Research

M. Dercksen, L. IJlst, M. Duran, L. J. Mienie, A. van Cruchten,F. H. van der Westhuizen, & R. J. A. Wanders
Hyperammonemia is a frequent finding in various organic acidemias. One possible mechanism involves theinhibition of the enzyme N-acetylglutamate synthase (NAGS), by short-chain acyl-CoAs which accumulate dueto defective catabolism of amino acids and/or fatty acids in the cell. The aim of this study was to investigate theeffect of various acyl-CoAs on the activity of NAGS in conjunction with the formation of glutamate esters. NAGSactivity was measured in vitro using a sensitive enzyme assay with ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) product analysis.

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M. Dercksen, G. Koekemoer, M. Duran, R. J. A. Wanders, L. J. Mienie, & C. J. Reinecke
Isovaleric acidemia (IVA, MIM 248600) can bea severe and potentially life-threatening disease in affectedneonates, but with a positive prognosis on treatment forsome phenotypes. This study presents the first applicationof metabolomics to evaluate the metabolite profiles derivedfrom urine samples of untreated and treated IVA patients aswell as of obligate heterozygotes. All IVA patients carriedthe same homozygous c.367 G[A nucleotide change inexon 4 of the IVD gene but manifested phenotypic diversity.Concurrent class analysis (CONCA) was used tocompare all the metabolites from the original completedata set obtained from the three case and two controlgroups used in this investigation.

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M. Dercksen, A. C. Crutchley, E. M. Honey,M. M. Lippert, G. Matthijs, L. J. Mienie,H. C. Schuman, B. C. Vorster, & J. Jaeken
ALG6-CDG (formerly named CDG-Ic) (phenotypeOMIM 603147, genotype OMIM 604566), is caused bydefective endoplasmic reticulum a-1,3-glucosyltransferase(E.C 2.4.1.267) in the N-glycan assembly pathway(Gr€unewald et al. 2000). It is the second most frequentN-glycosylation disorder after PMM2-CDG; some 37 patientshave been reported with 21 different ALG6 gene mutations(Haeuptle & Hennet 2009; Al-Owain 2010).We report on theclinical and biochemical findings of five novel CaucasianSouth African patients. The first patient had a severe neurogastrointestinalpresentation. He was compound heterozygousfor the known c.998C>T (p.A333V) mutation and the novelc.1338dupA (p.V447SfsX44) mutation. Four more patients,presenting with classical neurological involvement wereidentified and were compound heterozygous for the knownc.257 + 5G>Asplicemutation and the c.680G>A(p.G227E)missense mutation.

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M. Dercksen, M. Duran, L. IJlst, L. J. Mienie,C. J. Reinecke, J. P. N. Ruiter, H. R. Waterham, &R. J. A. Wanders
Isovaleric acidemia (IVA) is one of the mostcommon organic acidemias found in South Africa. Since1983, a significant number of IVA cases have been identifiedin approximately 20,000 Caucasian patients screenedfor metabolic defects. IVA is caused by an autosomal recessivedeficiency of isovaleryl-CoA dehydrogenase (IVD)resulting in the accumulation of isovaleryl-CoA and itsmetabolites. In total, 10 IVA patients and three carriers wereavailable for phenotypic and genotypic investigation in thisstudy. All patients were found to be homozygous for asingle c.367 G > A (p.G123R) mutation.

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J. Viljoen, J. J. Bergh,L. J. Mienie, H. F. Kotze, &G. Terre’Blanche
Valproate administration increases the level of theinhibitory transmitter, glycine, in the urine and plasma ofpatients and experimental animals. Nonketotic hyperglycinemia(NKH), an autosomal recessive disorder of glycine metabolism,causes increased glycine concentrations in blood,urine, and cerebrospinal fluid (CSF), most likely due to adefect in the glycine cleavage enzyme or possibly deficits inglycine transport across cell membranes. We investigated therelationship between the hyperglycinemic effect of valproateand induced pyroglutamic aciduria via paracetamol in thevervet monkey. Firstly it was determined if valproate couldinduce hyperglycinemia in the monkey. The second aim wasto increase glutamic acid (oxoproline) urine excretion usingparacetamol as a pre-treatment and to assesswhether valproatehas an influence on the γ-glutamyl cycle.

