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Background Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene ( ETFDH) . Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population. Methods Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations. Results Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH , with SA population-specific allele frequencies of < 0.00067–0.00084%. Conclusions This study reveals the first extensive genotype–phenotype profile of a MADD patient cohort from the diverse and understudied SA population. The pathogenic variants and associated variable phenotypes were characterised, which will enable early screening, genetic counselling, and patient-specific treatment of MADD in this population.

Thyroid function testing on an Advia Centaur® Immunoassay System (Siemens Medical Solutions Diagnostics) revealed an increased concentration of serum free thyroxine (FT4)2 of 90.1 pmol/L (6.97 ng/dL) (reference range 11.5-22.7 pmol/L), a nonsuppressed thyroid-stimulating hormone (TSH) concentration of 1.8 mlU/L (1.8 jxIU/mL) (reference range 0.35-5.5 mIU/ L), and normal free triiodothyronine (FT3) concentration of 4.2 pmol/L (0.33 ng/dL) (reference range 3.5-6.5 pmol/ L). Other less common causes include antibody interference in the FT^sub 4^ assay causing falsely increased FT^sub 4^, thyroid hormone resistance syndromes, TSH-secreting pituitary adenoma, familial dysalbuminemic hyperthyroxinemia, amiodarone therapy, and primary hyperthyroidism with antibody interference in the TSH assay causing falsely increased TSH results.

MPV17-related mitochondrial DNA depletion syndrome is a rare, lethal, autosomal recessive primary mitochondrial disorder characterised by infantile onset liver disease and neurological features, including hypotonia, developmental delay, failure to thrive and neuropathy. The aim of this study was to describe the presentation and clinical course of infants diagnosed with MPV17 neurohepatopathy, comparing those who were HIV-exposed on antiretroviral therapy (ART), including zidovudine and nevirapine to prevent perinatal HIV transmission, to infants who were not HIV exposed, using data from a multicentre MPV17 natural history study in South Africa. Between 2013 and 2024, 25 infants were diagnosed with MPV17 neurohepatopathy, 8 (32%) of whom were HIV-exposed and received ART at birth (7 received zidovudine), none were HIV-infected. Median birth weight was lower at 2.45 kg (IQR 2.28-2.71) in infants who were HIV-exposed compared to 2.86 kg (IQR 2.54-3.13) in HIV-unexposed infants (p = 0.02). Symptom onset occurred much earlier at a median of 3 days of age (IQR 0-10 days) in HIV-exposed infants compared to 60 days (IQR 14-90) in HIV-unexposed (p = 0.006). Infants exposed to HIV were more likely to develop liver failure (p = 0.02). Perinatal therapy with the nucleoside reverse transcriptase inhibitor zidovudine, a known mitochondrial toxin, was associated with accelerated clinical presentation and clinical course of MPV17 neurohepatopathy. Our findings suggest that less toxic antiretroviral therapy should be considered for perinatal HIV prophylaxis in HIV-exposed infants, particularly in our setting where there is a high carrier frequency of a single pathogenic MPV17 variant.

Background The mutations responsible for cystinosis in South African patients are currently unknown. A pertinent question is whether they are similar to those described elsewhere in the world. Methods Children who were being managed for cystinosis in the Western Cape Province of South Africa between 2002 and 2013 were studied. All underwent molecular analysis to detect sequence variations in the cystinosis gene. Results This cohort study included 20 patients, 13 of whom were Xhosa-speaking black South Africans and seven were Cape Coloureds (mixed race); none were Caucasian. All had nephropathic infantile-type cystinosis with evidence of proximal tubulopathy, with glycosuria and renal phosphate wasting. Diagnosis was confirmed in 19 cases by demonstrating an elevated cystine concentration in leukocytes. Molecular analysis of the cystinosin gene revealed that 19 patients had a G > A mutation in intron 11 ( CTNS -c.971-12G > A p.D324AfsX44) which caused an out-of-frame 10-bp insertion. Of these 19 patients, 16 were homozygous for this mutation, which was the most frequent mutation identified in the alleles of the black South African and Cape Coloured patients (96 and 71 %, respectively). Conclusion We recommend that black South African and Cape Coloured patients presenting with cystinosis be tested for CTNS -c.971-12G > A in the first instance, with the possibility of prenatal testing being offered to at-risk families.

