Browsing by Author "Henderson, Howard"

Now showing 1 - 9 of 9
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    The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa
    (BioMed Central Ltd, 2002) Henderson, Howard; Leisegang, Felicity; Brown, Ruth; Eley, Brian
    BACKGROUND:The objective of this study was to document the clinical, laboratory and genetic features of galactosemia in patients from the Cape Town metropolitan region. METHODS: Diagnoses were based on thin layer chromatography for galactosuria/galactosemia and assays of erythrocyte galactose-1-phosphate uridyltransferase (GALT) and galactokinase activities. Patients were screened for the common S135L and Q188R transferase gene mutations, using PCR-based assays. Screening for the S135L mutation in black newborns was used to estimate the carrier rate for galactosemia in black South Africans. RESULTS: A positive diagnosis of galactosemia was made in 17 patients between the years 1980 to 2001. All had very low or absent galactose-1-phosphate uridyltransferase (GALT) activity, and normal galactokinase levels. The mean age at diagnosis was 5.1 months (range 4 days to 6.5 months). A review of 9 patients showed that hepatomegaly (9/9), and splenomegaly, failure to thrive, developmental delay, bilateral cataracts (6/9) were the most frequent features at diagnosis. Six had conjugated hyperbilirubinemia. Four experienced invasive E. coli infection before diagnosis. Ten patients were submitted to DNA analysis. All 4 black patients and 2 of mixed extraction were homozygous for the S135L allele, while all 3 white patients were homozygous for the Q188R allele. The remaining patient of mixed extraction was heterozygous for the Q188R allele. The estimated carrier frequency of the S135L mutation in 725 healthy black newborns was 1/60. CONCLUSIONS: In the absence of newborn screening the delay in diagnosis is most often unacceptably long. Also, carrier frequency data predict a galactosemia incidence of approximately 1/14 400 for black newborns in the Cape Metropole, which is much higher than the current detection rate. It is thus likely that many patients go undetected.
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    DNA analysis of Ornithine Transcarbamylase (OTC) deficiency in South African patients
    (2004) Swarts, Liezel Catharine; Henderson, Howard; Owen, Tricia
    Hyperammonaemia is not an infrequent presentation in the newborn or neonatal period. While the majority are transitory in nature and due to infective processes or liver pathology/immaturity, a significant number are due to defects in enzymes of the urea cycle. This cycle has evolved to cope with waste nitrogen disposal and the de novo synthesis of arginine. There are five distinct enzymatic steps in the urea cycle, and defects in each, result in a biochemically distinct disease. Four of these diseases, deficiencies of carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccmic acid synthetase (ASS), and argininosuccinate lyase (ASL) can present dramatically within the first 24 to 48 hrs of life with progressive lethargy, hypothermia and apnea, all related to very high plasma ammonia levels. These diseases may also present later in infancy, childhood and adulthood with hyperammonemia and episodic mental status changes. The fifth defect, arginase deficiency presents as progressive spastic quadriplegia and mental retardation but with milder elevation of blood ammonia levels. The molecular genetics of these disorders in South Africans has not been explored and there is thus very little information on phenotype/genotype relationships, specific for citizens of this country. This study aims to correct this imbalance and has concentrated initially on OTC deficiency, which is X-linked and therefore the most common defect encountered. Initial work on this project has concentrated on subjects with a classical X-linked OTC phenotype.
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    Growth of luciferase-transfected BCG in whole blood : use of a novel assay to study immune responses to mycobacteria in children
    (2003) Tena, Nontobeko Gwendoline; Henderson, Howard; Eley, Brian; Kampmann, Beate
    The existing Bacille Calmette-Guerin (BCG) vaccine offers some protection against TB, but its efficacy varies for unknown reasons. In order to develop an effective vaccine, a comprehensive understanding of protective immunity in adults and children is needed. Studies involving host-pathogen interactions are complex and have been hampered by the slow growth of mycobacterial organisms.
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    L-2 hydroxyglutaric aciduria in a South African Staffordshire Bull Terrier
    (2014) Böhm, Marlies; Henderson, Howard; van der Zwan, Henriette; Basson, Sandra
    L-2 hydroxyglutaric aciduria is an autosomal recessive error of metabolism that manifests as an encephalopathy. The most common presenting signs are seizures, tremors, ataxia and/ or dementia. Some affected dogs show only subtle behavioural changes. Amongst canines, the condition has been best described in Staffordshire Bull Terriers. Although this is the first reported case in South Africa, at least three other affected dogs have been indentified by polmerase chain reaction (PCR) in this country. Affected dogs have normal haematology, serum biochemistry and routine urine analysis. This report discusses the advantages and limitations of the three main diagnostic modalities, namely: magnetic resonance imaging, urine gas chromatography-mass spectrometry and genetic testing. The aim of this report is to increase awareness of the condition, assist diagnosis in encephalopathic dogs and improve detection of carriers amongst breeding stock.
