Ambroise Wonkam

Knowledge and attitudes concerning medical genetics amongst physicians and medical students in Cameroon (sub-Saharan Africa)

Purpose: Little is known about physicians knowledge of, and attitudes toward genetics in sub-Saharan Africa.Methods: Survey of 101 pre-clinical, 95 clinical medical students, and 110 physicians, in Cameroon.Results: The awareness of DNA diagnosis was poor: 0, 2.2, and 1.2%, respectively, for sickle cell anemia. The majority of the respondents considered genetic counseling as indispensable (97.6, 98.9 and 100%); and prenatal diagnosis as acceptable. The acceptance of medical abortion increased with the level of medical education (62.6, 74.7 and 90.7%). Sickle cell anemia was considered as a “serious disease” by a greater majority of respondents than Down syndrome (P < 0.001). But, in all three groups, the acceptance of termination of affected pregnancy “if the respondents own child was affected” was lower for sickle cell anemia than Down syndrome (22.4 versus 40.2%, 10.8 versus 29.3% and 36.1 versus 70.4%).Conclusions: The data suggest a poor knowledge of genetic tests among medical students and physicians. This cohort appears to accept the principles of medical genetics. Our data emphasized a need to introduce genetics and to develop research on its ethical and social implications in Cameroon.

Association of Variants at BCL11A and HBS1L-MYB with Hemoglobin F and Hospitalization Rates among Sickle Cell Patients in Cameroon

Background Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort. Methods and Findings Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region (HMIP) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region (HMIP) and BCL11A affect both other hematological indices and rates of hospitalization. Conclusions This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants.

The epidemiology of stroke in sickle cell patients in Yaounde, Cameroon

BACKGROUND AND PURPOSE Stroke, a severe and recurrent but preventable complication of sickle cell disease (SCD), has not been well studied in Cameroon. To obtain baseline data towards the development of a national stroke prevention programme in SCD, we studied a sample of sickle cell patients with the aim of determining stroke prevalence, clinical presentation and management practices. PATIENTS AND METHODS Homozygous sickle cell patients in two centres in Yaounde were screened for stroke, in a cross-sectional study. Stroke was diagnosed clinically and confirmed where possible with brain computerized tomography. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Management practices were noted from patient charts. RESULTS One hundred and twenty patients aged 7 months to 35 years (mean age 13.49+/-8.79 years) were included. Eight cases of stroke (mean age 16.6+/-11.2 years) were identified, giving a stroke prevalence of 6.67%. Cerebral infarction was thrice as common as cerebral hemorrhage and clinical presentation was classical. Cerebral infarction was more frequent in patients aged below 20 years and hemorrhage in those above 20 (p=0.11). The annual recurrence rate was 25%. Missed diagnosis rate by attending physician was 25%. The NIHSS and mRS showed high stroke severity. Stroke management practices were insufficient and no patient received any form of stroke prophylaxis. CONCLUSION Stroke prevalence and presentation in sickle cell patients in Yaounde is similar to that observed in developed countries, but the wide management gap calls for rapid action. Our situation is ideal for the study of the natural history of stroke in sickle cell disease.

The Co-Inheritance of Alpha-Thalassemia and Sickle Cell Anemia Is Associated with Better Hematological Indices and Lower Consultations Rate in Cameroonian Patients and Could Improve Their Survival

Background Co-inheritance of α-thalassemia was reported to be associated with a delayed age of disease onset among Cameroonian Sickle Cell Anemia (SCA) patients. The present study aimed to explore the correlation between α-thalassemia, hematological indices, and clinical events in these patients. Methods and Findings We studied 161 Cameroonian SCA patients and 103 controls (59.1% HbAA) with median ages of 17.5 and 23 years. RFLP-PCR was used to confirm SCA genotype and to describe haplotypes in the HBB-like genes cluster. Multiplex Gap-PCR was performed to investigate the 3.7 kb α-globin gene deletions. SNaPshot PCR, capillary electrophoresis and cycle sequencing were used for the genotyping of 10 SNPs in BCL11A, HMIP1/2, OR51B5/6 and HBG loci, known to influence HbF levels. Generalised linear regression models adjusted for age, sex and SNPs genotypes was used to investigate effects of α-thalassemia on clinical and hematological indices. The median rate of vaso-occlusive painful crisis and hospitalisations was two and one per year, respectively. Stroke was reported in eight cases (7.4%). Benin haplotype was the most prevalent (66.3%; n = 208 chromosomes). Among patients, 37.3% (n = 60) had at least one 3.7 kb deletion, compared to 10.9% (n = 6) among HbAA controls (p<0.001). Among patients, the median RBC count increased with the number of 3.7 kb deletions [2.6, 3.0 and 3.4 million/dl, with no, one and two deletions (p = 0.01)]. The median MCV decreased with the number of 3.7 kb deletion [86, 80, and 68fl, with no, one and two deletions (p<0.0001)], as well as median WBC counts [13.2, 10.5 and 9.8×109/L (p<0.0001. The co-inheritance of α-thalassemia was associated with lower consultations rate (p = 0.038). Conclusion The co-inheritance of α-thalassemia and SCA is associated with improved hematological indices, and lower consultations rate in this group of patients. This could possibly improve their survival and explain the higher proportion of α-thalassemia among patients than controls.

