Molecular Genetics and Metabolism 101 (2010) 178–182
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Molecular Genetics and Metabolism j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y m g m e
Glutaric aciduria type 1 in South Africa—high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans George van der Watt a,⁎, Elizabeth P. Owen a, Peter Berman a, Surita Meldau a, Nicholas Watermeyer b, Simon E. Olpin c, Nigel J. Manning c, Ingrid Baumgarten a, Felicity Leisegang a, Howard Henderson a a b c
Division of Chemical Pathology, Groote Schuur and Red Cross Children's Hospitals, University of Cape Town, Cape Town, South Africa Department of Chemistry, University of Cape Town, Cape Town, South Africa Department of Clinical Chemistry, Sheffield Children's Hospital, Sheffield, United Kingdom
a r t i c l e
i n f o
Article history: Received 20 May 2010 Received in revised form 27 July 2010 Accepted 27 July 2010 Available online 3 August 2010 Keywords: Glutaric aciduria type 1 Glutaryl-CoA dehydrogenase Newborn screening A293T Glutaric acid 3 hydroxyglutaric acid
a b s t r a c t Glutaric Aciduria type 1 (GA 1) is an inherited disorder of lysine and tryptophan catabolism that typically manifests in infants with acute cerebral injury associated with intercurrent illness. We investigated the clinical, biochemical and molecular features in 14 known GA 1 patients in South Africa, most of whom were recently confirmed following the implementation of sensitive urine organic acid screening at our laboratory. Age at diagnosis ranged from 3 days to 5 years and poor clinical outcome reflected the delay in diagnosis in all but one patient. Twelve patients were unrelated black South Africans of whom all those tested (n = 11) were found homozygous for the same A293T mutation in the glutaryl-CoA dehydrogenase (GCDH) gene. Excretion of 3-hydroxyglutarate (3-OHGA) was N 30.1 μmol/mmol creatinine (reference range b 2.5) in all cases but glutarate excretion varied with 5 patients considered low excretors (glutarate b 50 μmol/mmol creatinine). Fibroblast GCDH activity was very low or absent in all of five cases tested. Heterozygosity for the A293T mutation was found 1 in 36 (95% CI; 1/54 - 1/24) unrelated black South African newborns (n = 750) giving a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) in this population. GA 1 is a treatable but often missed inherited disorder with a previously unrecognised high carrier frequency of a single mutation in the South African black population. © 2010 Elsevier Inc. All rights reserved.
1. Introduction Glutaryl-CoA dehydrogenase (EC 1.3.99.7) activity is required for the catabolism of the essential ketogenic amino acids lysine and tryptophan. Autosomal recessive inherited deficiency of GCDH causes glutaric acidaemia type 1 (GA 1; MIM 231670), a cerebral organic acidaemia that typically presents in affected children after a period of normal development with acute encephalopathy and irreversible striatal injury during non-specific illness between the ages of 6 and 18 months of age [1]. The brain in this age group is particularly dependent on ketones and ketogenic amino acids during periods of catabolic stress and in affected individuals, large amounts of GA and to a lesser extent, 3-OHGA accumulate in the brain [2,3]. Neuronal death is most likely induced by mitochondrial tricarboxylic acid cycle failure due to alpha-ketoglutarate depletion triggered by excess GA[2] [4]. Abbreviations: GCDH, glutaryl-CoA dehydrogenase; GA 1, glutaric acidaemia type 1; GA, glutaric acid; 3-OHGA, 3 hydroxyglutaric acid; GC-MS, gas chromatography-mass spectrometry; C5DC, glutaryl carnitine; DBS, dried blood spots; m/z, mass charge ratio; HIV, human immunodefiecency virus. ⁎ Corresponding author. Division of Chemical Pathology, NHLS and University of Cape Town, Red Cross Children's Hospital, Rondebosch, Cape Town, South Africa, 7700. Fax: + 27 216585225. E-mail address:
[email protected] (G. van der Watt). 1096-7192/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2010.07.018
