by congenital cataract, hypertrophic cardiomyopathy, and mitochondrial myopathy are described. The patients died at 7, 10 and 18 days, respectively from cardiorespiratory failure. Mitochondrial abnormalities were observed in the heart and skeletal muscle. Despite the presence of a severe lactic acidaemia pointing to a disturbed pyruvate oxidation rate in vivo, a normal pyruvate oxidation rate was demonstrated in skeletal muscle homogenates. The activities of several enzymes of the mitochondrial respiratory chain appeared to be normal, indicating an intact respiratory chain. A myoglobinopenia could be excluded. The activities of some mitochondrial enzymes and the concentration of myoglobin increase with age. [ABSTRACT FROM AUTHOR]

The clinical identification of patients with defects in the mitochondrial respiratory chain is almost impossible. We describe screening tests that should be performed in order to select those patients in whom a skeletal muscle biopsy should be carried out for more specific biochemical assays. The importance of performing in vivo function tests is stressed. The biochemical diagnosis in disorders of the respiratory chain is presented and the application of immunological methods discussed. [ABSTRACT FROM AUTHOR]

A patient with severe muscular hypotonia, failure to thrive, a metabolic acidosis and a renal tubular dysfunction is presented. The disease followed a fatal course. Blood lactate and pyruvate levels as well as lactate/pyruvate ratios were strongly elevated. There were a massive excretion of lactate in urine, a generalized hyperaminoaciduria, a proteinuria and a mellituria. The carnitine concentration was diminished in blood and muscle tissue. Biochemical investigations of skeletal muscle and liver tissue revealed a defect in the respiratory chain at the level of succinate: cytochrome c oxidoreductase. The defect could not be demonstrated in cultured fibroblasts. [ABSTRACT FROM AUTHOR]

A female infant presented with signs of general muscle hypotonia and increasing hypertrophy of the heart muscle. There was a constant lactic acidosis worsened after glucose intake. Serum lactate levels were increased up to 6.7 mmol/l. Serum alanine levels reached maximum concentrations of 2,800 mumol/l. The patient died after sudden cardiac arrest at 22 months of age. Histology of the heart showed the pattern of foamy myocardial transformation with accumulation of mitochondria and an increased glycogen content. Biochemical analysis of the skeletal muscle and the heart demonstrated signs of a disturbed respiratory chain. The content of cytochrome aa3 protein was decreased in skeletal muscle and heart mitochondria. It is suggested that respiratory chain defects may be the cause of foamy myocardial transformation of the heart. [ABSTRACT FROM AUTHOR]

A patient is presented who had therapy-resistant epileptic seizures from the 7th day of life. Examination at the age of 17 months revealed a mentally retarded boy with epileptic seizures, generalised myoclonic contractions, and abnormal ocular movements. A cerebral CT scan showed central and cortical atrophy. Lactate levels in serum, cerebrospinal fluid and urine were elevated, the pyruvate level was raised in serum. A quadriceps muscle biopsy revealed aspecific morphologic signs of a myopathy. Biochemical analysis showed decreased substrate oxidation rates in the mitochondria associated with low rates of ATP production. Total and free carnitine levels were decreased. Investigation of the respiratory chain revealed a defect in the proximal part of respiratory chain involving the region of coenzyme Q. Based on clinical and chemical data it is likely that the patient is suffering from a multi-system disorder. [ABSTRACT FROM AUTHOR]

A patient with demyelination is described. Lactate levels were elevated in serum, urine, and cerebrospinal fluid. A decreased pyruvate oxidation rate due to a pyruvate dehydrogenase complex deficiency was demonstrated in muscle and cultured fibroblasts. In muscle mitochondria no structural abnormalities were seen. The clinical course was progressive and the patient died at the age of 6 months. [ABSTRACT FROM AUTHOR]