Less common causes are MTHFR defi- ciency, defects of methionine synthase [involving mutations in 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR, also known as CbIG)], and defects in vitamin B12 metabolism, such as mutations in methionine synthase reductase [5-methyltetrahydrofolate- homocysteine methyltransferase reductase (MTRR, also known as CblE)] and the CblD-variant-1 defect of the methylmalonic aciduria (cobalamin defi- ciency) cblD type, with homocystinuria (MMADHC) gene. Low methionine and high homocysteine concentra- tions also result in a high SAH-to-SAM ratio, which inhibits over 115 different methylation reactions, in- cluding synthesis of neurotransmitters, posttransla- tional methylation of myelin basic protein, and DNA methylation, which is essential for the epigenetic regu- lation of gene expression (8). [...]this type of screening becomes a main- stream assessment procedure, clinicians should be aware that MTHFR deficiency is one of the treatable metabolic disorders not identified by current NBS and, therefore, plasma total homocysteine should be considered in the laboratory workup of an infant or child with progressive neurological dysfunction.

In July 2009, a 14-yr-old male caracal (Caracal caracal) at the National Zoological Gardens of South Africa was found, on abdominal ultrasound, to have a single large cystolith. The cystolith was removed, and the composition was determined to be 100% cystine. Blood and urine samples were also collected from three other apparently healthy caracals at the zoo and were submitted, together with the samples from the affected animal, for analysis using gas chromatograph mass spectrometry for cystine, lysine, alanine, and ornithine levels. The cystine levels in the urine, the fractional excretion of cystine, and the normalized excretion of cystine (μmol/g of creatinine) were all higher in the affected caracal than in the healthy animals. Only a single other case of cystine urolithiasis has been previously reported in any wild felid in the literature.

