Greetje de Jong

Aminoglycoside: induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients

Background. Ototoxicity following aminoglycoside treatment for multidrug-resistant tuberculosis (MDR-TB) is a significant problem. This study documents the incidence of ototoxicity in HIV-positive and HIV-negative patients with MDR-TB and presents clinical guidelines relating to ototoxicity. Methods. A prospective cohort study of 153 MDR-TB patients with normal hearing and middle ear status at baseline controlling for 6 mitochondrial mutations associated with aminoglycoside-related ototoxicity, at Brooklyn Chest Hospital in Cape Town. Pure tone audiometry was performed monthly for 3 months to determine hearing loss. HIV status was recorded, as was the presence of 6 mutations in the MT-RNR1 gene. Results. Fifty-seven per cent developed high-frequency hearing loss. HIV-positive patients (70%) were more likely to develop hearing loss than HIV-negative patients (42%). Of 115 patients who were genetically screened, none had MT-RNR1 mutations. Conclusion. Ototoxic hearing loss is common in MDR-TB patients treated with aminoglycosides. HIV-positive patients are at increased risk of ototoxicity. Auditory monitoring and auditory rehabilitation should be an integral part of the package of care of MDR-TB patients.

Somatic mutations of the APC, KRAS, and TP53 genes in nonpolypoid colorectal adenomas

Colorectal adenomas are macroscopically visible morphological changes of the mucosa that can develop focal carcinoma in the absence of surgical intervention. The successive molecular changes proposed to occur at different stages in the adenoma‐carcinoma sequence were primarily based on DNA studies of exophytic, polypoid‐type adenomas. Not all colorectal lesions, however, display an exophytic phenotype and a presumed distinct colorectal neoplasm, the nonpolypoid adenoma, was subsequently described as a precursor of colorectal cancer. The low incidence of KRAS mutations in nonpolypoid colorectal adenomas reported previously suggested a different genetic basis for the transformation process in these lesions. We have pursued the identification of genetic changes in benign sporadic nonpolypoid colorectal adenomas in a selected Swedish patient group with no family history of colorectal cancer. Mutation screening of the adenomatous polyposis coli (APC), KRAS, and TP53 genes was conducted using the protein truncation test, heteroduplex–single‐strand conformation polymorphism analysis, and denaturing gradient gel electrophoresis on PCR‐amplified fragments. Fourteen mutations in the APC gene were characterized in 10/20 samples. Mutations in the KRAS and TP53 genes were identified in 3/57 and 4/51 adenomas, respectively. The mutation frequencies and distribution of mutations in APC correlate with published data on exophytic adenomas. The low mutation frequency of the TP53 gene is consistent with the benign nature of the research material. KRAS activation (an early event in polypoid colorectal adenomas) apparently does not play a significant role in nonpolypoid adenoma development but may result in the development of a polypoid configuration. Genes Chromosomes Cancer 27:202–208, 2000.

Familial hypercholesterolemia: potential diagnostic value of mutation screening in a pediatric population of South Africa.

Three founder‐related low‐density lipoprotein receptor (LDLR) gene mutations, D154N, D206E and V408M, cause familial hypercholesterolemia (FH) in approximately 90% of South African Afrikaners. Two hundred and twenty‐one South African children, from 85 affected families, were screened for the specific mutation identified previously in the index case. Sixty boys and 56 girls were heterozygous for mutation D154N (FH3), D206E (FH1) or V408M (FH2). Total and LDL cholesterol (LDLC) levels were similar among the children heterozygous for the three founder mutations, and mean values were significantly higher compared to those without a known mutation (p < 0.0001). Plasma cholesterol levels overlapped considerably between the different groups, suggesting that modifiable lifestyle factors remain important in children with FH. This study demonstrates the potential diagnostic value of mutation screening in a pediatric population with an enrichment of particular gene mutations.

