South African Medical Journal - Supplement 1, June 2016
Volumes & issues
Supplement 1, June 2016
Source: South African Medical Journal 106, pp 65 –66 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.10998More Less
In certain autosomal recessive disorders there is suggestive evidence that heterozygous carriers may have some selective advantage over normal homozygotes. These include, for example, cystic fibrosis, Tay-Sachs disease and phenylketonuria. The best example so far, however, is that of significant heterozygous advantage in sickle-cell anaemia with increased resistance to falciparum malaria.
Duchenne muscular dystrophy in the Western Cape, South Africa : where do we come from and where are we going? : the new millenniumSource: South African Medical Journal 106, pp 67 –71 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.10999More Less
Duchenne muscular dystrophy (DMD) is one of the most common and severe of the inherited dystrophies, with an incidence of 1 in 3 500 live, male births worldwide. Becker muscular dystrophy (BMD) has a lower incidence of 1:14 000 - 18 000 boys and a milder progression and longer life expectancy. Over the last two decades, better understanding of the underlying disease aetiology as well as major advances in medical technology have brought about significantly improved genetic diagnosis and clinical care for B/DMD patients. Exciting developments in the field of gene-based therapies have once again put B/DMD in the limelight, with renewed focus on the importance of comprehensive genetic testing protocols. We present a historical overview of the medical and molecular service for B/DMD offered over the last three decades in South Africa, specifically in the Western Cape, from a clinical as well as a laboratory perspective.
Source: South African Medical Journal 106, pp 72 –74 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11000More Less
Background. Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA).
Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA.
Method. This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA.
Results. A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered.
Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.
Cone opsins, colour blindness and cone dystrophy : genotype-phenotype correlations : the new millenniumSource: South African Medical Journal 106, pp 75 –78 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11001More Less
X-linked cone photoreceptor disorders caused by mutations in the OPN1LW (L) and OPN1MW (M) cone opsin genes on chromosome Xq28 include a range of conditions from mild stable red-green colour vision deficiencies to severe cone dystrophies causing progressive loss of vision and blindness. Advances in molecular genotyping and functional analyses of causative variants, combined with deep retinal phenotyping, are unravelling genetic mechanisms underlying the variability of cone opsin disorders.
Source: South African Medical Journal 106, pp 79 –81 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11002More Less
In Australia, 58 patients with Gaucher disease were managed by a Gaucher Disease Advisory Committee (GDAC) through a centrally administered national programme, the Life Savings Drug Program (LSDP). In June 2009, Genzyme Corporation, which manufactures imiglucerase (Cerezyme), the only enzyme replacement therapy (ERT) registered for the treatment of Gaucher disease in Australia at that time, announced that due to a viral contamination problem there would be no further shipments of Cerezyme to Australia prior to the end of 2009. The GDAC allocated available drug supplies in order to maintain treatment to those most in need on a hierarchal clinical severity basis. A cohort of 24 patients with Type 1 Gaucher disease was withdrawn from therapy, 22 of whom had no discernible clinically significant adverse effects when reviewed off therapy for up to 6 months. In this paper, we review the course of 20 of the patients who have been on imiglucerase for periods of at least 24 months after the end of their 'drug holiday'. No patient experienced a bone crisis nor clinical nor magnetic resonance imaging evidence of new avascular necrosis events during this period. Two years after recommencing ERT after a 6-month drug holiday, no patient had developed an overt irreversible complication of their Gaucher disease, with the majority returning to their previous clinical status.
Source: South African Medical Journal 106, pp 90 –93 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11005More Less
Individuals with osteogenesis imperfecta type III (OI III) are severely physically disabled due to frequent fracturing. Their disability poses numerous barriers that challenge their social development. Despite these limitations, several affected persons are able to rise above these problems and achieve success in their personal and professional life. This outcome is directly relevant to their psychosocial development. The achievements of five individuals with OI III living in Cape Town are highlighted in this article, as well as the challenges that they have experienced and continue to experience in their daily lives. The authors intend to promulgate understanding of the psychosocial circumstances of affected persons, thereby facilitating the deployment of appropriate efforts and resources to address these challenges.
Dental needs of intellectually disabled children attending six special educational facilities in Cape Town : the new millenniumSource: South African Medical Journal 106, pp 94 –97 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11006More Less
Objective. To assess the dental needs of a group of children with intellectual disability (ID) attending six special educational facilities in Cape Town, South Africa.
Methods. This was a cross-sectional study based on a convenience sampling method. One hundred and fifty-seven children with ID attending six special educational facilities in Cape Town were included in the survey. Five schools were exclusively funded by the State and one school received additional private financial support. The oral examinations complied with guidelines drafted by Special Olympics Special Smiles programme and the Centers for Disease Control, USA.