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G. Koekemoer, M. Dercksen, J. Allison, L. Santana, & C. J. Reinecke
Metabolomics data are typically complex andhigh dimensional. Multivariate dimension-reducing techniqueshave thus been developed for analysing metabolomicsdata to disclose underlying relationships, withprincipal component analysis (PCA) as the techniquemostly applied. Despite its widespread use in metabolomics,PCA has shortcomings that limit its applicability.Several approaches have been made to overcome theselimitations and we describe an advanced disjoint PCA(DPCA) model, termed concurrent class analysis andabbreviated as CONCA. CONCA is a new model, and isunique in linking DPCA models to a traditional PCAmodel.

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C. J. Reinecke, G. Koekemoer, F. H. van der Westhuizen,R. Louw, J. Z. Lindeque, L. J. Mienie, & I. Smuts
Metabolomic analysis of the urinary organicacids from 39 selected children with defined respiratorychain deficiencies (RCDs) was performed using untargetedgas chromatography–mass spectrometry, revealing thepresence of 255 endogenous and 46 exogenous substances.Variable reduction identified 92 variables from the endogenoussubstances, which could be analysed by univariate andmultivariate statistical methods. Using these methods, nocharacteristic organic acid biomarker profile could bedefined of practical value for diagnostic purposes for complexI (CI), complex III (CIII) and multiple complex (CM)deficiencies.

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G. Terre’Blanche, M. M. van der Walt, J. J. Bergh, & L. J. Mienie
This is a case report of adrenomyeloneuropathy (AMN), the adult variant of adrenoleukodystryphy (ALD). Thediagnoses in the patient, aged 34, was confirmed via increased serum very long chain fatty acid concentration(VLCFA). Treatment started with the cholesterol lowering drug, atorvastatin, followed by add-on therapy withLorenzo’s oil (LO) and finally supplementation with docosahexaenoic acid (DHA). The magnetic resonance imaging(MRI) scan of the AMN patient before DHA treatment, already showed abnormal white matter in the brain.Although the MRI showed no neurological improvement after 6 months of DHA treatment, no selectiveprogression of demyelination was detected in the AMN patient. Contrary to what was expected, LO failed tosustain or normalize the VLCFA levels or improve clinical symptoms. It was however, shown that DHAsupplementation in addition to LO, increased DHA levels in both plasma and red blood cells (RBC). Additionally,the study showed evidence that the elongase activity in the elongation of eicosapentaenoic acid (EPA) todocosapentaenoic acid (DPA) might have been significantly compromised, due to the increased DHA levels.

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I. Ross, A. Boulle, S. Soule, N. Levitt, F. Pirie, A. Karlsson, J. Mienie, P.Yang, H. Wang, J-X. She, W. Winter, & D. Schatz
We sought to determine whether autoimmunity is thepredominant cause of Addison’s disease in South Africa andwhether human leucocyte antigen (HLA) DQ association exists.Design We compiled a national registry of patients from primarycare, referral centres and private practices.Patients A total of 144 patients, 94 of European descent, 34 MixedAncestry, 5 Asian and 11 Black Africans (mean age 45Æ9 years, range2Æ7–88 years; mean duration of disease 13Æ1 years, range 0–50 years) and controls were matched for gender and ethnicity. Allpotential causes were investigated.

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G. Terre’Blanche, N. Heyer,J. J. Bergh, L. J. Mienie,C. J. van der Schyf, & B. H. Harvey
Exposure to the industrial solvent, styrene,induces locomotor and cognitive dysfunction in rats, andparkinsonian-like manifestations in man. The antipsychotic,haloperidol (HP), well known to induce striataltoxicity in man and animals, and styrene share a commonmetabolic pathway yielding p-fluoro phenylglyoxylic acidand phenylglyoxylic acid (PGA), respectively. Using anexposure period of 30 days and the vacous chewingmovement (VCM) model as an expression of striatal-motortoxicity, we found that incremental PGA dosing(220–400 mg/kg) significantly increased VCMs up to day25, but decreased to control levels shortly after reachingmaximum dose.

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I. Smuts, R. Louw, H. du Toit,B. Klopper, L. J. Mienie, &F. H. van der Westhuizen
Mitochondrial disorders are frequently encounteredinherited diseases characterized by unexplainedmultisystem involvement with a chronic, intermittent, orprogressive nature. The objective of this paper is to describethe profile of patients with mitochondrial disorders in SouthAfrica. Patients with possible mitochondrial disorders wereaccessed over 10 years. Analyses for respiratory chain andpyruvate dehydrogenase complex enzymes were performedon muscle. A diagnosis of a mitochondrial disorder wasaccepted only if an enzyme activity was deficient. Sixtythreepatients were diagnosed with a mitochondrial disorder,including 40 African, 20 Caucasian, one mixed ancestry, andtwo Indian patients.

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