Most patients are diagnosed by the demonstration of markedly elevated GA with moderately increased 3-OHGA in urine by GC-MS of organic acids, as well as by elevated C5DC in plasma, DBS and urine by electrospray-ionization tandem mass spectrometry [5,6]. The diagnosis is confirmed by GCDH enzyme activity assay in cultured fibroblasts or isolated lymphocytes, or by demonstration of two known disease causing mutations in the GCDH gene [7]. In DBS newborn screening programs, GA 1 is flagged for follow up testing when elevated C5DC is detected. The major diagnostic pitfall of all forms of biochemical testing for GA 1 is the fact that patients fall into two defined groups based on diagnostic urine metabolite excretion, i.e. low excretors and high excretors of GA ,both presenting with the same variable clinical phenotype [1,8]. Patients of the low excretor phenotype can be missed by routine biochemical methods as well as by DBS newborn screening [9–12]. They can, however, be detected in DNA-based newborn screening programs. This approach has been followed in populations where a low excretor phenotype is common and is associated with a high carrier frequency for a known GCDH gene mutation [13,14]. The importance of pre-symptomatic diagnosis of GA 1 is supported by the fact that it is a treatable disorder. Although outcomes are variable, a low lysine diet, carnitine supplementation and aggressive management of intercurrent illness with additional glucose (plus insulin) significantly reduces the frequency of acute encephalopathic
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crises and the severity of associated bilateral striatal injury and movement disorders [14–17]. Newborn screening programs report an incidence of between 1 in 65 000 and 1 in 181 000, with an estimated overall prevalence of 1 in 100 000 [15,16,18]. The disease is genetically heterogeneous and 108 known pathogenic mutations have been recorded in the Human Gene Mutation Database [19,20]. In addition, there are two known genetically isolated populations with a GA 1 founder effect and high carrier frequencies of a single disease-causing mutation. In the Old Order Amish of Pennsylvania, approximately 1 in 500 newborns are homozygous for the missense mutation A421V and in the Oji-Cree Island Lake First Nations communities of Canada 1 in 235 newborns are homozygous for the splice site mutation IVS-1 + 5G → T [13,21]. The disease is also assumed to be over-represented in the Irish Travelers with five identified mutations [22] and in the Israeli Palestinians with nine identified mutations [23]. Prior to this publication, 3 cases of GA 1 had been described in South Africa. All 3 in black South African children, one of whom was known to be homozygous for the A293T mutation in the GCDH gene [24,25]. The disease was presumed to have a low incidence, similar to other studied populations. Following the implementation of sensitive urinary organic acid screening by GC-MS at our institution however, an additional 11 unrelated cases of GA 1 have been confirmed since the beginning of 2008. Due to the paucity of information regarding the spectrum of this disease in Southern Africa and the likelihood that it may be more prevalent than believed, we investigated and reviewed all available cases and present the biochemical and molecular findings here. 2. Materials and methods 2.1. Patients Information regarding the first known patient has been previously reported [25]. Diagnostic laboratory samples, and collated clinical and demographic information were obtained through the treating physicians of 13 known GA 1 patients from throughout South Africa. Dried cord-blood spots from 750 randomized anonymised black African babies, born in the Cape Town Metropole during 2002 were available from a previous study investigating the carrier frequency of transferase deficiency galactosaemia [26]. The samples were randomized by selecting every 5th DBS from 3600 consecutively enrolled black children, over a period of 6 months, from the thyroid newborn screening program, based at Red Cross Children's hospital. Approval for the study was obtained from the Health Sciences Faculty Research Ethics Committee at the University of Cape Town (ref 094/2009, 093/ 2002). 2.2. Urine organic acid analysis Quantitative analysis of GA and 3-OHGA was performed on an Agilent 7890A/5975C GC-MS (Agilent Technologies, Santa Clara, CA, USA) following standard ethylacetate/diethyl-ether liquid/liquid extraction of organic acids from acidified urine and trimethylsilyl derivatisation. For quantitation, the mass spectrometer was operated in single ion monitoring mode and the ion currents of GA (m/z 261), 3-OHGA (m/z 259) and pentadecanoate (PDA, internal standard m/z 299) were measured and used to quantitate GA and 3-OHGA against standard curves generated from purified standards. Standards were obtained from Sigma-Aldrich, Inc (St Louis, MO, USA). For qualitative organic acid screening with the MS in scan mode, the ratio of m/z 259/299, representing the ratio of 3-OHGA to PDA specific ions were used to flag 3-OHGA during routine urine organic acid screening analyses [27]. Reference intervals were derived in-house from 35 children aged 7 days to 5 years.
