Browsing by Author "Beighton, Peter"

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    A clinical and molecular investigation of two families with Simpson-Golabi-Behmel syndrome
    (2014) Pretorius, Careni Elizabeth; Fieggen, Karen; Beighton, Peter
    Includes abstract (p. 30-32). Includes bibliographical references.
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    Dental implications of genetic and congenital intellectual disabilities in Cape Town
    (2018) Roberts, Tina Sharon; Beighton, Peter; Stephen, LXG
    Introduction Intellectual disability (ID) is a common and significant problem which has many social, financial, medical and dental implications in South Africa. The severity of the ID varies, ranging from mild to profound impairment and numerous environmental and genetic factors play a role in the aetiology. Oral health is crucial to the overall health and well-being of children with ID. The dental problems of children with ID may be overshadowed by their intellectual dysfunction, and in some instances, by syndromic manifestations. These dental abnormalities may be unnoticed or considered of lesser importance than systemic health issues. There is a paucity of information in both the international and local scientific literature regarding the dental needs, the dental management implications and barriers to oral care pertaining to children with ID. For these reasons, the principal focus of this thesis is the identification, documentation and analysis of the dental abnormalities a group of children with ID in Cape Town, South Africa. Methodology A total of 206 children with ID were assessed during the investigation; 157 children at six Special Educational Facilities (SE Facilities) and 49 at the Red Cross Children’s Hospital (RXH) in Cape Town. The children were referred to the author by the Medical Genetics team of the University of Cape Town. This clinical study was based on a cross-sectional, quantitative, exploratory, descriptive design. When appropriate, clinical photographs and panorex radiographs were obtained. Signed permission for these records were granted by the parents or legal caregivers. Results The frequency of unmet dental disorders among children with ID both at the SE Facilities and RXH was high: dental caries (67% and 84%); gingival disease (69% and 86%); missing teeth (46% and 51%); malocclusion (30% and 66%); structural tooth abnormalities (7.5% and 38%). Based on clinical observation, forty-three percent of children at the SE Facilities had abnormalities of the jaw and midface that required surgical intervention. Dental fillings were present in only 8% of children at the SE Facilities and 12% of children at the RXH. Many parents and caregivers of children with ID experienced difficulty attending dental clinics. Financial and psychosocial issues were the key barriers that prevented their children from accessing dental services. Conclusions Intellectual disability varies in complexity and affects several South African children. Oral health plays a significant role in the general health and well-being of children with ID. The prevalence of unmet dental needs among children with ID is high, and in South Africa, the limited financial resources dedicated to primary and specialized oral health care may preclude access of many affected children to the required dental services. Furthermore, psychosocial factors such as violence, limited finance, and logistical problems such as transport may also impact on the high frequency of dental disease in this country. The common occurrence of unmet basic and specialized dental need reported in this study reflects the plight of children with ID in the context of dental management. The possible challenges faced by affected children in the maintenance of acceptable levels of oral health together with those encountered by oral healthcare professionals in the management of dental problems are complex yet integral to patients’ quality of life. This study aims to heighten the awareness of the importance of oral health among children with ID in South Africa.
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    Dental implications of inherited connective tissue disorders in South Africa
    (2016) Chetty, Manogari; Beighton, Peter; Stephen, Lawrence X G
    The prevalence of Osteogenesis imperfecta type III (OI III) as a category of the inherited connective tissue disorders in South Africa is of paramount importance. Although worldwide, autosomal recessive(AR) OI is rare, it had emerged that the frequency of OI III is relatively high in the indigenous Black African population of South Africa. A review of the literature revealed a paucity of information regarding the dental and craniofacial manifestations of the disorder in this ethnic group. For these reasons, the central theme of this thesis is the identification, documentation and analysis of these features in individuals with OI III in the Black African population of SA. Osteogenesis imperfecta type III (OMIM 259420) is a severe autosomal recessive disorder in which frequent fractures and progressive limb and spinal deformity result in profound physical disability. The condition is heterogeneous and dentin genesis imperfecta (DI) is an important syndromic component of some types of OI III. Other maxillofacial and dental manifestations also have significant implications in terms of management.