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    The molecular and cellular defect underlying autosomal recessive hypercholesterolemia (ARH) in the first kindred identified in South Africa
    (2005) Abera, Aron; Henderson, Howard; Marais, A David
    Monogenic defects in the low density lipoprotein (LDL) uptake pathway occur commonly in South Africans, particularly in the Afrikaner community where inheritance is typically autosomal dominant, arising predominantly from abnormal structure and thus function of the LDL receptor (LDLr). Defects in LDLr binding domain of apolipopreteinB-100 (apoB-100) are rarely encountered and are know as Familial defective apoB-100 (FDB). Several critical proteins are active in the LDL uptake pathway and their deficiencies are now being shown to underlie the rare autosomal recessive forms of hypercholesterolemia (ARH). One of these proteins is the LDLr adaptor protein know as ARH, which is presumed to facilitate interaction of the cytoplasmic tail of the LDLr with the internal protein matrix required for the receptor internalisation.
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    Polymorphic variation in TIRAP is not associated with susceptibility to childhood TB but may determine susceptibility to TBM in some ethnic groups
    (Public Library of Science, 2009) Dissanayeke, Shobana Rebecca; Levin, Samuel; Pienaar, Sandra; Wood, Kathryn; Eley, Brian; Beatty, David; Henderson, Howard; Anderson, Suzanne; Levin, Michael
    Host recognition of mycobacterial surface molecules occurs through toll like receptors (TLR) 2 and 6. The adaptor protein TIRAP mediates down stream signalling of TLR2 and 4, and polymorphisms in the TIRAP gene ( TIRAP ) have been associated with susceptibility and resistance to tuberculosis (TB) in adults. In order to investigate the role of polymorphic variation in TIRAP in childhood TB in South Africa, which has one of the highest TB incidence rates in the world, we screened the entire open reading frame of TIRAP for sequence variation in two cohorts of childhood TB from different ethnic groups (Xhosa and mixed ancestry). We identified 13 SNPs, including seven previously unreported, in the two cohorts, and found significant differences in frequency of the variants between the two ethnic groups. No differences in frequency between individual SNPs or combinations were found between TB cases and controls in either cohort. However the 558C→T SNP previously associated with TB meningitis (TBM) in a Vietnamese population was found to be associated with TBM in the mixed ancestry group. Polymorphisms in TIRAP do not appear to be involved in childhood TB susceptibility in South Africa, but may play a role in determining occurrence of TBM.
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    Screening of the human tumor necrosis factor (TNF) gene and its receptor 1 (TNFR1) gene for DNA alterations and the subsequent investigation of these and an IL12p40 polymorphism for an association with paediatric tuberculosis
    (2004) Lampel, Netanya; Henderson, Howard; Beatty, Dave
    Infection with Mycobacterium tuberculosis is characterised by diverse outcomes; the majority of infected individuals remain well and yet others develop disease ranging from limited pulmonary tuberculosis to severe disseminated disease. The reasons for this diverse outcome are poorly understood, but host factors are thought to play an important role. In particular, a genetic component to susceptibility to tuberculosis has been proposed. An important clue was the description of a group of Maltese children with an unusual susceptibility to progressive non-tuberculous mycobacterial infections. These patients showed defective tumor necrosis factor (TNF) production in response to endotoxin and a failure to upregulate TNF production in response to interferon gamma as well as diminished interferon gamma production during T-cell proliferation. They were found to lack expression of the interferon gamma receptor ligand-binding chain (IFN-yR1) on their cell surfaces due to a single point substitution resulting in a truncated protein. Since then other defects in the type 1 cytokine pathway leading to susceptibility to non-tuberculous mycobacteria, as well as to tuberculosis, have been described in rare isolated cases. From these findings, the hypothesis arose that less severe mutations in such pathways might individually, or in combination, lead to increased susceptibility to tuberculosis in the general population. The following study forms part of a larger multi-centre collaboration, which aims to better understand the genetic basis of susceptibility to mycobacterial infection by addressing this hypothesis. The approach taken has been the recruitment and immuno-phenotyping of a large group of children with tuberculosis as well as control subjects. Candidate genes, of the type 1 cytokine pathways being investigated, include interferon gamma, interleukin­12 and their receptors and TNF. The focus of the study described in this thesis has been the screening of a sub-cohort of patients and control subjects for DNA sequence alterations in the TNF and TNFR1 genes. The individuals in this cohort were selected on the basis of their whole blood stimulation assays, where either high or low levels of TNF in response to non-specific stimulatory factors, were the determining criteria. It was assumed that these two phenotypic groupings would be enriched for gene variants contributing to the TNF responses recorded in the stimulation assays. Once identified, these polymorphisms would be screened for frequencies in the broader patient and control groupings and assessed for any association with susceptibility to tuberculosis. This study was considered important in attempting to explain which genes and their polymorphisms are involved in determining the high prevalence of tuberculosis in African populations.