Association between biological markers of sickle cell disease and cognitive functioning amongst Cameroonian children

Background: Some of the major complications of sickle cell disease (SCD) occur in the brain and apart from overt stroke, patients also present with cognitive impairments. We sought to evaluate the prevalence of cognitive deficits as well as their biological predicting factors in young SCD patients in Cameroon. Methods: The cognitive performances of Cameroonian SCD young patients were evaluated using a neuropsychological test battery assessing four domains of cognitive functioning (executive functions, attention, memory, and sensory-motor skills) previously adapted and normalized on healthy subjects in Yaoundé. Findings: Up to 37.5% of the 96 SCD patients aged 6 to 24 years (M = 13.5, SD = 4.9) had mild-to-severe cognitive deficits. The cognitive deficits tend to increase with age. There was a significant effect of SCD on executive functions and attention, whereas SCD patients performed as well as controls on memory and sensory-motor skills tests. Structural equation models showed a significant association between (a) severe anemia and lower executive functioning, (b) low fetal hemoglobin levels and lower executive functioning and attention, (c) history of cerebrovascular accidents and lower performances in executive functioning, sensory-motor skills, and memory, (d) pathological electroencephalogram and lower attention, and (e) abnormal Transcranial Doppler and lower memory. Conclusion: SCD patients in Cameroon presented a very high prevalence of cognitive deficits, with a specific impairment of executive functions and attention. Routine neuropsychological evaluation for early detection of cognitive deficits in SCD patients could represent a cost-effective tool to implement in resource-limited contexts such as in sub-Saharan Africa.

Cytochrome P450 pharmacogenetics in African populations: implications for public health

Introduction: Africa harbors a disproportionate burden of disease when taking into account the triple challenge caused by HIV/AIDS, tuberculosis (TB) and malaria, against a backdrop of an increasing burden of noncommunicable diseases. More than 80% of therapeutic drugs used in the management of these diseases/conditions are metabolized by CYP enzymes that exhibit genetic polymorphisms. Areas covered: There is variability in the expression and activities of CYPs resulting in interindividual differences in the response to standard doses of therapeutic drugs, due to genetic polymorphisms, which exhibit both quantitative and qualitative differences between racial and between ethnic groups. The review aims to evaluate the implications of the genetic variation in CYPs on the public health of Africans. The CYPs reviewed here metabolize most of the commonly used therapeutic drugs and include CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 and 3A5. Allele frequencies are compared between African ethnic groups and among populations of African, Asian and European origin. Data are obtained from our own studies and literature. Expert opinion: The variability in the pattern of genetic variation between populations translates into differences in drug response. Understanding CYP variability improves rational drug use and has public health significance.

Initiation of a medical genetics service in sub-Saharan Africa: experience of prenatal diagnosis in Cameroon.

BACKGROUND Initiation of Prenatal Genetic Diagnosis (PND) has laid the foundation of the first medical genetic service in Cameroon. METHOD Cross-sectional descriptive study, illustrating some aspects of the genetic service using a small 24-months PND experience. RESULTS The service began with a medical geneticist who had to follow-up the building and equipments supplies of the diagnosis laboratory; and to personally perform genetic consultations, molecular experiments and post-results counseling. PND was indicated for sickle cell disease (SCD) in 33 cases (55%) and chromosomal anomalies in 27 cases (45%). With international collaboration, DNA analysis revealed 6 SCD-affected foetuses (20.7%); QF-PCR (N=25) and full karyotype (N=8) analysis revealed cases of trisomy 21 and trisomy 18. Following PND success, national effort granted more human and material resources to improve the service. The preliminary experience was made possible by three factors: 1) the availability of a trained Cameroonian medical geneticist 2) the availability of obstetricians trained in fetal medicine and 3) advocacy initiatives at national and international levels, which have proven invaluable for advice, training, sourcing of materials, and back-up reference diagnostic laboratory. CONCLUSION The practice of medical genetics, involving prenatal genetic diagnosis of sickle cell disease and chromosomal anomalies, is possible in Cameroon (sub-Saharan Africa).

