Research Notes: Reye Syndrome

Acta Paediatr Jpn. 1990 Aug.
Carnitine deficiency in inherited organic acid disorders and Reye syndrome.
Sugiyama N, Kidouchi K, Kobayashi M, Wada Y.
Department of Pediatrics, Nagoya City University, Medical School, Japan.

A large quantity of propionylcarnitine in the urine of patients with propionic acidemia and methylmalonic aciduria was demonstrated. The amount excreted depended on the administered L-carnitine dose from 25 to 75 mg/kg/day. A high level of propionylcarnitine was also detected in the amniotic fluid of fetuses at risk of methylmalonic aciduria. Glutaric aciduria type 1 was characterized by excessive urinary excretion of glutarylcarnitine. In a neonate with glutaric aciduria type 2, several specific acylcarnitines were detected in the urine. These included isovaleryl-, acetyl-, isobutyryl-, and butyrylcarnitine as major carnitine esters and glutaryl-, and octanoylcarnitine as minor components. However, the pattern of acylcarnitines excreted changed from isovalerylcarnitine (via leucine) to isobutyrylcarnitine (via valine) during early life. In patients diagnosed as Reye syndrome, tissue carnitine deficiency was not always recognized and no decrease in the free/total carnitine ratio was found in the liver or muscle. The clinical and pathophysiological manifestations seen in these disorders are considered to relate to mitochondrial activity. Therefore, it is necessary to measure acylcarnitine fractions in the urine in order to obtain more precise information about mitochondrial function because carnitine and acylcarnitine compounds may express the metabolic state of mitochondria.

Clin Chim Acta. 1988 Jun 30.
Urinary C6-C12 dicarboxylic acylcarnitines in Reye's syndrome.
Tracey BM, Cheng KN, Rosankiewicz J, Stacey TE, Chalmers RA.
Perinatal and Child Health, MRC Clinical Research Centre, Harrow, Middlesex, UK.

C6-C12 dicarboxylic acylcarnitines have been identified for the first time in urine from a 2-year-old girl presenting with Reye's syndrome. The acylcarnitines were extracted by ion-exchange chromatography and analysed, both underivatised and as methyl esters using high-resolution fast-atom-bombardment mass spectrometry and B/E-linked scanning. The acylcarnitines were quantified by capillary gas chromatography of the acids extracted after hydrolysis of the acylcarnitine esters. Dodecandioylcarnitine was present in the highest concentration (35.9 mmol/mol creatinine) which exceeded the urinary free dodecandioic acid concentration. The adipic, suberic and sebacic acylcarnitine concentrations were less than 10% of the respective free acid concentrations. It is possible that beta-oxidation of dicarboxylic acids is partially inhibited in Reye's syndrome leading to accumulation of precursor dodecandioyl CoA which is metabolised to dodecandioylcarnitine. The accumulation of these metabolic intermediates may be significant in the pathogenesis of Reye's syndrome.

J Pediatr. 1986 Sep.
Serum dicarboxylic acids in patients with Reye syndrome.
Tonsgard JH.

Reye syndrome resembles disorders of fatty acid metabolism. Analysis of serum free fatty acids from 18 patients with Reye syndrome revealed that dicarboxylic acids comprise as much as 55% (range 4% to 55%) of the patients' total free fatty acids; both medium- (6 to 12 carbon lengths) and long-chain (14 to 18 carbon lengths) dicarboxylic acids were identified. Long-chain dicarboxylic acids were not found in any control samples, whereas 86% +/- 4% of the serum dicarboxylic acids were long chain in 10 patients with Reye syndrome in state 3 to 4 coma and 31% +/- 8% in eight patients with a milder illness. The serum concentration of dicarboxylic acids correlated with the clinical state (P less than 0.001) and with the elevation in blood ammonia concentration (r2 = 0.8767). No long-chain dicarboxylic acids were found in the urine. The dicarboxylic acidemia in Reye syndrome may be secondary to the general mitochondrial dysfunction or could indicate that an insult to fatty acid metabolism or the stimulation of omega-oxidation is important in the pathogenesis of the illness. Measurement of serum dicarboxylic acids, especially long chain, may be important in assessing Reye syndrome and may prove useful in distinguishing this from other diseases.