Countries across the world have different expectations on carbon dioxide (CO2) capturing and the willingness to commit to international agreements continually change. At present, the CO2 capture market is weak as industries are reluctant to take up the costs and risks associated with implementing the capture technologies. Globally, and in the United States of America (U.S.A.) in particular, the perception is that emerging energy technologies with carbon capture are too expensive or inefficient to attract investors without government backing and subsidies. Coal usage has accordingly declined. By expanding the coal value chain into more than just electricity generation, it can possibly attract new investments and improve confidence in novel carbon capture technologies.Chemical looping combustion is a technology that can utilize coal and benefit both the electricity and valuable chemicals market. This flexibility of chemical looping combustion represents a promising technology to integrate the required time flexibility so urgently needed within the U.S.A. electricity generation sector. Fostering the development and scalability of chemical looping combustion related technologies, especially using coal, rather than focusing purely on the expected cost reduction and usefulness of chemical looping combustion as a CO2 capture technology, can ensure stability within the electricity generation and coal industry of the U.S.A.Chemical looping combustion is an induced fuel combustion process that uses recyclable redox materials as oxygen carriers to transfer oxygen selectively from an air stream to a fuel reactor, thus eliminating the requirement for end-of-pipe CO2 gas separation processes. To date, no oxygen carriers have been identified or developed that exhibit adequate long-term performance. There is also a lack of sufficient experience related to the design and operation of full-scale chemical looping combustion systems.Oxygen carriers serve as oxygen sorbents that release or adsorb oxygen, depending on the temperature, pressure and gas composition within the chemical looping combustion system. Oxygen carrier performance is mainly characterized by its affinity to react under both oxidizing and reducing conditions and its resistance to attrition.Based on the research opportunities, two primary hypotheses have been developed:i) A laboratory-scale evaluation system, operating under high temperature and reacting conditions, can be used to assess oxygen carrier performance. The experimental results can be used to develop correlations for determining oxygen carrier lifetime in scaled-up processes.ii) A spouted fluid bed reactor can improve carbon conversion efficiencies as compared to a bubbling fluidized bed reactor. Computational fluid dynamic simulations can be used to model the movement of oxygen carriers in such a spouted fluid bed reactor to gain a better understanding of the transport phenomena involved deep within the reactor.To prove or disprove the research hypotheses, the research scope was broken down into three main efforts:i) Evaluate several materials being considered by the chemical looping combustion development community to ascertain whether a single test procedure is adequate for oxygen carrier performance characterizationii) Further develop the oxygen carrier performance evaluation methodology (based on jet attrition testing) to include a second attrition source (cyclonic attrition) critical in chemical looping combustion systems involving circulation of oxygen carriersiii) Assess whether a spouted fluid bed can be used for chemical looping combustion and if it is scalable using a modular approach based on experimental and computational fluid dynamic tools. This effort will target the development of a computational modeling tool for the design of a multi-zone spouted fluid bed.Parts i) and ii) of the research scope pertained to testing different oxygen carriers in a jet attrition unit and a cyclonic attrition unit. An attrition unit can be defined as a device that is used to attain information concerning the ability of material to resist particle size reduction. The ASTM D5757 test method is typically used to determine the relative attrition characteristics of fluid catalytic cracking (FCC) catalysts under ambient conditions.In contrast to the ASTM D5757 test method, the jet and cyclonic attrition units were set up to expose the oxygen carriers to various operating conditions that could typically be encountered in actual chemical looping combustion systems. The operating principle of the jet- and cyclonic-induced attrition systems provides a vast improvement over previous methods that neglect chemical and thermal stresses.The cyclonic attrition unit ultimately represents a more favorable test method for assessing the attrition of oxygen carriers compared to the jet attrition unit. The cyclonic attrition test method merely speeds up the particle impact frequency compared to large-scale cyclones. However, the particle impact velocity within the cyclonic attrition unit is similar to large-scale cyclones (9.0–27 m/s). The cyclonic attrition unit can therefore provide relevant attrition data on an oxygen carrier within 9 hours, using as little as 70 grams of material.Two attrition models (cyclonic and jet) were identified that could be used to investigate attrition rates at operational chemical looping combustion conditions. The models were based on the concept of efficiency within a comminution process. The models related particle attrition to the kinetic energy used to produce fines. The cyclonic attrition model provided the best fit for the attrition data with coefficients of determination ≥ 0.94.Part iii) of the research scope related to exploring the use of a spouted fluid bed as a reactor configuration for chemical looping combustion. The spouted fluid bed was identified as a suitable configuration to improve fuel conversion and operational flexibility over the typically employed bubbling fluidized bed designs. This part of the study had two objectives: i) to assess the viability of a single-spouted fluid bed as an efficient chemical looping combustion reactor, and ii) to assess if computational fluid dynamic based simulations can be employed to show the hydrodynamic behavior of both a single- and multi-spouted fluid bed reactor.A modeling and experimental approach were followed to accomplish the objectives. Firstly, Multiphase Flow with Interphase eXchanges (MFiX) software was used to establish a spouted fluid bed reactor design using the two-fluid model. An experimental setup was built to supplement the model. The experimental setup was modified for testing under high temperature, reacting conditions (1073–1273 K). The setup was operated in either a spouted fluid bed or a bubbling bed regime, to compare the performance attributes of each using a mixture of carbon monoxide and hydrogen as fuel.For the single-spouted fluid bed investigation, the cold flow model results provided key information for rapid experimental design and operating envelope determination. The single-spouted fluid bed modeling and experimental results illustrated the potential of the configuration to improve gas/solid contact, lower energy requirements and increase operational robustness in comparison to a bubbling fluidized bed reactor. The cold flow models proved adequate in depicting the intermittent spouting regime as well as providing valuable information pertaining to material circulation rate.The modeling and experimental work on the single-spouted fluid bed reactor were used as the starting point to investigate the scalability of the system into a multi-spouted fluid bed reactor. MFiX software was again used to design a multi-spouted fluid bed and compare the hydrodynamic aspects of the system to that of a bubbling fluidized bed. A reactor comprising nine spout/draft tubes, arranged in a 3 × 3 setup, was modeled in 2-D using the two-fluid model. The model incorporated both inlet and outlet regions to study to bulk movement of solids within the reactor design. The focus of this work was on capturing the hydrodynamic trends associated with a multi-spouted fluid bed. The modeling results indicated that the solids in a multi-spout system has a slightly narrower residence time distribution compared to that in a bubbling fluidized bed. The narrower residence time distribution could potentially improve fuel conversion in chemical looping combustion systems. Ultimately, a baseline model was configured that can be used to investigate alternative layouts of modular spouted fluid bed reactors for various applications.

Human immunodeficiency virus (HIV) infection and the pharmacological treatment thereof have both been shown to affect mitochondrial function in a number of tissues, and each may cause specific organ pathology through specific mitochondrial pathways. HIV has been shown to kill various tissue cells by activation of mitochondrial apoptosis. Nucleoside analogues, used extensively to treat HIV infection, are known to influence a number of steps affecting mitochondrial DNA integrity. This review describes the basic physiology, pharmacology and pathophysiology of HIV infection and the nucleoside analogues regarding mitochondrial function and discusses the progress made in this field with respect to the measurement of these effects and the prediction of potential drug toxicity.