Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl-CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient.

The urinary excretion of seven selected low molecular weight organic acids in normal neonates was measured by gas chromatography. First and third to fourth day of life excretion of the following compounds was significantly unchanged: 3-OH-butyric acid (less than 13 mumol/mmol creatinine), succinic acid (approx. 43 mumol/mmol creatinine), adipic acid (approx. 12 mumol/mmol creatinine), 2-OH-glutaric acid (approx. 23 mumol/mmol creatinine), 3-OH-3-Me-glutaric acid (approx. 25 mumol/mmol creatinine) and citric acid (approx. 115 mumol/mmol creatinine). The excretion of 4-OH-phenyl-acetic acid increased during the first four days of life (from less than 8 mumol/mmol creatinine to approx. 20 mumol/mmol creatinine). It is postulated that urinary orgainc acid excretion in the neonate, which is clearly different from the adult urinary pattern, is a reflection of the specific neonatal metabolic situation, including a high fatty acid utilisation and a low protein catabolism.

A boy with riboflavin-responsive beta-oxidation deficiency (multiple acyl-CoA dehydrogenation deficiency) was assessed clinically and biochemically after 3 years of continuous riboflavin medication. He was diagnosed at the age of three years after an attack of a Reye's syndrome-like disease. During the 3 years of assessment he has experienced no serious disease; although short episodes of fatigue and loss of appetite have been noted. His mental and physical development has been normal. Biochemically the abnormal excretion of organic acid metabolites, characteristic of the acyl-CoA dehydrogenation deficiency, has been continuously present. Quantitatively there has been a trend to a more simple picture with ethylmalonic acid as the predominant metabolite. However, because of the large within-day variation in the excretion of all the metabolites, changes following diet and riboflavin trials must be interpreted with caution in these patients.

The excretion of C6-C10-dicarboxylic acids, i.e. adipic, suberic and sebacic acids, was measured during the three first days of life in 3 fasting newborns, 2 newborns fed with isocaloric glucose and 2 newborns given mothers'-milk. On the second and third day of life the starved children excreted 27-84 mmol adipic acid/mol creatinine, 6-22 mmol suberic acid/mol creatinine and 4-7 mmol sebacic acid/mol creatinine. The excretion of C6-C10-dicarboxylic acids in the neonates given glucose or mothers'-milk was, for the first three days of life, 0-9 mmol adipic acid/mol creatinine, 0-10 mmol suberic acid/mol creatinine and 0-4 mmol sebacic acid/mol creatinine. The latter amounts are equivalent to the excretion of dicarboxylic acids in older children. It is argued that the detected dicarboxylic acids are formed by omega-oxidation of long-chain monocarboxylic acids followed by beta-oxidation, and that the excreted amounts reflect omega-oxidation activity. It is speculated that the substantial omega-oxidation activity in the starving newborn serve to provide succinyl-CoA-substrate for the citric acid cycle and for gluconeogenesis.