J. Inher. Metab. Dis. 14 (1991) t65-173 © SSIEM and KluwerAcademicPublishers. Printed in the Netherlands

Atypical Riboflavin-Responsive Glutaric Aciduria, and Deficient Peroxisomal Glutaryl-CoA Oxidase Activity: a New Peroxisomal Disorder M. J. BENNETT1., R. J. POLLITT1, S. I. GOODMAN2, D. E. HALE3 and J. VAMECQ4"

1Departments of Chemical Pathology and Paediatrics, The Children's Hospital, Sheffield SIO 2TtI, UK; 2Department of Pediatrics, University of Colorado School of Medicine, Denver, CO 80262, USA; 3Endocrine/Diabetes Division, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; 4Laboratoire de Chimie Therapeutique, Ecole de Pharmaeie, Universit~ Catholique de Louvain, Brussels, B-1200, Belgium

Summary: Investigation of cultured skin fibroblasts in a patient with atypical riboflavin-responsive glutaric acidura revealed a marked deficiency of peroxisomal glutaryl-CoA oxidase. This is the first patient to be reported with glutaric aciduria caused by a peroxisomal rather than a mitochondrial dysfunction. This enzyme appears to be specific for glutaryl-CoA, as lauryl-CoA and dodecanedioyl-CoA oxidase activities in the fibroblasts were both normal. The urinary excretion of glutaric acid (0.5mmotmmol creatinine-1) suggests that the flux through this pathway is considerably less than the mitochondrial flux through glutaryl-CoA dehydrogenase. The elevated glutaric acid excretion (to 0.8 mmol mmol creatinine-1) in response to tysine loading suggests that lysine is a precursor.

INTRODUCTION Three distinct genetic disorders have been described in which there is excessive urinary excretion of glutaric acid. All three involve defects in mitochondrial pathways. Isolated deficiency of glutaryl-CoA dehydrogenase (EC 1.3.99.7) results in glutaric aciduria type I (GAI, McKusick 23167). First described by Goodman and colleagues in 1975, approximately 40 patients have now been described. Most of these cases presented between 6 months and 1 year of age with a neurodegenerative picture including profound dystonia, seizures, episodic encephalopathy, choreoathetoid * Present address and correspondence: Lipid-Heart Research Center, Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

MS received 10.10.90 Accepted 4.12.90 165

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movements and cerebral patsy (Amir et al., t989, Goodman and Frerman, 1989). Glutaric aciduria type II (GAII, McKusick 23168), initially considered to be a single disorder, has subsequently been demonstrated to be caused by deficiency of either electron transfer flavoprotein (ETF) or of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO). Both of these disorders prevent the transfer of electrons from the flavin in the acyl-CoA dehydrogenase to the electron transport chain. As a consequence, the normal function of all the mitochondrial acyl-CoA dehydrogenases, requiring the ETF and the ETF:QO electron transferring pathway, is disrupted. The presentation of GAII is variable and ranges from acute neonatal hypoglycaemia, metabolic acidaemia and frequently early death, to later onset involving a chronic myopathic presentation (Frerman and Goodman, 1989). Clinical riboflavin responsiveness has been described in a few patients with GAI (Brandt et al., 1978) and GAII due to both ETF and ETF:QO deficiences (Gregersen et aI., 1990). We present here the investigation of a child with glutaric aciduria which is biochemically responsive to riboflavin, in whom we have been unable to demonstrate a mitochondrial defect. The patient has no detectable activity of peroxisomal glutarylCoA oxidase and represents both a new cause of glutaric aciduria (type III) and a new example of the peroxisomal disorders presenting as an isolated single enzyme defect. CASE REPORT

