Morphological observations in skeletal muscle from patients with a mitochondrial myopathy

The regional distribution of the phenylalanine-sensitive ATP-sulphurylase in fetal calf brain coincides with demyelinated lesions observed in the central nervous systems of untreated PKU patients. This would be expected if this species of ATP-sulphurylase played a role in the pathogenesis of brain dysfunction in the untreated or poorly controlled phenylketonuria patient.     

A retrospective study of patients with the hereditary syndrome of congenital cataract,mitochondrial myopathy of heart and skeletal muscle and lactic acidosis

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.     

A prognostic index as diagnostic strategy in children suspected of mitochondriocytopathy

The aim of this study was to assess an optimal screening for paediatric patients suspected of mitochondriocytopathy to justify a muscle biopsy. Forty-five patients were included. Medical history, physical examination, cardiac and ophthalmologic evaluation, clinical chemical investigations, in vivo function tests, neuroimaging and a skeletal muscle biopsy were performed in all patients. The results of the biochemical muscle studies were compared with the results of the other investigations. First, parameters with a statistical relationship with the result in muscle, normal or deficient, were selected. Secondly, a prognostic index was constructed using these parameters. Five parameters were selected: age <4 years, elevated fasting lactate to pyruvate ratio, elevated thrombocyte count, elevated lactate, and elevated alanine. Each parameter was scored 0 (not present) or 1 (present). The chance of a normal biopsy with a given value of this index (sum of the scores) was calculated: logit (Pr) = alpha + beta x index; alpha: -0.8167 and beta: 0.8331. (Pr: probability of normal biopsy.) The chance of a normal biopsy with an index value of 5 is 0.03, 4 is 0.07, 3 is 0.16, 2 is 0.30, 1 is 0.50 and 0 is 0.69. This prognostic index is a valuable instrument in deciding whether the suspicion of mitochondriocytopathy is strong enough to merit a muscle biopsy.     

Review: Modelling placental amino acid transfer − From transporters to placental function

Amino acid transfer to the fetus is dependent on several different factors. While these factors can be understood in isolation, it is still not possible to predict the function of the system as a whole. In order to do this an integrated approach is required which incorporates the interactions between the different determinants of amino acid transfer. Computational modelling of amino acid transfer in the term human placenta provides a mechanism by which this integrated approach can be delivered. Such a model would be invaluable for understanding amino acid transfer in both normal and pathological pregnancies.In order to develop a computational model it is necessary to determine all the biological factors which are important contributors to net amino acid transfer and the ways in which they interact. For instance, how different classes of amino acid transporter must interact to transfer amino acids across the placenta. Mathematically, the kinetics of each type of transporter can be represented by separate equations that describe their transfer rate as a non-linear function of amino acid concentrations. These equations can then be combined in the model to predict the overall system behaviour. Testing these predictions experimentally will demonstrate the strengths and weaknesses of the model, which can then be refined with increasing complexity and retested in an iterative fashion.In this way we hope to develop a functional computational model which will allow exploration of the factors that determine amino acid transfer across the placenta. This model may also allow the development of strategies to optimise placental transfer in pathologies associated with impaired amino acid transfer such as fetal growth restriction.     

Isolated and combined deficiencies of NADH dehydrogenase (complex I) in muscle tissue of children with mitochondrial myopathies

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.     

A mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme Q

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 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.Abbreviations EEG electroencephalogram - CT computed tomography - CSF cerebrospinal fluid - Ap₅A P, P⁵-di(adenosine-5-)pantaphosphate - BSA bovine serum albumin - CPT carnitine palmitoyltransferase - SCC succinate: cytochrome c oxidoreductase - SQ succinate:coenzyme Q oxidoreductase - DCPIP 2,6-dichlorophenol indophenol This investigation is part of the research program Disorders of the Neuromuscular System     

Disorders of the mitochondrial respiratory chain: clinical manifestations and diagnostic approach

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.Abbreviations ATP adenosine triphosphate - CoA coenzyme A - DCPIP 2,6-dichlorophenol indophenol - KCN potassium cyanide - NAD⁺ nicotinamide adenine dinucleotide (oxidized) - NADH nicotinamide adenine dinucleotide (reduced) - PMS phenazine methosulfate     

Features of a syndrome with congenital cataract and hypertrophic cardiomyopathy

We studied 12 patients from six unrelated families with a syndrome that has an autosomal recessive pattern of inheritance and can be diagnosed from clinical, histologic, and biochemical characteristics. The four major symptoms are congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy of voluntary muscles, and exercise-related lactic acidosis. The patients had bilateral and total cataract in the first weeks of life, underwent cataract surgery, and developed nystagmus and strabismus. Corrected visual acuity was lower than 20/40 in aphakic eyes. Patients were mentally normal, and at school age they visited a school for blind and visually impaired children. The majority of the patients developed axial myopia with myopic fundus changes; aphakic refraction usually was lower than 10.0 diopters after the first decade. The cardiac myopathy was progressive and the cause of premature death. Three of the 12 patients died in the neonatal period and six patients died in early adulthood.     

Dihydropyrimidine dehydrogenase deficiency. Neurological aspects

A family with dihydropyrimidine dehydrogenase (DPD) deficiency is presented. In 3 persons a complete deficiency, and in 3 others a partial deficiency was detected in cultured fibroblasts. Two homozygote subjects and 1 heterozygote subject suffered from epileptic manifestations, in one of these homozygote subjects also microcephaly was found. DPD deficiency might be an etiological factor in the clinical picture of these patients. An autosomal recessive mode of inheritance of this deficiency was found.