Aminoglycoside-induced hearing loss : South Africans at risk

South Africa is currently experiencing a TB epidemic with an estimated incidence of 940 / 100 000 population / year, and the country has been ranked 4th among the 22 high-burden TB countries worldwide by the World Health Organization (WHO). A potentially devastating threat to TB control is the emergence of multidrug-resistant TB (MDR-TB) and, more recently, extensively drug-resistant TB (XDR-TB), mainly as a result of poor drug adherence by TB patients and incorrect management or treatment regimens by health providers ; however, direct transmission of drug-resistant strains also plays an important role. The MDR / XDR-TB strains necessitate prolonged chemotherapy for up to 2 years or more, and the use of more toxic second-line drugs including the aminoglycoside (streptomycin, kanamycin and amikacin) and polypeptide (capreomycin) antibiotics. In South Africa, in accordance with WHO guidelines, streptomycin is used for retreatment of TB while kanamycin, amikacin and capreomycin are used to treat MDR / XDR-TB.

Defects of blastogenesis: Counseling dilemmas in two families

Three patients are described with defects of blastogenesis and predominantly midline defects. Two were sibs of whom the firstborn were female cephalothoracopagus-conjoined twins with multiple predominantly midline defects initially thought to be a sporadic occurrence. A subsequent brother presented with severe hydrocephalus, rhombencephalosynapsis, conotruncal defect, ambiguous genitalia, and unilateral pre-axial polydactyly; an autosomal recessive defect is postulated in this case. Patient 3 had hydrocephalus, small cerebellum, cleft lip and palate, and a large sacrococcygeal teratoma, the better differentiated part of which included ovarian tissue with primordial follicles. The latter may occur in incomplete twinning as a defect of blastogenesis. The mother had had a previous termination of a fetus with hydrocephalus from a different relationship. Counseling was difficult since no examinations were done on the previous fetus and no further investigations of this family could be obtained, but a genetic origin is suspected. Most defects of blastogenesis are sporadic; however, some cases have a genetic cause and ultrasound examinations should be offered in subsequent pregnancies.

Heavy Prenatal Alcohol Exposure is Related to Smaller Corpus Callosum in Newborn MRI Scans

BACKGROUND Magnetic resonance imaging (MRI) studies have consistently demonstrated disproportionately smaller corpus callosa in individuals with a history of prenatal alcohol exposure (PAE) but have not previously examined the feasibility of detecting this effect in infants. Tissue segmentation of the newborn brain is challenging because analysis techniques developed for the adult brain are not directly transferable, and segmentation for cerebral morphometry is difficult in neonates, due to the latters incomplete myelination. This study is the first to use volumetric structural MRI to investigate PAE effects in newborns using manual tracing and to examine the cross-sectional area of the corpus callosum (CC). METHODS Forty-three nonsedated infants born to 32 Cape Coloured heavy drinkers and 11 controls recruited prospectively during pregnancy were scanned using a custom-designed birdcage coil for infants, which increases signal-to-noise ratio almost 2-fold compared to the standard head coil. Alcohol use was ascertained prospectively during pregnancy, and fetal alcohol spectrum disorders diagnosis was conducted by expert dysmorphologists. Data were acquired using a multi-echo FLASH protocol adapted for newborns, and a knowledge-based procedure was used to hand-segment the neonatal brains. RESULTS CC was disproportionately smaller in alcohol-exposed neonates than controls after controlling for intracranial volume. By contrast, CC area was unrelated to infant sex, gestational age, age at scan, or maternal smoking, marijuana, or methamphetamine use during pregnancy. CONCLUSIONS Given that midline craniofacial anomalies have been recognized as a hallmark of fetal alcohol syndrome in humans and animal models since this syndrome was first identified, the CC deficit identified here in newborns may support early identification of a range of midline structural impairments. Smaller CC during the newborn period may provide an early indicator of fetal alcohol-related cognitive deficits that have been linked to this critically important brain structure in childhood and adolescence.