I.N. is the fourth child of distantly related Pakistani parents. She was born at term by normal delivery and weighed 2.4kg. Due to failure to thrive with postprandial vomiting, a series of investigations was initiated at 11 months of age. These studies revealed two abnormalities. First, she was shown to be homozygous for/~-thalassaemia and the thalassaemia trait was confirmed in her parents. Second, she was shown to have a significant glutaric ac~duria (urine gtutaric acid = 0.5 mmot mmol creatinine- ~). All other metabolic analyses including amino acids (blood and urine), liver function tests, lactate, pyruvate and acid/base balance, revealed normal results. Following diagnosis she commenced a course of riboflavin (200 mg b.d.). At the age of 2 years 6 months she had a right lower motor neurone facial palsy which slowly resolved and did not appear to be associated with acute metabolic decompensation. At the age of 5 years 8 months (July, 1990) she remains well on riboflavin. She requires transfusions at 5-6 weekly intervals and chelation therapy for her thalassaemia. Investigation of her siblings revealed none with homozygous/%thalassemia. There was a small and persistent excretion of glutaric acid (8 #mol mmol creatinine-1) in an older sibling, who is otherwise well at 10 years of age. MATERIALS AND METHODS In vivo studies: Urine samples from all of the in vivo loading studies were stored at -20°C until use. All urines were examined using capillary gas chromatography/mass spectrometry. Glutaric acid levels were quantitated as previously described (Bennett et aI., 1986). Fasting urine samples were the first urines voided following an overnight J. Inher. Metab. Dis. 14 (1991)

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(12 h) fast. Random samples were collected at the time of clinic visits. For the loading tests, the patient was admitted, fasted overnight (12 h) and gi,~en oral lysine (200 mg/kg). She was then allowed to feed normally. All urines voided were collected for the next 24 h and analysed for glutaric acid excretion. A similar protocol was used for the oral leucine load on the next day (200mg/kg), designed to determine whether metabolites consistent with GAII could be detected.) She was then maintained on a normal diet for three days in order to determine baseline glutaric acid excretion, prior to starting riboflavin therapy (200 mg b.d.). Random urines were collected after one week of therapy. Riboflavin was discontinued for two weeks, after which time further urines were collected. Riboflavin was reintroduced after this time, with further urine collections after one week of therapy. She has subsequently remained on the same dose of riboflavin. In vitro studies." A skin biopsy was taken for fibroblast culture for the following investigations. Samples from the parents were not available. Glutaryl-CoA dehydrogenase activity was assayed according to the method of Goodman and colleagues (1975), in which conversion of [1,5-14C]glutaryl-CoA to 14CO2 is measured using methylene blue as the terminal electron acceptor. We also measured glutaryl-CoA dehydrogenase activity using the natural electron acceptor, ETF, essentially using the method described for long-, medium- and short-chain acylCoA dehydrogenase (Hale et aI., 1990). The concentration of glutaryl-CoA used in the assay was 50 #mol/L. The flux through the fatty acid oxidation pathway (and activity of ETF and ETF:QO) was assessed in intact cultured fibroblasts using the oxidation of [9,10-3H]myristic acid as decribed by Manning and colleagues (1990) for long- and medium-chain length fatty acid oxidation rates, and [1-14C]octanoic acid (Bennett et al., 1984) for medium-chain length fatty acids. Immunoblots of ETF and ETF:QO antigens in fibroblasts were carried out as previously described (Loehr et al., 1990). The peroxisomal hydrogen peroxide-producing oxidases (glutaryl-, lauryt- and dodecandioyl-CoA oxidases) were assayed in fibroblasts according to the method of Vamecq (1990). The CoA ester of dodecanedioic acid was formed by chemical synthesis from dodecandedioic anhydride and CoA (Vamecq et al., 1989). The assay medium (1 ml) contained an aliquot of the fibroblast homogenate (prepared in 0.02 mmol/L FAD), 80 mmol/L of glycylglycine buffer, pH 8.3, 0.02 mg of horseradish peroxidase (Sigma type II), 2.5 mmol/L of homovanillic acid, 0.02 mmol/L of FAD, 20#mol/L of fatty acid-free bovine serum albumin and (for the test but not blank conditions) 100#mol/L of acyl-CoA substrate. A continuous monitoring of fluorescence was performed in test and blank conditions, test minus blank values being used for the calculation of the oxidase activities. RESULTS Urine organic acids: Urine organic acid analysis by GC/MS was carried out on a total of 32 samples collected under a variety of conditions (random, fasting, and following loading trials with lysine, leucine and riboflavin). The only abnormal metabolite level detected was that of glutaric acid. We were unable to detect the