Pediatr Neurol. 1986 Mar-Apr.
Carnitine status in Reye and Reye-like syndromes.
Matsuda I, Ohtani Y.
Department of Pediatrics, Kumamoto University Medical School, Japan.

Fourteen children with the following Reye and Reye-like syndromes were studied to determine each patient's carnitine status: valproate-induced Reye-like attack, ornithine transcarbamylase deficiency, systemic carnitine deficiency, methylmalonic acidemia, and propionic acidemia. Reduced free carnitine and increased serum and urine acylcarnitine levels were found in all patients except for 2 with Reye syndrome, in whom serum creatinine levels were mildly elevated and serum free carnitine levels were not reduced. The renal free carnitine reabsorption rate was reduced in all cases. The free carnitine content of autopsied liver samples were reduced in 2 Reye syndrome patients, 2 OTC deficiency patients, and in a single systemic carnitine deficiency patient. The observed secondary free carnitine deficiency may be a factor in the pathogenesis of Reye and Reye-like syndromes.

Brain Dev. 1986.
Serum and urinary carnitine and organic acids in Reye syndrome and Reye-like syndrome.
Sugimoto T, Nishida N, Woo M, Takeuchi T, Yasuhara A, Kobayashi Y, Sakane Y.

Free and acyl-carnitine in serum and urine, and urinary organic acids were measured in 6 patients with Reye syndrome and Reye-like syndrome. The free and total carnitine concentrations were significantly reduced in serum during the acute phases of the diseases. Thus, the ratio of acylcarnitine to free carnitine was significantly increased. Urinary excretion of acylcarnitine was greatly increased, and the acylcarnitine to total carnitine ratio was therefore greater than in controls. The urinary organic acids comprised large amounts of lactic acid, dicarboxylic acids and ketone bodies. It is suggested that carnitine deficiency is induced as more carnitine is consumed to buffer the increased amount of toxic acyl-CoA compounds metabolized from free fatty acids and the many organic acids. These results indicate that administration of L-carnitine should generally be considered in patients with Reye syndrome and Reye-like syndrome.

J Pediatr. 1985 Jul.
Urinary dicarboxylic acids in Reye syndrome.
Tonsgard JH.

Urine from 12 patients with Reye syndrome was examined by gas-liquid chromatography for identification of organic acids. Large amounts of lactic acid, dicarboxylic acids (adipic, suberic, and sebacic), and 3-OH butyric acid were noted. The mean (+/- SD) total dicarboxylic acid concentration was 0.98 +/- 0.24 mg/mg creatinine, compared with 0.006 +/- 0.010 mg/mg creatinine in controls, n = 140; the mean in patients with Reye syndrome was higher (1.40 +/- 0.26 mg/mg creatinine, n = 8) when the samples were obtained prior to initiation of therapy, but declined rapidly after administration of hypertonic glucose, exchange transfusion, and osmotic diuretics. The total urine excretion of dicarboxylic acids plus urine ketones at the time of presentation correlated well with the plasma lactate (r2 = 0.9676) and peak blood ammonia (r2 = 0.9216) levels. Our results document the occurrence of significant dicarboxylic aciduria in Reye syndrome and indicate that fatty acid metabolism is more impaired in this disorder than previously appreciated.

J Chromatogr. 1983 Aug 12.
Identification of long chain dicarboxylic acids in the serum of two patients with Reye's syndrome.
Ng KJ, Andresen BD, Hilty MD, Bianchine JR.

Sera from two patients with Reye's Syndrome were analysed by computerized capillary gas chromatography--mass spectrometry profiling techniques. The most striking abnormalities were the accumulation of long chain dicarboxylic acids. Four saturated dicarboxylic acids (dodecanedioic, tetradecanedioic, hexadecanedioic, and octadecanedioic), and six unsaturated long chain dicarboxylic acids (dodecenedioic, tetradecenedioic, tetradecadienedioic, hexadecenedioic, octadecadienedioic, and octadecenedioic) were identified. The C16 and C13 dicarboxylic acids have never been reported for Reye's Syndrome or any other dicarboxylic acidemias. The data might reflect marked increase of extramitochondrial omega-oxidation of long chain fatty acids or impaired metabolism of omega-dicarboxylic acids formed in Reye's patients.