An 18-month-old boy presented with general hypotonia, decreased muscle strength, retarded motor development and stunted growth. The excretion of dicarboxylic acids was enhanced. EMG was normal. A muscle biopsy revealed a lipid storage myopathy. Oral daily supplementation with 2 g D, L-carnitine resulted in: (1) an increase of the growth velocity; (2) increased muscle strength, and (3) a decrease in the lipid fraction of the fibre volume. The carnitine content of the muscle biopsied prior to treatment appeared to be normal. [ABSTRACT FROM AUTHOR]

The results of needle biopsies of skeletal muscle in 95 infants (age-range 2/12--17 1/12 year) are presented. The biopsies were carried out using the Vondra-needle. In all but one case an amount of material was obtained which was sufficient for histopathological examination. The needle biopsy technique has the advantage that it can be performed by the paediatrician in the outpatient department. In our experience the procedure entails no risk. [ABSTRACT FROM AUTHOR]

Myophosphorylase deficiency (McArdle's syndrome) is an uncommon condition characterized by exercise intolerance, muscle cramps and myoglobinuria. The present report describes the clinical, histochemical, electronmicroscopic and biochemical findings in a 12-year-old boy with myophosphorylase deficiency. The diagnosis should have been suspected when the boy was 6 years old. Most index cases have not been diagnosed until adult life, but this syndrome has to be considered in the differential diagnosis of exercise intolerance in childhood. [ABSTRACT FROM AUTHOR]

Unlabelled: Knowledge concerning the approximately 70 human nuclear genes creating the essential building-blocks of the five multi-protein subunit complexes of the oxidative phosphorylation (OXPHOS) system has been expanded greatly in the past few years. However, knowledge concerning the numerous human genes involved in the regulation of transcription, translation, post-translational modification, mitochondrial signalling, import, quality control, folding and assembly of the OXPHOS system is still rather scanty. It may be expected that this scenario, by the application of direct (candidate gene identification by comparison between known genes in lower species and the human expressed sequence tag database) and indirect genetic strategies (the chromosome transfer technique, linkage analysis and positional cloning) will rapidly change. By now, a limited number of structural and non-structural nuclear gene defects have been found.Conclusion: This review summarises the state of our current knowledge of nuclear gene mutations in oxidative phosphorylation disorders. [ABSTRACT FROM AUTHOR]

This case report documents the fetal outcome of two full term pregnancies in a patient with phenylketonuria (PKU). She was treated with a low phenylalanine diet preceeding and during both pregnancies. During her first full term pregnancy she was not able to maintain the rigid diet, and this pregnancy resulted in the delivery of a growth-retarded, microcephalic boy. In her second pregnancy the patient maintained the diet until her delivery at full term. Maternal blood phenylalanine levels remained with two exceptions below 600 mumol/l throughout pregnancy and an infant of normal weight and head circumference was born. [ABSTRACT FROM AUTHOR]

A girl was presented suffering from generalised weakness and cardiorespiratory insufficiency. She succumbed at the age of 5 months. Lactate levels were elevated in serum, cerebrospinal fluid and urine. Histopathological examination revealed a mitochondrial myopathy. In muscle tissue the cytochrome oxydase activity was strongly reduced. The content of cytochromes b and aa3 was very low. At autopsy a cardiomyopathy was found. [ABSTRACT FROM AUTHOR]

An infant with severe deficiency of complex III combined with less severe deficiencies of complexes I, II and IV of the mitochondrial respiratory chain in skeletal muscle tissue presented with intra-uterine growth retardation, generalized hypotonia and delayed motor development. In the following 3.5 years muscle tone and motor development gradually normalized whereas the lactic acidosis and enzyme activities did not improve.Conclusion This report documents a favourable clinical course in a child with combined respiratory chain deficiency despite persistent biochemical abnor-malities. [ABSTRACT FROM AUTHOR]