Results. The most common dental disorders requiring management were gingival disease (69%) and untreated dental caries (68%). Almost 50% of the children had missing teeth. Twenty-nine percent needed orthodontic correction of malocclusion and 7% had structural abnormalities of their teeth that required either aesthetic or functional intervention. Fillings were evident in only 8% of the children. Females required more dental treatment than males. The dental needs of children with ID increased with age. There were no significant differences in the dental needs of children attending State-funded schools and those attending the single school that received additional financial assistance.
Conclusion. The frequency of unmet dental needs of children with ID attending special educational facilities in Cape Town was high and the dental care available to them was minimal. The study highlights the need for improved dental services to ensure that optimal oral health is accessible to children with ID attending special educational facilities in Cape Town.
Source: South African Medical Journal 106, pp 98 –99 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11007More Less
Infantile cortical hyperostosis - Caffey-Silverman disease - is a familial disorder manifesting in the late fetal period or infancy with excessive periosteal bone formation. Signs and symptoms regress spontaneously within months and result in expanded, deformed bones. The paucity of clinical symptoms may lead to delayed investigation and confusion of the remaining bone changes with those in other conditions. This problem is exemplified by two siblings misdiagnosed as osteogenesis imperfecta. The diagnosis of Caffey-Silverman disease was confirmed by molecular analysis showing the specific COL1A1 mutation in the patients and their clinically unaffected mother. Reduced penetrance rather than autosomal recessive inheritance explains multiple affected siblings born to healthy parents.
Source: South African Medical Journal 106, pp 100 –102 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11008More Less
The osteoporosis-pseudoglioma syndrome (MIM 259770) is a rare autosomal recessive disorder in which bone fragility and frequent fractures are associated with serious ocular changes. The skeletal manifestations resemble those of osteogenesis imperfecta while hyperplasia of the vitreous, eye and corneal opacities often mimics the appearance of intraocular glioma. This disorder was previously reported in a South African family of Indian stock as 'the ocular form of osteogenesis imperfecta'. Terminological discussion followed and it was suggested that these individuals had osteoporosis-pseudoglioma syndrome. This article describes and depicts the manifestations of the disorder and discusses the nosology.
Source: South African Medical Journal 106, pp 103 –106 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11009More Less
Background. Fetal alcohol spectrum disorder (FASD) is an under-diagnosed condition in South Africa (SA). Fetal alcohol syndrome and FASD community prevalence studies were undertaken in 17 towns in three of the nine provinces in SA.
Objective. The objective for all the studies was to determine the FASD prevalence rates by assessing the grade 1 learners in all the studies, using international FASD diagnostic criteria.
Methods. The same methodology was used for all the studies in Gauteng, Western and Northern Cape provinces. Consenting grade 1 learners received anthropometric screening, clinical examinations and neurodevelopmental assessments. Structured interviews were used to assess maternal alcohol consumption during pregnancy.
Results. Reported prevalence rates ranged from 29 to 290 per 1 000 live births.
Conclusion. FASD rates from studies conducted in SA are among the highest worldwide. FASD affects all communities in SA and is therefore a major public health concern in SA. Multidisciplinary and intersectoral interventions are urgently required to raise awareness about the dangers of prenatal alcohol exposure and the devastating effect of FASD on the lives of children, families and communities.
Spinocerebellar ataxia type 7 in South Africa : epidemiology, pathogenesis and therapy : the new millenniumSource: South African Medical Journal 106, pp 107 –109 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11010More Less
Disorders of the nervous system represent a significant proportion of the global burden of non-communicable diseases, due to the trend towards ageing populations. The Department (now Division) of Human Genetics at the University of Cape Town (UCT) has been involved in pioneering research into these diseases since the appointment of Prof. Peter Beighton as Head of Department in 1972. Beighton's emphasis on understanding the genetic basis of disease laid the groundwork for investigations into several monogenic neurodegenerative conditions, including Huntington's disease and the polyglutamine spinocerebellar ataxias (SCAs). In particular, SCA7, which occurs at an unusually high frequency in the South African (SA) population, was identified as a target for further research and therapeutic development. Beginning with early epidemiological surveys, the SCA7 project progressed to molecular genetics-based investigations, leading to the identification of a founder effect in the SA SCA7 patient population in the mid-2000s. Capitalising on the founder haplotype shared by many SCA7 patients, UCT researchers went on to develop the first population-specific gene-silencing approach for the disease. More recently, efforts have shifted to the development of a more accurate model to decipher the precise mechanisms of neurodegeneration, using induced pluripotent stem cells derived from SA SCA7 patients. In many ways, the SA SCA7 journey reflects the legacy and vision of Prof. Peter Beighton, and his efforts to establish world-class, collaborative research into diseases affecting the African continent.