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    Duchenne muscular dystrophy in South Africa : molecular aspects
    (1992) Ballo, Robea; Beighton, Peter; Ramesar; Rajkumar
    Robea Balle, Department of Human Genetics, MRC Unit for Skeletal Disorders, UCT Medical School, Observatory, Cape Town, South Africa. Duchenne muscular dystrophy (DMD) is a lethal X-linked neuromuscular disorder, characterised by progressive muscle wasting and weakness. DMD has its onset in early childhood, leading to physical handicap by the mid-teens and usually death by the age of twenty years. Becker muscular dystrophy (BMD) is the allelic form of DMD and is differentiated by its age of onset and milder phenotype. DMD and BMD are incurable and the most effective way of managing affected families is by preventing the recurrence of the di9order. The use of intragenic and closely linked flanking markers facilitates the identification of the defective X chromosome in female carriers and their affected male foetuses. DMD is thought to be the most common of the heritable muscle disorders, having an incidence of l in 3 300. When extrapolated to the large South African population, it presents a significant socioeconomic problem. For this reason, it was decided to develop a molecular genetic service for carrier identification and diagnostic predictions. The first step in the South African study involved the collection of biological material from affected individuals. In so doing, minimum prevalence's in the four major ethnic groups of Black, Caucasian, Indian and Mixed ancestry, were established. Although ascertainment was incomplete for a number of reasons, a markedly increased DMD frequency in the Indian population and a low frequency in the Black population was apparent. In the Caucasian group, an unexpectedly high BMD frequency, compared to DMD, was observed. 110 males affected with DMD and 18 with BMD were screened for deletions using genomic and cDNA probes and multiplex polymerase chain reaction (PCR) technology. Deletions were detected in the dystrophin gene of 47 DMD and 6 BMD patients, occurring predominantly in the 3' region of the gene (65%) and to a lesser extent in the 5' region of the gene (287.). The deletion frequency within individual ethnic groups,
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    Gaucer Disease in the Ashkenazi-Jewish Community of South Africa
    (1980) Goldblatt, Jack; Beighton, Peter
    Gaucher disease is a biochemical genetic disorder of the lipid storage group. It is characterised by an accumulation of a glycosphingolipid, glycosyl ceramide in the reticulo-endothelial system. The condition presents clinically with hepatosplenomegaly, haematologic and orthopaedic problems. Affected individuals suffer from chronic ill-health and debility, with a clinical course of acute exacerbations, remissions and relapses. The basic defect has been shown to be a genetically determined abnormality in the enzyme beta-glucosidase, (Brady et aZ, 1965; Patrick, 1965). The diagnosis can now be accurately confirmed by laboratory procedures, which also enable determination of carrier status. Of particular interest is the high prevalence of the condition in the Ashkenazi-Jews. Fried, (1958), in a survey of cases in Jerusalem, estimated the minimal carrier or heterozygote rate to be 1 in 25. Other studies of Ashkenazi-Jews have revealed carrier frequencies ranging from 1 in 25 to about 1 in 40. This stimulated the investigation which was initially undertaken under the supervision of Professor Beighton in the Department of Human Genetics, University of Cape Town Medical School in 1975 and 1976. Further data has been accumulated by the author as a medical registrar at Groote Schuur Hospital in the ensuing period until 1979.
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    Genetic disorders on the island of Mauritius
    (1988) Wallis, Colin E; Beighton, Peter
    Inherited disorders are an important cause of physical handicap, deafness, mental retardation and blindness. There is considerable variation in the geographic and ethnic distribution of genetic disease due to biological pressures and historical accidents. In this context the relative prevalence of common inherited disorders and the recognition of rare conditions in isolated communities is of great academic importance. Oceanic islands are of special significance in the study of inherited disease. Virtually nothing has been documented concerning genetic disorders on the Island of Mauritius with a population of one million people. This study was undertaken to document the impact of inherited disorders on handicapping conditions in this community. As genetic disease concentrates in institutions, formal screening of all the schools for the deaf and blind, and the associations for the physically and mentally handicapped on Mauritius was undertaken. This involved a careful history, clinical examination and genealogical study, with radiographic, biochemical and ancillary testing performed where appropriate. Referral clinics were also established for the assessment of individuals and families known, or thought to be afflicted with abnormalities or handicap of a genetic origin. To ensure completeness, a similar survey was performed on Rodrigues, a neighbouring island, as this community is included under the responsibilities of the Mauritian Ministry of Health. Accumulated data concerning 681 patients were analysed. Genetic disorders accounted for disability in 265 individuals representing 38,6% of the causes of handicap. Of these persons 54 were deaf, 30 were blind, 99 were mentally retarded and 80 were physically handicapped. Several new entities, considered unique to the area and a consequence of either consanguinity or the founder effect, were documented. Karyotyping on selected individuals was undertaken in the laboratories of the Department of Human Genetics, University of Cape Town. A molecular genetic study of a large family with X-linked deafness of Nance, conducted by the same laboratory, revealed tight linkage with the probe pDP34; linkage analysis was performed on patients with Duchenne muscular dystrophy. The collation of these original data, the delineation of the new genetic conditions and an analysis of the results form the subject of this thesis and provide a basis for the future development of genetic services on Mauritius.