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presence of glutaconic acid to support a diagnosis of GAI, nor were we able to find increased amounts of adipic, suberic, sebacic or ethylmalonic acids or of isovaleryt-, butyryl-, hexanoyl- or suberylglycine to support a diagnosis of GAII. In 15 samples collected when the patient was not subjected to loading or riboflavin, the glutaric acid excretion varied between 0.2 and 0.5 mmol mmol creatinine - 1. Small amounts of both 3- and 2-hydroxyglutarate (less than 10#molmmolcreatinine-1) were detected in all samples but the ratios and amounts of these were identical in all family members and thus did not support a diagnosis of GAI or GAII. Figure 1 shows the response of gtutaric acid excretion to the loading trims. Lysine toading resulted in an increase in the gtutarate excretion, reaching a peak of 0.8 mmol mmol creatinine - 1, whereas the excretion fell to less than 0.1 mmol mmolcreatinine- 1 following the leucine load and in the initial trial of riboflavin. Withdrawal of riboflavin resulted in an increase in glutaric acid excretion to pretreatment levels within three days. Subsequent levels while on riboflavin have remained below 0.1 mmol mmol creatinine - 1. Glutaryl-CoA dehydrogenase: The activity of glutaryl-CoA dehydrogenase in cultured fibroblasts using the 14COz production assay was 55 pmol rain- i m g protein- 1 (normal range 17-50); patients with GAI usually have activities less than 5, and the enzyme activity is frequently undetectable. The activity of glutaryl-CoA dehydrogenase using the E T F linked assay was

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Figure 1 Urine glutaric acid levels in a patient with peroxisomal glutaryl-CoA oxidase deficiency in response to loading trials with lysine (200mg/kg) and leucine (200mg/kg) and on riboflavin therapy (200 mg b.d) J. tnher. Metab. Dis. 14 (1991)

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0.80 + 0.13 nmot m i n - x (mg protein)-1 (normal range 0.52-0.84, n = 4). OctanoylCoA dehydrogenase activity was 4 . 5 9 n m o l m i n - t ( m g protein) -~ (normal range 4.17 + 0.37, n = 142). Oxidation of radio-labelled Jatty acids by intact fibroblasts: The production of tritiated water from [9,10-3H]myristate in the patient's fibroblasts was 3.25 ± 0.50 nmol h - 1 (nag protein)- 1 (n = 6); simultaneous normals were 3.80 _ 0.34 (5 lines, 15 assays). Patients with GAII have activities of the order of less than 0.1 (Manning et aI., 1990). The oxidation of [1 - 14C]octanoate was 303 pmol h - 1 (mg protein)- 1 (within batch control values, 228-768, n = 5); patients with GAII have less than 5% of normal activity. E T F a n d E T F : QOproteins: ETF and ETF:QO antigens were present in apparently normal size and amount; catalytic assays of E T F and ETF:QO were not carried out. Peroxisomal acyt-CoA oxidase activities: Three types of aeyt-CoA oxidase activity was measured directly on homogenized fibroblasts from the patient and controls (Table 1). While glutaryl-CoA oxidase activity was not detected in preparations from the patient, oxidase activities assayed with either lauryl-CoA or dodecanedioyl-CoA as substrate were detected. The three acyl-CoA oxidases were detected in controls. In fibroblasts from the patient, besides a deficiency in glutaryl-CoA oxidase, an increase in both lauroyl-CoA and dodecanedioyl-CoA oxidase activities was recorded. Fibroblasts from a patient with Zellweger syndrome and from one with a diagnosis of neonatal adrenoleukodystrophy demonstrated little or no activity to all three substrates. DISCUSSION Our studies in this patient clearly point towards a previously unrecognized defect in peroxisomal glutaryl-CoA oxidase, at least as expressed in cultured skin fibroblasts. This defect is one of a growing number of isolated peroxisomal enzyme defects recently described (Moser et al., 1990; Wanders et al., 1990). The results exclude the diagnosis of either GAI, with normal results obtained using two different enzyme Table 1 Oxidase activities with various acyl-CoAs in fibroblasts from the patient and control subjects

