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C,-C,O-Dicarboxylic Aciduria: Investigations of a Patient with Riboflavin Responsive Multiple Acyl- Coa Dehydrogenation Defects

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C,-C,O-Dicarboxylic Aciduria: Investigations of a Patient with Riboflavin Responsive Multiple Acyl- Coa Dehydrogenation Defects Pediatr. Res. 16: 861-868 (1982) C,-C,o-Dicarboxylic Aciduria: Investigations of a Patient with Riboflavin Responsive Multiple Acyl- CoA Dehydrogenation Defects N. GREGERSEN,'~'' H. WINTZENSEN, S. KBLVRAA E. CHRISTENSEN, M. F. CHRISTENSEN, N. J. BRANDT, AND K. RASMUSSEN Research Laboratory for Metabolic Disorders, University Department of Clinical Chemistry, Aarhus Kommunehospital, Aarhus; Department of Pediatrics, Herning Hospital, Herning; Institute of Human Genetics, University of Aarhus, Aarhus; and Section of Clinical Genetics, University Department of Pediatrics and of Gynaecology and Obstetrics, Rigshospitalet, Copenhagen, Denmark. Summary one or more acute attacks, most frequently characterized by a Reye-like syndrome (37) with vomitGg and increasing lethargy The abnormal metabolites-adipic, suberic, and sebacic acids- that eventually leads to coma. Biochemical characteristics includes were detected in large amounts in the urine of a boy during a metabolic acihosis, hypoglycemia, fatty infiltration of the liver, Reye's syndrome-like crisis. Substantial amounts of 5-OH-caproic and large amounts of the Cs-CIO-dicarboxylicacids, i.e., adipic, acid, caproylglycine, glutaric acid, and 3- OH-butyric acid and suberic, and sebacic acids in the urine. In spite of the similarities moderately elevated amounts of ethylmalonic acid, methylsuccinic between the clinical pictures during the acute attacks in these acid, 3-OH-isovaleric acid, and isovalerylglycine were also found. patients, the biochemical presentation exhibited a high degree of These metabolites were consistently present in urine samples heterogeneity within the group. The precise location of the enzyme collected in the boy's habitual condition after the attack. 1-[14C]- defect has not been found in any of the patients, but preliminary Palmitic acid was oxidized at a normal rate, whereas U-[14C]- enzyme studies and the excretion pattern of organic acids suggest Palmitic acid was oxidized at a reduced rate in cultured skin that the defect in the patients described by us (15), by Truscott fibroblasts from the patient, thus indicating a defect at the level of and coworkers (36) and by Naylor and coworkers (27) is localized medium- and/or short-chain fatty acid oxidation. Riboflavin med- to the dehydrogenation of medium-chain fatty acids, whereas the ication (100 mg three times a day) significantly reduced the defect in the patient reported by Mantagos et al. (25) is restricted excreted amounts of pathologic metabolites, suggesting a flavi- predominantly to the dehydrogenation of the short-chain fatty neadeninedinucleotide-related acyl-CoA dehydrogenation defect acids. During the attack the case described here exhibited clinical as the cause of the disease. symptoms very similar to the above-mentioned cases including Carnitine in plasma was low in the patient (6 pmole/liter, large amounts of Cs-Clo-dicarboxylic acids in the urine. Unlike controls 26-74 pmole/liter), suggesting carnitine deficiency as a the other cases, this patient excreted substantial amounts of these secondary effect of the acyl-CoA dehydrogenation deficiency. metabolites together with 3-OH-butyric acid in the habitual con- dition. We are, therefore, possibly dealing with a new inborn error Speculation of the /?-oxidation of fatty acids. The aim of the present report is The present patient, who presented with a Reye's syndrome-like to characterize the disease clinically and biochemically and to attack, suffers from impaired dehydrogenation of acyl-CoA result- describe the first successful attempt to treat one of these diseases ing in accumulation of acyl-CoA in the cells. Attacks with similar with vitamins. Both clinically and biochemically he responded symptoms are seen in other acyl-CoA dehydrogenation deficien- positively to riboflavin treatment, and as a result the boy is now cies, such as glutaric aciduria types I and 11, other types of Ce-ClO- receiving permanent riboflavin medication. dicarboxylic acidurias and isovaleric acidemia. Reduced flow through the acyl-CoA dehydrogenation steps may therefore be an MATERIALS AND METHODS ethiologic factor in Reve's" svndrome." Several of the accumulated ~C~I-C~A'sare toxic and may be responsible for some of the Family history. The patient (P.J.) is a male, now aged 5 years symptoms. The low carnitine level in plasma and the elevated and 6 months. A brother, (J.J.), who is 10 years older had an esterified carnitine excretion in the present patient indicate that attack of Reye's syndrome, versed by liver biopsy, when he was acyl-CoA accumulation may cause a functional carnitine deficiency 2 years old. He suffered from a slight hypotonia during the by sequestration of carnitine as acyl-carnitines. As the inborn following 2 years, but since then he has been clinically normal. In defect, systemic carnitine deficiency may exhibit symptoms like the routine screening of the family members, a slight organic those of Reye's syndrome, it may be speculated whether functional aciduria was found in J.J. (Table 1) indicating a /?