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2.3. GCDH enzyme activity in cultured fibroblasts GCDH activity was determined in sonicates of cultured fibroblasts based on a described method [7,28]. Briefly, confluent fibroblasts from a 75-ml culture flask equivalent to 1 mg cell protein were suspended in 200 μL buffer (5 mM Na2HPO4, pH 7.5 containing 0.5 mM cysteine and 0.1 mM FAD) and sonicated briefly on ice. Sonicate (100 μl) was mixed with 900 μl reagent containing Na2HPO4 (50 mM, pH 7.5), L-cysteine (0.5 mM), FAD (0.1 mM), new methylene blue (2 mM), and [1,5-14C] glutaryl CoA (25 μM, ±6 Ci/mol) (the final concentration of each component in the reaction mix given in parenthesis). The reaction mixture was incubated for 1 h at 37 °C in a sealed plastic petri dish containing a glass microfibre filter impregnated with 0.1 ml 2 M NaOH in its lid. The reaction was terminated by anaerobic addition of 300 μl 50% trichloroacetic acid and 14CO2 evolved by the action of GCDH was trapped in the filter by incubating for a further 30 min at room temperature, and quantitated by beta-scintillation counting. Samples were run in duplicate and the cpm corrected for a blank in which sonication buffer was substituted for cell extract. An aliquot of [1,5-14C] glutaryl CoA was counted separately to correlate 14CO2 cpm to pmol, thereby permitting enzyme activity to be expressed in pmol h−1 mg cell protein−1. Protein concentration was determined by BioRad Protein Assay (Bio-Rad laboratories, GmbH, Munchen, Germany). Glutaryl-CoA [1,5-14C] was synthesized using a novel modified method: Glutaric anhydride [1,5-14C] was synthesized by drying down an aqueous solution of 1 mg glutaric acid and 50 μCi glutaric acid [1,5-14C] (ICN Biochemicals, Inc, Aurora, OH, USA) under reduced pressure in a rotary evaporator, followed by a high vacuum pump. Acetic anhydride (8 ml) was added to the residue and the solution heated for 3 h at 85 °C under protection of a CaCl2 drying tube. Thereafter, excess acetic anhydride was removed under reduced pressure in the rotary evaporator for 30 min at 65 °C and residual acetic anhydride driven off under nitrogen to afford a brown oily residue. This residue was reacted with 2 mL of a cold aqueous solution containing 10 mg CoASH (Sigma-Aldrich, Inc, St Louis, MO, USA) and 100 mg NaHCO3, adjusted to pH 7.3 with HCl after dissolution of the CoASH. The reaction was cooled in an ice bath throughout to yield a 2.5 mmol/l glutaryl CoA [1,5-14C] solution, specific activity ±6 Ci/mol. The solution was acidified with 1 N HCl to pH 5.5 and stored in aliquots at −20 °C. 2.4. GCDH genotyping Mutational analysis of the GCDH gene was performed on genomic DNA isolated from peripheral whole blood. All 11 exons with flanking intronic regions were amplified and sequenced using genomic GCDH sequences as references (GenBank accession nos. GI3150003, GI2316108, GI2316109, and GI2316110). In a single case mRNA extracted from whole blood was sequenced using reverse transcriptase PCR to confirm expression of a novel substitution. A total of 750 black African new-born cord blood samples were tested for the A293T mutation, to determine the carrier frequency in the local population. This mutation was detected by PCR using the following miss-matched primer pair: Forward 5'-ccttcggctgcctgaacgac-3' and reverse 5'-acacctgtcgagggcgtactg-3'. These primers generate a PCR product of 104 bp and introduce an Acy I cutting site into the amplicon from the normal allele. Agarose gel electrophoresis was used to determine amplicon fragment length after restriction digestion. Samples positive for the A293T substitution were confirmed by sequencing. 3. Results 3.1. Clinical and demographic information Available clinical and demographic information of all 14 known patients with GA 1 are reported in Table 1. Twelve patients were black Southern African children of Xhosa, Tswana, Sotho or Zulu descent, a
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Table 1 Clinical and laboratory findings in 14 known South African children with GA 1. Patient Age and sex at diagnosis
1 2 3
4
5 6
7 8 9 10
11
12 13 14