The ultrastructural findings in the Kupffer cells of a liver biopsy of a 5-week-old baby, who had received repeated i.v. administration of Intralipid (10%) in a dose of 20 ml/kg body weight/day for 12 days, are presented. Heterophagocytosis of free lipid droplets occurs by invagination of the Kupffer cell membrane. Large, solitary or conglomerated fat droplets surrounded by a membrane (lipophagosomes) are present within the hypertrophic and most active Kupffer cells. Small, round or elongated dark bodies (primary lysosomes) are linked with and/or seem to fuse with these lipophagosomes. In addition, smaller phagosomes almost completely surrounded by a dark small rim and a less electron-dense center probably represent further stages of the lysosomal breakdown. The latter is also expressed by the condensation from the periphery towards the center of the original lipid droplets enclosed within the lysosomes. Angular inclusion bodies, build up of lipid remnants and a granular matrix of medium electron density, constitute far advanced stages of lysosomal digestion and represent the development or transformation of the phagocytosed lipids into lipogenous pigments. On the electron-microscopic level a distinction between lipofuscin granules and ceroid pigment can hardly be made at that stage. These pigment granules can be found in various amounts within the Kupffer cells and can stay there for a long time. This accumulation probably inhibits the clearance capacity of the cellular elements of the hepatic reticuloendothelial system. The hepatocytes and spaces of Disse seem not to be directly involved in the process of fat phagocytosis and breakdown as summarized above. [ABSTRACT FROM AUTHOR]

The objectives of this study were to describe the course of two forms of an hereditary syndrome characterised by congenital cataract, mitochondrial myopathy of heart and skeletal muscle and lactic acidosis. We also sought to determine clinical, physicochemical and histopathological data which might allow early distinction between the two forms. We compared the ages at which clinical and physicochemical signs appeared in 16 patients. In 5 patients, enzyme-histochemical and ultrastructural data of skeletal muscle were available and muscle fibre composition analysed morphometrically. In any particular family only one form of the syndrome occurred. Amongst the patients who did not survive (range 14-34 years) 4 patients died in the neonatal period and 7 died at a median age of 23 years. The median age of the survivors was 19 years (range 15-42 years). Outflow obstruction of the left ventricle was noted in four deceased patients at variable times prior to death. The other deceased patients were not examined, but the cause of death was invariably heart failure. In none of the surviving patients was outflow obstruction noted. Enzyme-histochemical and ultrastructural findings were not specific for the course of the disease. In one biopsy, taken at the age of 3.5 months from a patient who survived, strong lipid accumulation was noted. Morphometric analysis showed proliferation of the mitochondria in muscle fibres, which increased during the course of the disease. [ABSTRACT FROM AUTHOR]

The objectives of this study were to describe the course of two forms of an hereditary syndrome characterised by congenital cataract, mitochondrial myopathy of heart and skeletal muscle and lactic acidosis. We also sought to determine clinical, physicochemical and histopathological data which might allow early distinction between the two forms. We compared the ages at which clinical and physicochemical signs appeared in 16 patients. In 5 patients, enzyme-histochemical and ultrastructural data of skeletal muscle were available and muscle fibre composition analysed morphometrically. In any particular family only one form of the syndrome occurred. Amongst the patients who did not survive (range 14-34 years) 4 patients died in the neonatal period and 7 died at a median age of 23 years. The median age of the survivors was 19 years (range 15-42 years). Outflow obstruction of the left ventricle was noted in four deceased patients at variable times prior to death. The other deceased patients were not examined, but the cause of death was invariably heart failure. In none of the surviving patients was outflow obstruction noted. Enzyme-histochemical and ultrastructural findings were not specific for the course of the disease. In one biopsy, taken at the age of 3.5 months from a patient who survived, strong lipid accumulation was noted. Morphometric analysis showed proliferation of the mitochondria in muscle fibres, which increased during the course of the disease. [ABSTRACT FROM AUTHOR]

Muscle biopsies from 17 children with exercise intolerance and other miscellaneous symptoms and signs showed changes in mitochondrial content. The patients could not be classified according to known criteria. The histopathological changes were quantified by morphometric analysis and the clinical data were statistically analysed to detect intercorrelations. After a mean follow up period of 6.8 years (range 0.5-13.6), patients were re-examined and the course of the disease was determined. No clinical entity could be established. None of the patients showed aggravation of the exercise intolerance, but 71% noted no improvement. An increased volume density of peripheral mitochondria was shown in 59%. Based on clinical history, histopathological changes and course we suggest that some of these patients suffer from a yet unknown disturbance in energy metabolism. Recognition of these patients is important for appropriate counselling. [ABSTRACT FROM AUTHOR]