-oxidation defect carnitine deficiency in patients with accumulated acyl-CoA is (see below). another causal factor in the development of the symptoms during The patient (P.J.) has another older healthy brother (B.J.) and attacks. a twin sister (S.J.) with prurigo besnier, who is otherwise clinically healthy. The mother suffer from rheumatoid arthritis. The father is healthy. Since the first report of patients with saturated CsClo-dicar- Case history. The patient (P.J.) was born 2 wk before term after boxylic aciduria due to possible /?-oxidation defect (13), several an uncomplicated pregnancy. Birthweight was 2050 g. In the patients with similar clinical and biochemical characteristics have neonatal period, he was once admitted to a hospital with pneu- been described (15,25,27,36). All the patients reported have had monia and slight icterus. During early childhood, he suffered from 86 DICARBOXYLIC ACIDURIA frequent upper respiratory tract infections. One year before the present admission he had an episode of vomiting, lethargy, and fever. He recovered without treatment. Physically he was less developed than his twin sister. He suffered from a slight reduction in muscle strength and muscle tonus and he was 16 months old when he first walked alone. At the age of 2 years and 8 months he was admitted to, the hospital after 2 wk of weariness, loss of appetite, and occassional vomiting. The last 3 days before admis- sion his clinical condition deteriorated with frequent attacks of vomiting. His temperature was 38°C. At admission (August 22, 1979), he was drowsy, with normal respiration and lightly infected in the respiratory tract. Hepatomegaly was not present. Plasma glucose and pH were normal (Table 2). He was treated with i.v. glucose and electrolytes. The following day his condition deteri- orated. He became more drowsy and developed Cheyne-Stokes respiration. His temperature was normal. Blood glucose was de- creasing and a metabolic acidosis developed. Spinal glucose was low. The liver was not enlarged but the activity of liver enzymes in serum was very high (Table 2). Two days after admission (August 24, 1979) he was very lethargic and difficult to contact. Hepatomegaly was now pronounced with 100-fold increased liver enzymes. Consent for liver biopsy was not given by the parents. He suffered now from hypoglycemia and the metabolic acidosis was not fully compensated. Plasma ammonia concentration was just below the upper control limit (Table 2), and he was still undergoing treatment with glucose and electrolytes. The following day (August 25, 1979), his condition improved (Table 2). The hepatomegaly gradually decreased, but 4 wk later when he was discharged, the liver could still be palpated 7 cm below the right curvature. As before admission he suffered from a slight to mod- erate muscle hypotonia, but creatine kinase was within control limits, as it was during the crisis. Liver enzymes were normalized. One wk after the crisis the ammonia level was 37 pmole/liter. One month after discharge, the clinical condition was satisfactory, although he had reduced mus- cle strength, was slightly hypotonic and had slight hepatomegaly. Before the trials with riboflavin (100 mg 3 times a day) thorough clinical investigations secured the fact that the patient was in his habitual condition. At the time of the first trial the habitual condition was characterized by a slight hypotonia, but no hepa- tomegaly. The level of aminotransferases were slightly above controls and a slight metabolic acidosis existed (February 28, 1980 in Table 2). After both trials, the riboflavin treatment was termi- nated. The patient had a second attack of drowsiness and vomiting (July, 28, 1980). On admission, he was not hypoglycemic and metabolic acidosis was not present, but the liver was enlarged (4 cm below the curvature) and liver enzymes concentration were increased (Table 2). Riboflavin treatment was instituted at once. Within 1 wk, the patient was in a satisfactory condition again (Table 2), without having gone through lethargic and hypogly- cemic stages. One and one-half months later i.e., after 1% month of riboflavin treatment, he was in a very good condition (Table 2). Since this last attack, the patient has been treated with 100 mg riboflavin 3 times a day, except for a short period in January 198 1. After 1 wk without riboflavin the patient started vomiting, whereafter riboflavin treatment was instituted again. A few days later he was free of symptoms. During the riboflavin treatment the patient has been in a satisfactory clinical condition and is now developing normally; however, occassionally he has been fatigued and has lost his appetite. The hypotonia has decreased and the hepatomegaly has not been present since the second attack. Biochemical methods. Blood glucose, standard bicarbonate, pH, base-excess, serum aspartate aminotransferase (ASAT) and serum alanine aminotransferase (ALAT) were analysed by means of standard methods. Amino acids in serum and urine were measured with an automatic amino acid analyzer (6). Free and esterified carnitines were determined by the carnitine acetyltransferase method described by McGarry and Foster (10).
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