Aetiology of childhood hearing loss in Cameroon (sub-Saharan Africa)

BACKGROUND Severe hearing loss is a global problem affecting particularly developing countries. There is scarcity of recent published data on the epidemiology of childhood deafness in sub-Saharan Africa. OBJECTIVE To determine the etiological profile of severe childhood deafness in Cameroon. METHODS Prospective cross-sectional study of patients with a severe hearing loss that started before the age of 15 years. Detailed family and medical history was obtained; careful clinical, otological and audiological examinations were performed. RESULTS A total of 582 patients with a severe hearing loss were examined. Prelingual deafness accounted for 75.1% (n = 437), with a mean age at medical diagnosis of 3.3 ± 1.2 years. This late presentation may be explained by limited parental awareness of signs raising suspicion of hearing loss, poor access to health care and the absence of neonatal screening for hearing loss in Cameroon. Identified genetic causes accounted for 14.8% (n = 86), putative environmental causes for 52.6% (n = 306) and unknown causes for 32.6% (n = 190). Amongst Genetic causes, the syndromic hearing loss accounted for 13.1% (n = 12) of cases, the rest being non syndromic (n = 74). Consanguineous families accounted for 5.7% (n = 33) of the whole sample, and 15.1% (n = 13) of genetic cases. No union between deaf parents was observed. CONCLUSION These data highlight the possible predominance of putative environmental causes of childhood deafness in Cameroon, and emphasize the need for improved policies for prevention of infectious diseases and for neonatal hearing screening. However, further molecular analyses and targeted CT scan investigations are required to more accurately gauge the contribution of genetics etiologies.

CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 Polymorphisms in Two Bantu-Speaking Populations from Cameroon and South Africa: Implications for Global Pharmacogenetics

The health burden resulting from parasitic and infectious diseases such as HIV/AIDS, tuberculosis and malaria, requires that available medication and limited healthcare resources be used optimally. However, due to co-morbidities, patients are often exposed to many drugs concurrently. Most of these drugs are metabolised by similar enzymes which are polymorphic, thus, drug-drug interactions are a constant problem. Quantitative and qualitative differences in drug metabolizing enzyme variants in different populations result in differential drug response. This study investigated the baseline frequencies of genetic variants in key drug metabolizing cytochrome P450 enzymes, CYP1A2, CYP2A6, CYP2B6, CYP3A4 and CYP3A5 in two previously understudied Bantu-speaking populations from Cameroon (N=72) and South Africa (N=163) using PCR-RFLP. Genotype frequencies for CYP1A2 C-163A and CYP3A4 A-392G single nucleotide polymorphisms (SNPs) were significantly different between these two populations (P=0.0004 and 0.0079, respectively). Significant differences were also observed when the two Bantu-speaking populations were each compared to other African populations as well as Caucasian and Asian populations. Importantly, correspondence analysis showed that the two Bantu-speaking African populations were separated from each other and from other African populations based on CYP1A2 C-163A and CYP2A6 G1093A SNPs. The data show that drugs that are substrates for these polymorphic enzymes are likely to have different response profiles among the Bantu-speaking populations and populations of either Caucasian or Asian origin, further emphasizing the need to genetically characterise as many African populations in order to realize personalised medicine. These data further emphasize that linguistically related Bantu-speaking populations are not necessarily genetically homogenous. Finally, we note that our observations also inform future pharmacogenetic- guided rational therapeutic drug monitoring to prevent or minimize the risk for adverse drug-drug interactions mediated by these genetically polymorphic pathways.

Capacity-Building in Human Genetics for Developing Countries: Initiatives and Perspectives in Sub-Saharan Africa

Background: Stakeholders who are committed to bridge the gap in genetics services need to be aware of current initiatives in sub-Saharan Africa. Methods: We reviewed selected experiences from African geneticists that led to specific recommendations. Results: The initiation of prenatal diagnosis of sickle cell anaemia founded the first medical genetic service in Cameroon. There remains a need for international collaborative effort to overcome the lack of human, technical and financial resources around the practice of medical genetics in Africa. The African Society of Human Genetics, Wellcome Trust and NIH have recently proposed a model on how to fully engage Africa in genomics. It includes a ‘Health and disease’ phase I: use of the case-control design to study genetic and epidemiological determinants of 7 important diseases in Africa, and a ‘Genetic variation’ phase II: comprehensive documentation of genetic variations in 100 carefully selected ethnic groups across Africa. The strategy would require the development of: (1) clinical phenotyping centres, (2) molecular phenotyping centres, (3) genotyping and sequencing capability, (4) data centres, and (5) a bio-repository in Africa. Conclusions: Governments and international health agencies need to recognise that genetics is important to the global medical community. The initiatives of African geneticists need advocacy and encouragement from the international community.