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Progressive infantile poliodystrophy (Alpers' disease) is associated with abnormalities in pyruvate metabolism or in cell mitochondria. A 3-year-old-boy had a severe and rapidly progressive neurologic disorder characterized by psycho-motor retardation, tetraparesis, ataxia, and myoclonic jerks, the illness being exacerbated during periods of infection. Lactate concentration in CSF was elevated. Histopathologic studies revealed lipid storage in liver and muscle. Autopsy showed a progressive infantile poliodystrophy. Mitochondrial abnormalities were found in heart muscle. Biochemical studies of muscle and liver tissue suggested a disturbance in nicotinamide adenine dinucleotide (reduced form) oxidation.

Three patients are described with different forms of isovaleric acidemia: a girl with the neonatal form and two brothers with an intermittent form. In all three patients the biochemical aspects are identical: Considerable amounts of metabolites of isovaleric acid, especially isovalerylglycine, are secreted with the urine. In the patients' cultured fibroblasts leucine oxydation is greatly depressed. The clinical presentation of the younger brother prompted to a direct search for a metabolic defect. After diagnosing an isovaleric acidemia in the younger brother, investigations on the presence of the same defect were performed in the elder brother too, though he did not show clinical symptoms. As a result, also isovaleric acidemia was found. It is concluded that sibs of patients with a proven inborn error of metabolism have to be studied too for the presence of the same defect. In all patients, especially in the girl with the neonatal form of isovaleric acidemia diet therapy had a beneficial effect on the further course of the disease.

A description is given of a 15-month-old girl with idiopathic arterial calcifications, detected during life time by X-ray. Radiological examination revealed calcifications in medium-sized arteries, histopathological examination showed distinct abnormalities of small vessels. The patient also had a metageria-like outward and retarded mental and motor development with myolysis. No cardiac failure was present.

A new patient with Leigh's syndrome (subacute necrotizing encephalomyelopathy due to pyruvate dehydrogenase complex deficiency) is presented. A Turkish boy of consanguinously married healthy parents developed progressive muscle weakness since infancy. At the age of 3 years he was unable to sit, stand or walk. Clinical examination showed general muscle weakness, hypotonia, muscle hypotrophy, bilateral ptosis, partial bilateral external ophthalmoplegia, nystagmus, intention tremor and hypoactive tendon reflexes. The EEG showed diffuse slowing, the cerebral CT scan disclosed mild hydrocephalus e vacuo. Motor nerve conduction velocity was slightly decreased, the EMG revealed signs of neuropathy. In the biopsied muscle only a mild hypotrophy of type 2 fibres was found, no abnormal mitochondria could be detected. The sural nerve was slightly abnormal: loss of large myelinated axons, loss of unmyelinated nerves. CSF protein was elevated to 80 mg/dl, protein electrophoresis revealed the pattern of markedly impaired blood-CSF barrier. Serum lactate and pyruvate were permanently elevated. In the urine the excretion of alanine was raised. The clinical state deteriorated during intercurrent infections; somnolence, vomiting and Cheyne-Stoke's respiration occurred. At the age of 3 1/2 years the child died of pneumonia. In the liver tissue a decreased activity of the pyruvate dehydrogenase complex was found. Neuropathological examination of the brain demonstrated wide-spread changes of Leigh's spongiform encephalopathy. Several enzyme deficiencies have hitherto been associated with Leigh's syndrome: This patients confirms earlier findings that a subgroup of Leigh's syndrome is caused by pyruvate dehydrogenase complex deficiency.

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.

Two male patients from one family are reported, who are affected with congenital hydrocephalus, mental retardation, short stature, obesity and hypogenitalism. Most probably the mode of inheritance is X-linked recessive.

This report documents the outcome of two pregnancies is a woman with phenylketonuria (PKU) who was treated with a low phenylalanine diet before conception and during pregnancy. Her first pregnancy resulted in an abortion at 17 wk. During the second pregnancy the patient was unable to maintain the right diet consistently, and her blood phenylalanine levels in the first and second trimester were elevated. This pregnancy ended in the birth of a growth retarded microcephalic infant after an amenorrhea of 42 wk. The infant has maintained a normal growth velocity below the tenth percentile, and has not shown signs of mental retardation.