Muscle biopsies from 17 children with exercise intolerance and other miscellaneous symptoms and signs showed changes in mitochondrial content. The patients could not be classified according to known criteria. The histopathological changes were quantified by morphometric analysis and the clinical data were statistically analysed to detect intercorrelations. After a mean follow up period of 6.8 years (range 0.5-13.6), patients were re-examined and the course of the disease was determined. No clinical entity could be established. None of the patients showed aggravation of the exercise intolerance, but 71% noted no improvement. An increased volume density of peripheral mitochondria was shown in 59%. Based on clinical history, histopathological changes and course we suggest that some of these patients suffer from a yet unknown disturbance in energy metabolism. Recognition of these patients is important for appropriate counselling. [ABSTRACT FROM AUTHOR]

An infant with moderate muscular hypotonia and congenital lactic acidosis died suddenly at the age of 3 months. Autopsy revealed no abnormalities responsible for this unexpected death. Measurement of mitochondrial enzymes involved in energy production indicated a severely decreased total pyruvate dehydrogenase complex (PDHC) activity in muscle tissue (0.23 nmoles x min-1 x mg protein-1, control range 2.8-8.7) and moderately decreased PDHC activity in fibroblasts (0.27 nmoles x min-1 x mg protein-1, control range 0.37-2.32). The activity of the first component E1 (pyruvate dehydrogenase) in muscle tissue was 10 times lower than that of controls (0.008 nmoles x min-1 x mg protein-1, control range 0.10-0.25). The activities of dihydrolipoyl dehydrogenase (E3) and various other mitochondrial enzymes were normal. Immunochemical analysis in skeletal muscle tissue and fibroblasts demonstrated a decrease in the amount of the alpha and beta subunits of E1. The features of this patient are compared with those of other patients reported in the literature with immunochemically confirmed combined E1 alpha and beta deficiency. [ABSTRACT FROM AUTHOR]

An infant with moderate muscular hypotonia and congenital lactic acidosis died suddenly at the age of 3 months. Autopsy revealed no abnormalities responsible for this unexpected death. Measurement of mitochondrial enzymes involved in energy production indicated a severely decreased total pyruvate dehydrogenase complex (PDHC) activity in muscle tissue (0.23 nmoles · min · mg protein, control range 2.8-8.7) and moderately decreased PDHC activity in fibroblasts (0.27 nmoles · min · mg protein, control range 0.37-2.32). The activity of the first component E (pyruvate dehydrogenase) in muscle tissue was 10 times lower than that of controls (0.008 nmoles · min · mg protein, control range 0.10-0.25). The activities of dihydrolipoyl dehydrogenase (E) and various other mitochondrial enzymes were normal. Immunochemical analysis in skeletal muscle tissue and fibroblasts demonstrated a decrease in the amount of the α and β subunits of E. The features of this patient are compared with those of other patients reported in the literature with immunochemically confirmed combined E α and β deficiency. [ABSTRACT FROM AUTHOR]

A boy presented suffering from generalised weakness, exercise intolerance and lactic acidosis. The weakness became evident at 2 years. A cerebral CT-scan showed cerebellar atrophy and central and peripheral atrophy of both hemispheres. With trichrome staining about 20% of the muscle fibres showed large areas containing redstaining granular material. Electron microscopic examination showed that this material consisted of areas of mitochondrial proliferation, most of the mitochondria having abnormal ultrastructural characteristics. Pyruvate dehydrogenase complex and citric acid cycle activities were determined by measuring CO production from various labelled substrates. Diminished oxidation rates were found with the patient's muscle homogenate for all substrates tested, indicating a defect in the respiratory chain. The cytochromes were present in normal quantities. Succinate cytochrome c reductase activity was very decreased. Carnitine concentration was decreased in serum and in muscle as well. [ABSTRACT FROM AUTHOR]