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    Whole Blood Mitochondrial DNA Depletion in Human Immunodeficiency Virus-Infected Children
    (2010) van der Watt, George Frederick; Henderson, Howard; Eley, Brian
    Background: Nucleoside reverse transcriptase inhibitors (NRTIs) interfere with mitochondrial DNA polymerase gamma causing significant toxic effects, including fatal lactic acidosis. Little is known about mitochondrial DNA (mtDNA) in human immunodeficiency virus (HIV) infected children who face a lifetime exposure to these agents. We performed a cross sectional observation of mtDNA levels in whole blood in a pediatric population to ascertain the relationship between mtDNA, NRTI regimens and parameters of HIV-infection severity. Methods: Whole blood mt:nDNA ratios were determined by real-time PCR in three groups: 27 presumed HIV-negative, 89 HIV-infected, NRTI-treated and 62 HIV-infected treatment-naive children. Multivariate analysis was used to identify variables independently associated with mtDNA depletion. Results: Mean mt:nDNA ratios were lower (P < 0.001) at 77% of control in the HIVinfected antiretroviral treatment (ART) Naïve group and 73% of control in the ART group, but not different between the two HIV-infected groups. Mt:nDNA ratios were negatively associated with age (P = 0.029), HIV status (P < 0.0001) and Log10 of the HIV-1 viral load (P = 0.035) and positively associated with CD4 % (p = 0.032). A 6 stavudine vs zidovudine based regimen was associated with lower but not significant levels of mtDNA (P = 0.1). Conclusions: Depletion of whole blood mtDNA in children is associated independently with HIV-infection and markers of HIV infection severity, and does not improve with either stavudine or zidovudine based ART despite virological control, suggesting that these agents also deplete mtDNA.
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    X-linked Hyper IgM (HIGM1) in an African kindred: the first report from South Africa
    (BioMed Central Ltd, 2003) Pienaar, Sandra; Eley, Brian; Hughes, Jane; Henderson, Howard
    BACKGROUND:The objective of this study was to describe the clinical and molecular features of the first South African family with X-linked hyper-IgM syndrome (HIGM1). METHODS: Diagnoses were based on immunoglobulin results and the absence of CD40 ligand (CD40L) expression on activated T-cells. Complete molecular characterisation involved CD40L cDNA sequencing, and genomic DNA analysis by polymerase chain reaction amplification, restriction enzyme digestion and sequencing. A PCR-based diagnostic assay was established for carrier detection and prenatal diagnosis in this family. RESULTS: There were originally six children, three males and three females. The eldest boy died after being diagnosed with hypogammaglobulinaemia, before HIGM1 was considered. This disorder was diagnosed in the second eldest boy at the age of 5 years, after failing to detect CD40L expression on his activated T-cells. A deficiency of CD40L was also confirmed in the youngest male at the age of 5 years. Both younger brothers have since died of infections relating to HIGM1. Molecular investigation showed that exon 3 was deleted from the CD40L mRNA of the affected males. Genomic DNA analysis identified a 1.5 kilobase deletion, spanning exon 3 and including extended flanking intronic sequence. Carrier status in the mother was confirmed by RT-PCR of her CD40L mRNA. Genetic analysis of the three female children was deferred because they were below the legal consenting age of 18 years. A PCR-based assay for genomic DNA was established for easy identification of female carriers and affected males in the future. CONCLUSIONS: This study confirmed the diagnosis of HIGM1 in the first South African family to be investigated and identified a novel mutation in the CD40L gene.