A study of meningiomas in South Africa: investigating a correlation between clinical presentation, histopathology and genetic markers.

Objective. To determine whether there are certain genetic markers which correlate with particular clinical characteristics of meningiomas including multiplicity, recurrence and calvarial erosion. Methods. Thirty-eight South African-born patients with meningiomas were recruited for this study. At surgery, blood and tumour specimens were obtained for histopathological, cytogenetic and molecular analysis. Loss of heterozygosity (LOH) on chromosomes 1p and 22q were investigated and the NF2 gene on 22q12.2 was screened for disease-causing mutations. Results. The commonest tumour locations were convexity (25%) and parasagittal (21%). The histology results showed that 86.8% of the patients had Grade I tumours and the remainder had Grade II tumours. A pathogenic nonsense mutation, R341X in the NF2 gene was found in only one patient. LOH on each of chromosomes 1p and 22q was observed in 44.7% of patients, but in different individuals. Significant associations were found between having specific tumour characteristics and both male gender (p-value = 0.0059) and 22q LOH (p-value = 0.0425). We estimated that having 22q LOH makes an individual approximately four times more likely to develop a tumour that exhibits multiplicity, recurrence or calvarial erosion (OR = 4.8; 95% CI: 1.2–23.4). Adjusting for gender strengthened this effect (OR = 6.1; 95% CI: 1.1–48.7). Conclusions. Our data indicate that male patients and patients with a meningioma that has 22q LOH are more likely to develop tumours exhibiting multiplicity, recurrence or calvarial erosion. We recommend that this subset of patients should be followed up more closely. Further study is needed to determine the benefit of adjuvant radiation therapy in this scenario.

Morphological features in a Xhosa schizophrenia population

BackgroundDemonstrating an association between physical malformation and schizophrenia could be considered supportive of a neurodevelopmental origin of schizophrenia and may offer insights into a critical period for the development of this illness. The aim of our study was to investigate whether differences in the presence of minor physical anomalies could be demonstrated between schizophrenia sufferers and normal controls in a Xhosa population with a view to identifying a means of subtyping schizophrenia for use in future genetic studies.MethodsSixty-three subjects with schizophrenia (21 sibling pairs, 1 sibship of four and a group of probands with an affected non-participating sibling (n = 17)), 81 normal controls (37 singletons and 22 sibling pairs) of Xhosa ethnicity were recruited. Each participant was then examined for minor physical anomalies using the Modified Waldrop scale. The relationship between each of the morphological features and the presence of an affected sib was examined using the Chi-squared test, followed by an intra-pair concordance analysis in the sibling pairs.ResultsGap between first and second toes was significantly more common in the affected sib pair group when compared to the non-affected sib pair group (p = 0.019) and non-affected singleton control group (p = 0.013). Concordance analysis also revealed increased concordance for this item in the affected sib pair group.ConclusionThese findings offer an intriguing possibility that in the Xhosa population, affected sib pair status may be linked to a neurodevelopmental insult during a specific period of the fetal developmental.

Chromosome 22q11 in a Xhosa schizophrenia population

Chromosome 22q11 aberrations substantially increase the risk for developing schizophrenia. Although micro-deletions in this region have been extensively investigated in different populations across the world, little is known of their prevalence in African subjects with schizophrenia. We screened 110 African Xhosa-speaking participants with schizophrenia for the presence of micro-deletions. As further verification for the presence or absence of 22q11 microdeletions, we screened 238 Xhosa schizophrenia patients and 240 healthy Xhosa individuals from a larger schizophrenia candidate 22q11 gene study using molecular analyses. Data from molecular and cytogenetic analyses confirmed the absence of 22q11 microdeletions in the Xhosa schizophrenia samples. Although the absence of chromosome 22q11 micro-deletions in this group of patients does not exclude the possibility that it may occur in Xhosa schizophrenia patients, we concluded an extremely low prevalence. Our findings suggest that unique susceptibility loci may be present in this group.