Presentation at diagnosis Neuro-imaging Urine GA Urine 3-OHGA GCDH activity in Ancestry (μmol/mmol (μmol/mmol cultured fibroblasts creatinine)a creatinine)a (pmol.h−1 mg−1 protein)a
5 years, male Dev. delay, dystonia 12 months, female Seizures, dev. delay 3 days old, male Asymptomatic macrocephaly, diagnosis by newborn screening 8 months, male Acute hypotonia with intercurrent illness, progression to dystonia 4 years, male Dev. delay, dystonia 8 months, male Acute hypotonia with intercurrent illness, progression to dystonia 16 months, male Macrocephaly, focal seizures, dev. delay 11 months, male Dev. delay, dystonia 27 months, female Dev. delay, dystonia, macrocephaly 6 months, female Progressive dev. delay and dystonia, after acute encephalopathic episode, macrocephaly 6 months, male Acute encephalopathy, seizures. Initial diagnosis of non-accidental injury. 14 months, male Progressive dev. delay 7 months, male Dev. delay, hypotonia, dystonia 16 months, female Dev. delay, dystonia
GCDH genotype Phenotype
Typical Typical Typical
520b 32.7 47.2
113b 34.7 52.8
n.d. n.d. n.d.
African African African
A293T/A293T A293T/A293T A293T/A293T
Severe Severe Mild
Typical
655
32.6
b 10
African
A293T/A293T
Severe
n.d. 50
African African
A293T/A293T A293T/A293T
Severe Severe
c
c
300 270
37.3 59.6
Typical
17.2
10.4
b 10
African
A293T/A293T
Severe
Typical
84.8 54.4 9.5
50
African
A293T/A293T
Severe
n.a.
1149 562 30
African
n.d.
Severe
Typical
23.4
10.2
n.d.
African
A293T/A293T
Severe
Typical
10,000
48
n.d.
n.a Typical
787 8548
66 79.6
n.d b 10
Mixed (African, A293T/R402W European, East-Indian) African A293T/A293T Asian Q59P/Q59Pd
Severe Severe
Typical
625
96.3
n.d
African
Severe
Typical Typical
A293T/A293T
Severe
n.d., not done ; n.a., not available; dev.delay, developmental delay. a Reference ranges derived in-house from hospitalized children without known organic aciduria—urine GA b 30 μmol/mmol creatinine; urine 3-OHGA b2.5 μmol/mmol creatinine ; GCDH activity in cultured fibroblasts 1500–3200 pmol h− 1 mg− 1 protein. b Reference ranges published in reference 25—urine GA b2 μmol/mmol creatinine ; urine 3-OHGA b3 μmol/mmol creatinine. c Markedly increased excretion of GA and 3-OHGA on qualitative organic acid screening but levels not quantified. d Homozygous substitution presumed to be a disease causing mutation—not confirmed by expression or population studies.
single patient was of mixed ancestry (admixture of black African, European and East-Indian extraction)) and a single patient was of Asian descent. All patients were unrelated and 4 patients were female. Three patients were diagnosed on presentation of acute metabolic encephalopathy associated with intercurrent illness or injury and 10 patients were diagnosed on investigation of progressive neurological signs and symptoms including seizures, dystonia, developmental delay and macrocephaly. A single child with asymptomatic macrocephaly was diagnosed in a trial newborn screening program. This child is currently 5 years old and is the only patient with a mild disability phenotype. All the other patients are more severely affected. Associated neuroimaging demonstrated varying degrees of typical changes seen in GA 1 in all patients. These included macrocephaly, fronto-temporal brain atrophy, widened and fluid-filled pre-temporal and Sylvian fissures, extracerebral fluid collections, white matter changes and basal ganglia lesions [29,30]. Due to the high cost of lysine restricted diets and supplements, 11 patients have been managed on a general protein restricted diet together with carnitine supplementation and aggressive sick day protocols through a tertiary centre. In all these patients, including the patient detected by newborn screening, subsequent crises requiring hospital admission have successfully been prevented to date. 3.2. Urine organic acid analysis Concentrations of urinary GA and 3-OHGA are reported in Table 1. All patients had highly elevated excretion of 3-OHGA, range 30.1– 114.4 μmol/mmol creatinine (reference range b2.5 μmol/mmol creatinine) whereas GA excretion varied from 23.4 to 10 000 μmol/mmol
creatinine (reference range b30 μmol/mmol creatinine). Of note were 3 samples that demonstrated GA concentrations within reference intervals.