Patient

Glutaryl-Co A

Lauro yl-Co A

Dodecanedio yL CoA

ND (< 10)

280

304

Controls (n = 7)

187 _ 43 (SD) 137 + 15 126 + 21 (range: 98-23 t) (110-156) (84-153) ND: no detectableactivity The acyl-CoAoxidaseactivitiesare expressedas pmol of hydrogenperoxideproduced per rain per mg of protein

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assays, or GAII, from the normal results of the myristate and octanoate oxidation studies. The normal results for the Western blots for ETF and ETF:QO proteins imply only that proteins of normal size are produced in this patient. The peroxisomal glutaryl-CoA oxidase has recently been described (Vamecq and Van Hoof, 1984) and the finding of a patient with the enzyme defect raises a number of important questions. Firstly, is the oxidase for glutaryl-CoA distinct from fatty acyl-CoA oxidase or dodecanedioyl-CoA oxidase activity? Our observations of normal or raised activities to lauryl-CoA and dodecanedioyl-CoA in this patient support the existence of a glutaryl CoA-specific enzyme. Alternatively, it remains possible that the mutation could be one which affects the substrate specificity of a single oxidase such that only activity towards glutaryl-CoA is affected. Increased activities of lauryl- and dodecanedioyl-CoA oxidation may reflect peroxisomal proliferation in the disorder. The second question raised by our observations concerns the physiological relevance of the pathway of glutaryl-CoA metabolism in peroxisomes. The product of peroxisomal glutaryl-CoA oxidase activity is glutaconyl-CoA. The fate of this metabolite as an intermediate in peroxisomal glutarate metabolism is unknown. Figure 2 outlines the various possible routes of glutarate production and metabolism. Our results clearly indicate normal mitochondrial metabolism of glutaryl-CoA, so it must be assumed that increased excretion of glutarate in our patient arises as a consequence of the peroxisomal defect. Vamecq and colleagues (1986) were unable to demonstrate mitochondrial to peroxisomal transfer of glutaryl-CoA in rat liver, therefore there must be alternative sources of this substance in the cell. One possibility is that the intraperoxisomal pool of glutaryl-CoA arises from the metabolism of pipecolate via the formation of piperidine as shown in Figure 2. Clinical studies on this patient support this idea, since loading with lysine, a precursor of pipecolate, resulted in an elevation of glutarate excretion. The lysine loading test also allows an estimate of the relative contribution of the peroxisomal pathway to the metabolism of lysine. The total dose of lysine given was 2 g (approximately 14 mmol). The mean excretion in excess of baseline excretion in seven urines collected over a period of 24h, and representing total output, was 0.14mmolmmolcreatinine -1 (range 0.070.29), after which time the excretion returned to baseline. The average creatinine excretion for these samples was 2.04 mmol/L (range 1.2-2.5). Assuming a total output of 1 litre of urine, the approximate additional excretion of glutarate over 24 h was 0.14 x 2.04 = 0.3 mmol, or approximately 2% of the given dose. The baseline level of glutarate excretion was less than we have previously measured in GAI and GAII (Bennett et al., 1984, 1986). This agrees with the earlier observations of Vamecq and colleagues (1984), who suggested that the peroxisomal enzyme made little or no contribution to the catabolism of glutaryl-CoA in 'normal' conditions. Another potential source of peroxisomal glutaryl-CoA is the fl-oxidation of longer chain odd-numbered dicarboxylic acids. Odd-numbered dicarboxylic acids, particularly azelaic and pimelic acids, are found in the urine in Zellweger syndrome (Rocchiccioli et al., 1986). The normal peroxisomal metabolism of these compounds is presumably by fl-oxidation to glutarate, and then further oxidation by glutarylCoA oxidase. In Zellweger syndrome, all peroxisomal fl-oxidation enzymes are J. lnher. Metab. Dis. 14 (1991)

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Peroxisomat Gtutaric Aciduria odd -chain fatty acids odd-chain

