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A patient suffering froma mitochondrial myopathy leading to severe insufficiency of the voluntary muscles is described. Severe cerebral damage was present. Major biochemical symptoms were extreme lactic acidemia, hypophosphatemia and hyperphosphaturia, and generalized aminoaciduria, renal glucosuria, and polyuria. Muscular insufficiency resulted in lethal asphyxiz. All therapeutic trials were insufficient. The patient and two other children of the same family with a similar clinical picture all died before the 4th month of life. The condition is probably inherited in an autosomal recessive way. A defective respiratory chain in the mitochondria of the striated muscles is proposed as the underlying mechanism. Cytochromes aa3 were absent, b was nearly absent, but cc1 was present. In heart muscle cytochromes aa3 and b were at the level of the controls.

Two siblings were found to be affected by long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, one of which died suddenly and unexpectedly on the 3rd day of life suffering from extreme hypoketotic hypoglycaemia. The younger sibling started to have feeding problems, lowered consciousness, and liver dysfunction at the age of 5 months. Her urine contained large amounts of C6-C14 3-hydroxydicarboxylic acids and conjugated 3-hydroxyoctanoic acid, as verified by gas chromatography/mass spectrometry. Plasma long-chain acylcarnitine was increased. A clue to the diagnosis was given by the results of a phenylpropionic acid loading test. This revealed small, but significant amounts of conjugated 3-hydroxyphenylpropionic acid (phenylhydracrylic acid) in the patient's urine. Subsequently, the activity of long-chain 3-hydroxyacyl-CoA dehydrogenase was found to be deficient in cultured skin fibroblasts. Based on the findings obtained by a medium-chain triglyceride load, a diet enriched in this type of fat was prescribed. On this regimen the patient started to thrive, signs of cardiomyopathy disappeared, and her liver function normalized.

Two brothers, aged 7 and 5 years, who excreted large amounts of the leucine metabolites 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid, are described THE PRESENT KNOWLEDGE of the inherited disorders of leucine metabolism has been collected by the careful study of patients who were suspected to have a so-called organic acidemia, l The most prominent symptoms have included metabolic acidosis with or without ketosis or hypoglycemia, feeding difficulties, neurologic abnormalities, and an abnormal body odor. Branched-chain ketoaciduria, isovaleric acidemia, 3-methylcrotonyl-CoA carboxylase deficiency, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency ( Figure) have been well documented. All defects can be observed as a severe (and often lethal) neonatal form or as a more benign, late-onset variant. There appears to be a positive correlation between the rate of metabolite production and the administration of the parent amino acid, leucine. One disorder of leucine metabolism, presumed 3-methylglutaconyl-CoA hydratase deficiency, has not yet been studied in detail because of the limited number of patients. personal communication), whereas the other two patients excreted very small amounts. The latter finding probably represents only a minor biochemical lesion, which is difficult to correlate with the severe clinical findings in those patients.We describe two brothers with excessive excretion of 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. The only clinical abnormality in these patients was retarded speech development. CASE HISTORIESPatient 1, a 7-year-old boy, was the second child of healthy, nonconsanguineous Moroccan parents. The neonatal period was unremarkable, but at the age of one year, when still in Morocco, he had an attack of unconsciousness which lasted for almost a day. His psychomotor development was reported to be delayed: he started to walk at the age of 2. In that period the family emigrated to the Netherlands. The patient was admitted at the age of 7 years for an evaluation of speech retardation. His speech consisted of single words only. On psychologic testing he had a short attention span. He had nocturnal enuresis. On physical examination no abnormalities were found. Routine laboratory investigations gave normal results. Results of the electroencephalogram was normal. Screening for inherited metabolic disorders revealed an abnormal urinary organic acid profile with excessive amounts of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and less 3-methylglutaric acid. The excretion of 3-hydroxy-3-methylglutaric acid appeared to be normal. The blood glucose concentration decreased to 3 mmol/L upon fasting for 18 hours, with a simultaneously

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