Pyle metaphyseal dysplasia in an African child : case report and review of the literature : the new millenniumSource: South African Medical Journal 106, pp 110 –113 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11011More Less
Pyle disease (OMIM 265900), also known as metaphyseal dysplasia, is a rare autosomal recessive disorder with no known gene mutation. We report a case of Pyle disease in a 7-year-old African boy of mixed ancestry who presented with finger and wrist fractures following minor trauma. The radiological findings revealed abnormally broad metaphyses of the tubular bones, known as Erlenmeyer-flask bone deformity, and mild cranial sclerosis, both hallmarks of the condition. We report the first case in a patient with African ancestry, which could help in the gene discovery of this rare autosomal recessive skeletal dysplasia with unknown mutations.
Application of advanced molecular technology in the diagnosis and management of genetic disorders in South Africa : the new millenniumSource: South African Medical Journal 106, pp 114 –118 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11012More Less
Background. Genetic testing has evolved from a niche speciality for diagnosis of rare disorders and carrier screening to subtyping of complex medical conditions for targeted treatment. Genes causing monogenic disorders are well characterised, but risk management of multifactorial and polygenic disorders guided from the genetic background remains a challenge.
Objective. This study describes the use of a pathology-supported genetic testing (PSGT) strategy designed to facilitate the move from single- to multi-gene testing and next-generation sequencing (NGS).
Methods. In contrast to direct-to-consumer genetic testing, PSGT requires preselection of patients and data integration to determine current and future risk implications. To enable this process, a genomics database resource generated at the interface between the laboratory and clinic is available for clinical interpretation.
Results. The PSGT approach led to the development of testing algorithms for improved clinical management of patients with cancer and other complex disorders with a genetic component. Local evidence is presented to demonstrate the application of PSGT for assessment of clinical relevance in patients with rare germline variants and functional polymorphisms underlying shared disease pathways.
Conclusion. PSGT is ideally suited to serve as a screening step for microarray analysis and whole genome/exome sequencing as the next frontier in personalised medicine. Use of these advanced molecular technologies to match genotype with phenotype provides a resource for diagnosis and discovery over a lifetime.
Evaluating the contribution of APOBEC3G haplotypes on influencing HIV infection in a Zimbabwean paediatric population : the new millenniumSource: South African Medical Journal 106, pp 119 –123 (2016) http://dx.doi.org/10.7196/SAMJ.2016.v106i6.11013More Less
Background. Apolipoprotein B mRNA-editing catalytic polypeptide like-3G (APOBEC3G) is an antiviral enzyme that reduces viral fitness by introducing uracil to thymidine hypermutations in viral genomes. Thus, polymorphisms in the APOBEC3G gene have been implicated in differential outcomes of HIV infection and disease progression. However, there is insufficient evidence on the role of APOBEC3G gene variants on HIV infection, especially in African populations. This study therefore describes polymorphisms in the APOBEC3G gene in a Zimbabwean paediatric population and evaluates their effects on susceptibility to HIV infection among children born to HIV-infected mothers.
Methods. A total of 104 children aged between 7 and 9 years, comprising 68 perinatally exposed to HIV (32 born infected (EI) and 36 born uninfected (EU)) and 36 unexposed and uninfected (UEUI) controls were recruited. Allelic variants (n=5) in the APOBEC3G gene were characterised.
Results. Frequencies for minor APOBEC3G alleles in the HIV-uninfected groups (EU and UEUI) were c.557G (40%), g.-90C (32%), g.-571C (12%), c.467-85C (42%), and c.582-162G (6%). APOBEC3G c.467-85C frequency was statistically significantly different when compared to the Masai of Kinyawa, Kenya population (42% v. 18%). None of the single nucleotide polymorphisms individually or as part of haplotypes were significantly associated with HIV infection when comparing the EI and EU groups.
Conclusions. Our findings suggest that APOBEC3G polymorphisms alone may not have significant predictive power for inferring genetic susceptibility to vertical transmission of HIV in children perinatally exposed to HIV.
Source: South African Medical Journal 106, pp 124 –125 (2016)More Less
Richard Burman : Division of Medical Biochemistry, Department of Integrative Biomedical Sciences (IBMS), Faculty of Health Sciences, University of Cape Town, South Africa
Janine Scholefield : Senior Researcher, Gene Expression and Biophysics Group, Synthetic Biology ERA, CSIR Biosciences, Pretoria, South Africa
Lecia Bartmann : Genetic Nursing Sister (retired), Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Source: South African Medical Journal 106 (2016)More Less
We thank the contributors for their participation in this endeavour and for their excellent articles. We are most grateful to the donors for financial support to defray the costs of printing and distribution, without which this Festschrift would not have been possible.