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deficient, hence the accumulation of the longer chain length odd-chain dicarboxylic acids. In our patient, the lack of detection of azelaic and pimelic acids points towards a high specificity of glutaryl-CoA oxidase for glutaryl-CoA and not to other odd chain length dicarboxylic acids. Indeed, the urine analysis in our patient was remarkable for the lack of other unusual metabolites. Urinary organic acid profiles are characteristic for GAI, with glutaric, 3-hydroxyglutaric and glutaconic acids being excreted in abnormal amounts. In GAII the urinary organic acids vary with the degree of metabolic decompensation. The major metabolites of diagnostic significance include glutaric, ethylmalonic, 2-hydroxyglutaric, adipic, suberic and sebacic acids and isovaleryl-, butyryl-, hexanoyt- and suberytglycine. Despite loading with lysine and leucine, we were unable to detect any abnormal metabolites other than glutaric acid in our patient. Our observation of decreased urinary excretion of glutarate in those samples collected after an overnight fast may be of possible significance in understanding metabolic flux through the peroxisomal pathway. It is likely that during periods of

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fasting when fewer dietary amino acids are available, there is a reduction in the precursor compounds which are available for the peroxisome, and that the preferred pathway of lysine metabolism is protein synthesis. The implication is that subjects with peroxisomal glutaryl-CoA oxidase deficiency may have reduced metabolite accumulation when fasting. The reduction of glutarate excretion following leucine loading may also be related to a sparing effect of lysine metabolism and has possible therapeutic potential. Our patient demonstrated an unequivocal biochemical response to riboflavin therapy, but it is not clear whether this is matched by a clinical response. If the neurodegenerative picture is related purely to the elevated tissue levels of glutaric acid then the source of the glutaric acid (mitochondrial or peroxisomat) is irrelevant. The instigation of riboflavin therapy may have prevented the severe consequences seen in GAI, a hypothesis which is now difficult to test. The enzyme defect may also be benign and have no severe clinical consequences; most of the clinical features could be attributed to the/%thalassaemia. The observation of a modest elevation in glutaric excretion in a well, older sibling would support this. However, caution must be taken when assessing disease severity in glutaric aciduria, since in GAI there has been considerable clinical heterogeneity, even in a single pedigree (Amir et al., 1989). The finding of a third cause of glutaric aciduria adds considerably to the diagnostic difficulties when investigating patients with abnormal amounts of glutaric acid in the urine. It is likely, for instance, that a number of patients with assumed, but nonenzyme-confirmed GAI, will eventually be shown to have this new disorder. Further study of patients with glutaryl-CoA oxidase deficiency may lead to a better understanding of its natural history and of the significance of the pathway of peroxisomal glutaryl-CoA metabolism. ACKNOWLEDGEMENTS We would like to thank Dr J. S. Lilleyman for allowing us to study his patient and Brenda O. Barnard and Joanne Dupres for typing this manuscript.

REFERENCES

Amir, N., Elpeleg, O. N., Shalev, R. S. and Christensen, E. Glutaric aciduria type I: Enzymatic and neuroradiologic investigations in two kindreds. J. Pediatr. 114 (1989) 983-989 Bennett, M. J., Curnock, D. A., Engle, P. C., Shaw, L., Gray, R. G. F., Hull, D., Patrick, A. D. and Pollitt, R. J. Glutaric aciduria type II: biochemical investigation and treatment of a child diagnosed prenatally. J. Inher. Metab. Dis 7 (1984) 57-61 Bennett, M. J., Marlow, N., Pollitt, R. J. and Wales, J. K. H. Glutaric aciduria type I: biochemical investigations and post mortern findings. Eur. J. Pediatr. 145 (1986) 403-405 Brandt, N. J., Brandt, S., Christensen, E., Gregerson, N., Rasmussen, V. Glutaric aciduria in progressive choreo-athetosis. Clin. Genet. 13 (1978) 77-80 Frerman, F. E. and Goodman, S. I. Glutaric acidemia type II and defects of the mitochondrial respiratory chain. In: Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D. (eds.), The Metabolic Basis of Inherited Disease, 6th edn., McGraw-Hill, New York, t989, pp. 915-931 Goodman, S. I. and Frerman, F. E. Organic acidemias due to defects in lysine oxidation: 2ketoadepic acidemia and glutaric acidemia. In: Scriver, C. R., Beaudet, A. L., Sly, W. S. and J. lnher. Metab. Dis. 14 (1991)