A boy with recurrent exertional rhabdomyolysis and stunted growth is described. Fetal movements were few and the boy was small for gestational age. He always experienced easy fatigability, and he, noted bouts of pigmenturia associated with episodes of considerable malaise. The change in color of the urine was caused by myoglobin. An electromyogram was myopathic. CPK rose during 60 minutes mild exercise. Prolonged moderate exercise could not be performed. Histopathological examination of muscle biopsy revealed an increase in the number of 11 C fibres (20%). Electronmicroscopy revealed the wavy outline of a number of fibres and hypertrophy of sarcoplasmic reticulum elements. No cause for the stunted growth could be detected. [ABSTRACT FROM AUTHOR]

This report describes a 3 year-old girl with signs of ventricular hypertrophy, short stature, and persistent diarrhoea (without steatorrhoea or creatorrhoea) which was resistant to therapy. There was no clinical evidence of myopathy but a myopathic pattern was found on electromyography. Biochemical studies revealed no abnormalities. Routine histological studies of biopsied muscle showed no obvious structural abnormalities. Examination of 1 μm tissue sections revealed groups of atrophic fibers. Electronmicroscopy revealed widened spaces between the myofibrils with disruption of filament arrangement. The mitochondria in the motor end-plates were very distended and almost devoid of cristae. [ABSTRACT FROM AUTHOR]

A very unusual pattern of organic acid excretion was established in the urine of two premature newborns with severe respiratory distress and cerebral haemorrhages. By combined gas chromatography/mass spectrometry the following acids were identified: lactic acid, α-hydroxy-butyric acid, β-hydroxy-butyric acid, α-hydroxy-isovaleric acid, and p-hydroxy-phenyllactic acid. Calculation of the concentration revealed an excessive excretion of lactic acid and also very high excretion of the other acids. A post mortem blood sample from one of the patients revealed a comparable pattern. The abnormal urinary organic acid excretion pattern was most probably caused by severe tissue hypoxia. [ABSTRACT FROM AUTHOR]

Objective: To study the effect of sufficient energy intake, by means of the protocolized administration of naso-gastric tube feeding, on the nutritional status of a child with cancer.Design: A comparative experimental study.Setting: Tertiary care at the Centre for Pediatric Oncology, South East Netherlands, University Hospital, Nijmegen.Subjects: Seven children, newly diagnosed with cancer, were included in the experimental study and all completed the trial period. Fourteen patients were included in the retrospective study. They were randomly chosen from a group of patients previously treated for a malignancy at our department and who had received naso-gastric tube feeding for at least 16 weeks.Intervention: Protocolized (experimental group) vs non-protocolized (retrospective group) administration of naso-gastric tube feeding over a period of 16 weeks. The main difference was the amount of tube feeding administered. In addition to energy from other foods, children in the experimental group received 106+/-13% of their total daily energy requirements (TDER) by means of tube feeding, whereas children in the retrospective group had received 75+/-24%.Main Outcome Measures: Weight as a percentage of weight for height according to the 50th percentile of a healthy reference population=ideal weight.Results: Weight, expressed as a percentage of the ideal weight, increased significantly in the experimental group (18.2 8.4; P=0.01) and the retrospective study group (5.2 7.3; P=0.001). However, the increase was statistically significant in favour of the experimental group (P=0.003), in which all the children reached their ideal weight, compared to 21% in the retrospective group.Conclusion: Aggressive protocolized nutritional intervention during the intensive phase of anti-cancer treatment, in the form of naso-gastric tube feeding that provides the child's total daily energy requirements, results in considerable improvement in the nutritional status. [ABSTRACT FROM AUTHOR]

The case of an infant with both dilated cardiomyopathy and 3-methylglutaconic aciduria is presented. The literature on this subject is reviewed. [ABSTRACT FROM AUTHOR]