3.3. GCDH genotyping Known disease-causing mutations were detected in both alleles of 11 patients and previously reported in one patient. All patients of African descent who were tested (n = 11) were found to be homozygous for the A293T mutation whereas the single patient of mixed ancestry tested heterozygous for the same A293T mutation together with R402W, which is common in many populations [19]. The patient of Asian ancestry was the only patient from a consanguineous relationship and was found to be homozygous for a novel Q59P substitution in the GCDH gene that was also confirmed in expressed leukocyte mRNA. No other known exon or exon/intron boundary mutations were detected in this patient and both parents were confirmed carriers of the same Q59P substitution. Messenger RNA studies only revealed Q59P homozygosis; otherwise the coding sequence was correct with no insertions or deletions. The indication of a common mutation and the recently increased detection rate prompted an assessment of the carrier frequency in the black African population. Newborn cord blood DNA was used and 21 of the 750 samples screened were positive for one copy of the A293T allele with a carrier frequency of 1 in 36 (95% CI; 1/54 - 1/24) individuals and a predicted prevalence rate for GA 1 of 1 in 5184 (95% CI; 1/11664 - 1/2304) amongst newborn African children in this population.
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3.4. Fibroblast GCDH activity Cultured fibroblast GCDH activity was low or absent at b50 pmol h−1 mg−1protein (controls 1500–3200 pmol h−1 mg−1protein) in 4 A293T/ A293T cell lines tested as well as in the Q59P/Q59P cell line. 4. Discussion GA 1, a severe and treatable inborn error of metabolism which is easily diagnosed with appropriate technology has been underdiagnosed in the Southern African population for many decades with only three known reported cases [24,25]. With the application of sensitive urine organic acid screening in a previously poorly served black population, the incidence of cases has increased dramatically. Fourteen unrelated patients are described. Thirteen of these were diagnosed only after clinical presentation, and a single patient was detected in a DBS newborn screening trial. The clinical outcomes of these children reflect the delay in diagnosis. Biochemically, all tested patients demonstrated elevated levels of urinary 3-OHGA with very low levels of fibroblast GCDH enzyme activity in all those tested. Glutaric acid excretion, however, was variable and five patients had urine GA levels b50 μmol/mmol creatinine that could be described as low excretors of GA. The previously reported poor correlation between phenotype and excretion of GA is corroborated by these findings which suggest that there is no relationship between GA excretion and biochemical phenotype or genotype as three of the low excretors were homozygous for the same A293T mutation as four of the high excretors and GCDH enzyme activity in the one tested low excretor is comparable to that of the high excretors. Excretion of GA in these patients is, therefore, most likely associated with the degree of cerebral ketogenic amino acid catabolism that in turn reflects the metabolic state at the time of urine production. Most strikingly, all the patients of African ancestry who have been tested have been homozygous for the same A293T mutation despite the fact that none were related. In addition these patients were widely distributed with 6 patients coming from the Western Cape, of Xhosa extraction, 2 patients from Kwa-Zulu Natal (Zulu), 1 patient from Lesotho (Sotho) and 3 patients from Central South Africa (Tswana). Further screening determined an unexpectedly high carrier frequency of 1 in 36 for this mutation in a mainly Xhosa South African black cohort from Cape Town, giving rise to an expected homozygous disease incidence of 1 in 5184 newborns. If these data are predictive for the rest of South Africa as is likely given the distribution of diagnosed patients, GA 1 may well be the most common and unrecognized inherited metabolic disorder in South Africa. The prediction of a high incidence of GA 1 in this population is supported by the increase in cases diagnosed at our institution over a relatively short period of time. By implication, the vast majority of GA 1 patients born in the Western Cape and presumably elsewhere in South Africa are not recognized or treated, and the outcome for these children is unknown. Of concern, is the fact that GA 1 is easily mislabeled as nonaccidental head injury due to the similarity of clinical and neuroradiological findings between the two conditions [31,32] as was the case in one of our patients prior to urine organic acid screening. This is a very unfortunate situation, given that with early diagnosis and cost effective intervention, many of the neurological sequelae of this devastating disorder can be prevented [33], making a strong case for the implementation of newborn screening in this population. Major challenges to the implementation of pre-symptomatic testing for GA 1 in South Africa include fragmented and limited healthcare funding together with the logistical and geographical challenges of moving patients and samples over long distances. Much has been achieved however regarding the infrastructure required to implement what has become the largest HIV antiretroviral program in the world. This includes testing, prophylaxis and treatment for all