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Valle, D. (eds.), The Metabolic Basis of Inherited Disease, 6th edn., McGraw-Hill, New York, 1989, pp. 847-853 Goodman, S. I., Markey, S. P., Moe, P. G., Miles, B. S. and Teng, C. C. Glutaric aciduria: a 'new' disorder of amino acid metabolism. Biochem. Med. 12 (1975) 12-21 Gregersen, N., Rhead, W. and Christensen, E. Riboflavin responsive glutaric aciduria type IL In: Tanaka, K. and Coates, P. M. (eds.), Fatty Acid Oxidation: Clinical, Biochemical and Molecular Aspects, Liss, New York, 1990, pp. 477-494 Hale, D. E., Stanley, C. A. and Coates, P. M. Genetic defects of acyl-CoA dehydrogenases: studies using an electron transfer flavoprotein reduction assay. In: Tanaka, K. and Coates, P. M. (eds.), Fatty Acid Oxidation: Clinical, Biochemical and Molecular Aspects, Liss, New York, 1990, pp. 333-348 Loehr, J. P., Goodman, S. I. and Frerman, F. E. Glutaric aciduria type II: Heterogeneity of clinical and biochemical phenotypes. Pediatr. Res. 27 (1990) 311-315 Manning, N. J., Olpin, S. E., Pollitt, R. J. and Webley, J. A comparison of [9,10 3HI palmitic and myristic acids for the detection of defects in fatty acid oxidation in intact cultured fibroblasts. J. Inher. Metab. Dis. 13 (1990) 58-68 Moser, H. W., Moser, A. B., Chen, W. W. and Watkins, P. A. Adrenoleukodystrophy and Zellweger syndrome. In: Tanaka, K. and Coates, P. M. (eds.) Fatty Acid Oxidation: Clinical, Biochemical and Molecular Aspects, Liss, New York, 1990, pp. 511-535 Rocchiccioli, F., Auberg, P. and Bougnerese, P. F. Medium and long-chain dicarboxylic aciduria in patients with Zellweger syndrome and neonatal adrenoleukodystrophy. Pediatr. Res. 20 (1986) 62-68 • Vamecq, J. Flurometric assay of peroxisomal oxidases. Anal. Biochem. 186 (1990) 340-349 Vamecq, J. and Van Hoof, F. Implications of a peroxisomal enzyme in the catabolism of glutaryl-CoA. Biochem. J. 221 (1984) 203-211 Vamecq, J., de Hoffman, E. and Van Hoof, F. Mitochondrial and peroxisomal metabolism of glutaryl-CoA. Eur. J. Biochem. 146 (1984) 663-669 Vamecq, J., Labert, R., Van Hoof, F., de Hoffman, E., Vallee, L., Cartigny, B., Nuyts, J. P., Christensen, E., Van Eldere, J., Eyssen, H., Evrard, P. and Misson, J. P. Peroxisomes and glutaric acidura type I. Arch. Int. Physiol. Biochim. 94 (1986) 1 Vamecq, J., Draye, J.-P. and Brison, J. Rat liver metabolism of dicarboxylic acids. Am. J. Physiol. 19 (1989) G680-G688 Wanders, R. J. A., van Roermund, C. W. T., Schutgens, R. B. H., Barth, P. G., Heymans, H. S. A., van den Bosch, H. and Tager, J. M. The inborn errors of peroxisomal t-oxidation: a review. J. Inher. Metab. Dis. 13 (t990) 4-36

J. Inher. Metab. Dis. 14 (1991)

Atypical riboflavin-responsive glutaric aciduria, and deficient peroxisomal glutaryl-CoA oxidase activity: a new peroxisomal disorder.

Investigation of cultured skin fibroblasts in a patient with atypical riboflavin-responsive glutaric acidura revealed a marked deficiency of peroxisom...
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