We report the cases of 18 patients with congenital muscular dystrophy, six of whom also have involvement of the central nervous system, corresponding to the Fukuyama type of congenital muscular dystrophy. In four patients, both the central nervous system and the eyes are involved, and the diagnosis of "muscle, eye and brain disease" was made. A comparative study of these patients with those whose cases were recently reported indicates that there is a wide variability of clinical and laboratory expression of the dystrophy, but a constant feature in all patients is a progression of motor disability. The association of congenital muscular dystrophy with brain abnormalities indicates a poor clinical prognosis. At present it remains an open question whether the three variants of the disease are separate diseases or only different expressions of the same syndrome, but our study tends to support the latter hypothesis.

A computer program is presented which calculates the action of adenylate kinase and creatine kinase during the process of adenosine-5'-triphosphate generation by the mitochondria in human skeletal muscle 600 X g supernatants. The results show that the mass action ratios of the two kinase reactions are not influenced by incubation time or decreased rate of oxidative phosphorylation as a result of mitochondrial dysfunction. The program is useful for establishing optimum initial adenosine-5'-diphosphate and creatine concentrations in the assay medium.

In the urine of a child with unexplained convulsions large amounts of uracil and thymine were detected by gas chromatography. Identification was performed by coupled gas chromatography-mass spectrometry. Quantitation of the urinary excretion by means of a sensitive high-performance liquid chromatographic (HPLC) method revealed a 1000-fold elevation compared to normal. Serum and cerebrospinal fluid levels of the two pyrimidine bases were about a hundred times higher than normal. In fibroblasts the activity of dihydrothymine dehydrogenase was determined by measuring the conversion of radioactive labelled thymine to dihydrothymine with HPLC of the reaction mixture. In the patient's cells a complete deficiency of dihydrothymine dehydrogenase activity was found. Our patient is the first case described with such a proven enzyme deficiency.

L-Ornithine-ketoacid-transaminase deficiency was established in cultured fibroblasts obtained from a patient with hyperornithinaemia (mean ornithine level in serum approximately 100 mumol/l) and gyrate atrophy of the choroid and retina. The deficiency was found both the L-ornithine concentrations of 3.0 mM (about twice the KM value) and 12 mM, indicating that the enzymic defect was not due to a decreased affinity for this substrate. The reliability of the colorimetric assay of ornithine-ketoacid-transaminase activity was established radiochemically. Performance of the radiochemical assay revealed the presence of an impurity in the substrate DL-[2-14C]ornithine - HCl being a strong inhibitor of the enzyme. The passage level and the subcultivation time of the fibroblasts did not influence the enzymic activity.

The patient described is a 14-year-old girl who suffered from an oculocutaneous albinism. The developmental milestones were reached with some delay. Gradually she experienced fatiques, and wasting of the pelvic girdle muscles and weakness appeared. In suralis nerve biopsy sections no abnormalities were found. In muscle biopsy sections the characteristic findings of a primary central neuronal muscular atrophy were seen. Based on clinical and histopathological findings it may be stated that the patient is suffering from a motor neuron disease. The chance of the combined occurrence of oculocutaneous albinism and motor neuron disease can be estimated to be one out of 750 X 10(6), unless an incestuous relation is supposed.

In a few months old baby a visceromegaly was found, without other clinical abnormalities. Using an artificial substrate a deficiency of sphingomyelinase could not be demonstrated. Histopathological examination of biopsied liver revealed a lipid storage disease. Using the natural substrate the deficiency of sphingomyelinase could be demonstrated in leucocytes and in cultured fibroblasts.

Mitochondrial myopathies are characterized by structural and functional abnormalities of the mitochondria. The diseases are best classified according to the underlying biochemical defect. In this article the variability of clinical expression and mitochondrial abnormalities is illustrated. An exact diagnosis is a prerequisite for a rational therapy and genetic counseling. In exceptional cases antenatal diagnosis should be possible.

A method is presented which allows the investigation of almost the complete mitochondrial content of small human skeletal muscle biopsy specimens. Thorough mechanical disruption with a chopper apparatus results in the release of about 50% of the mitochondrial content. Subsequent treatment of the 600 x g sediment with trypsin releases another 30% of the total mitochondrial population. The biochemical characteristics of the two mitochondrial fractions obtained in these two successive steps have been compared. No obvious differences could be established. The procedure is well suited for biochemical investigation of muscle biopsy specimens from patients suspected of suffering from a mitochondrial myopathy.