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HIV-exposed and infected infants, together with structures for tertiary referral of critically ill children [34]. Integrating screening and treatment of GA 1 into this existing infrastructure is likely to be the most effective way of addressing this disorder, particularly if molecular screening is employed that serves as both screening and confirmatory test and can be applied to samples collected immediately after birth. Currently the only newborn screening performed in South Africa consists of sporadic cord-blood based thyroid screening that is implemented in ±15% of new births. The fact that only 3 out of 14 patients were diagnosed on presentation of an acute encephalopathic crisis is in contrast to the reported natural history of this disease, where the majority of symptomatic patients present in this manner [1]. It is unlikely that A293T homozygosity predisposes a more insidious presentation given the universally low/absent enzyme activity of this mutation that is comparable to other mutations including R402W [1]. The discrepancy is therefore likely due to other influences. Factors such as the misdiagnosis of initial acute crises by poorly resourced or trained healthcare providers, especially in primary or secondary centers may play a role, as could additional dietary factors. Many black South African infants are breastfed on demand and with weaning, typically move on to a low protein (and low lysine) diet consisting principally of maize. These factors may also influence the natural history of GA1 in the population but at this stage they remain speculative. The lack of genetic variation in mutations causing GA 1 in black South Africans could be unexpected considering the fact that Africans in general are thought to harbor less deleterious disease causing mutations than Caucasians, with an overall higher degree of genetic diversity [35,36]. This paucity of variation is supported by other studies of recessive disease in black South Africans. Two examples include the fact that N98% of all black South Africans with galactose-1-phosphate uridyltransferase (EC 2.7.7.10) galactosaemia diagnosed at our institution (N100 patients) over the last 29 years have tested homozygous for the “African” S135L mutation with a carrier frequency of 1 in 60 for this mutation in this population. More recently, a study of glucocerebrosidase (EC 3.2.1.45) mutations causing Gaucher's disease in South African blacks yielded similar findings where a p.T36del mutation with a population carrier frequency of approximately 1 in 66 individuals was found in each of 19 patients studied [26]. Currently, studies of human genomic diversity within the local indigenous and immigrant populations in South Africa are underway and the outcome of these will shed more light on the scope of genetic diversity in the country [37]. If, as suggested by studies of recessive disease, a low genome wide degree of diversity is demonstrated in the black population of South Africa it may have significant implications regarding the approach to screening for this and other recessive diseases and may ultimately result in DNAbased methodology as opposed to conventional biochemical methods being implemented to screen for identified recessive inborn errors of metabolism. Until such time as effective population-wide newborn screening becomes available for this treatable disorder, we urge clinicians working in South Africa to maintain a high index of suspicion and low testing threshold for GA 1, especially in black children with associated acute or chronic neurology or in cases of suspected non-accidental head injury. Acknowledgments We wish to thank Professor Lorna Jacklyn and Drs Alvin Ndondo, Jennifer Cartwright, Els Dobbels, Louisa Bhengu, Priscilla Springer, Palaniappan Ragunathan, Dawid J Griessel and E du Plessis for providing the clinical information and samples from their GA 1 patients that made this work possible. Special thanks to Professor Ernst Christensen for providing valuable advice regarding the method for Glutaryl-CoA [1,5-14C] synthesis. Thanks to Dr Judy King for proofreading the manuscript.
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