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    Huntington’s chorea in South Africa
    (1979) Hayden, Michael Reuben; Beighton, Peter
    South Africa offers unique opportunities for the investigation of genetically determined illnesses in view of the excellent facilities available and the different origins of the various population groups. Huntington's chorea is generally considered to be a very rare disease in South Africa. Evidence in support of this, is the dearth of publications concerning the disorder in this country. By 1977 there had been only two such articles, in marked contrast to the plethora of reports from around the world. This investigation was concerned with the study of many different aspects of Huntington's chorea in South Africa. The primary aims were to determine the history, frequency, clinical presentation and course of Huntington's chorea in the Republic. In the wake of the genealogical and clinical findings, interesting new observations and exploration of the established concepts of the genetics of Huntington's chorea have been undertaken. A major attempt has been made to investigate the hypothesis that dopamine excess is important in the pathophysiology of this condition. Since dopamine has an important regulatory function on anterior pituitary hormone secretion, affected individuals might be expected to have abnormal patterns of hormonal regulation. The disturbances in prolactin, thyrotropin and growth hormone secretion reported in this thesis, support the concept of dopamine predominance. The demonstration of similar neuroendocrine abnormalities in twelve of 23 clinically normal first-generation relatives may have importance for presymptomatic diagnosis. Although not a primary focus of the investigation, it soon became apparent that the social implications of this disorder were extremely important and largely unexplored. The attention of all health professionals is drawn to the tremendous cost of the disorder, and recommendations for improved care are proposed. Huntington's chorea is a far more serious problem in South Africa than was initially suspected. The gene was probably introduced by the first Dutch settlers over 300 years ago, and is found today in all population groups. The South African population of mixed ancestry has amongst the highest frequency of juvenile Huntington's chorea in the world. Even though the present study deals with only one relatively uncommon illness, the concepts presented are pertinent to numerous other unrelated chronic diseases, with which Huntington's chorea has shared concerns and needs.
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    An investigation into the molecular basis of familial forms of osteoarthropathy in South Africa
    (1998) Ballo, Robea; Beighton, Peter; Ramesar, Rajkumar
    Generalised osteoarthritis (OA) is a common disorder of the joints which can lead to pain and disability. Identification of the determinant gene(s) is limited in part by the lack of Mendelian inheritance in most forms of the disorder, the combination of genetic and environmental influences and the late development of the condition. An approach to the investigation of the aetiology of OA would be to take advantage of the monogenic basis of inherited skeletal dysplasias in which OA is a major component. For this reason, the molecular genetic basis of the epiphyseal dysplasias, which encompass a spectrum of phenotypes ranging from mild to severe skeletal involvement, is addressed in this thesis. Familial skeletal disorders in South Africa in which OA is a major feature were identified and investigated using intragenic and closely linked microsatellite markers in order to determine linkage to candidate genes. Mutational analysis was undertaken to identify the genetic defect.
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    Microcomputer-assisted diagnosis of inherited disorders of the skeleton
    (1988) Van Greunen, Francois; Beighton, Peter; MacGregor, Ken
    Several hundred inherited disorders of the skeleton have been delineated. Individually these conditions are rare, but as a group they cause much crippling and hardship. Several factors, including the rarity and complexity of the manifestations of these conditions, as well as semantic overlap, impede the accurate diagnosis which is essential for effective treatment. In this regard, the adoption of microcomputers warrants evaluation as a high technology aid. Microcomputers have developed tremendous capabilities during recent years. The state of the art has become such that a diagnostic aid facility on such a device has been demonstrated in various disciplines of medicine and may also be feasible in the area of inherited skeletal disorders. The study which forms the basis of this thesis, concerns the investigation of this feasibility and has led to the development of an effective working model which sets the basis for microcomputer-aided diagnosis. The design features followed in this project are similar to those conventionally employed for "Expert systems" on mainframe computers. A comprehensive knowledge base consisting of over 200 skeletal disorders and 700 radiographic and clinical manifestations, has resulted. Furthermore, the application is capable of "learning", although inference as employed by the inference engines of real expert systems, is not employed. In this context learning implies that the knowledge base, with the passage of time, improves considerably when used by experts. Serendipitous findings in this regard are: • 1) Considerable improvement of existing profile descriptions can occur without any increased demands on computer memory and storage space; • 2) Growth of the knowledge base in the form of additional disease profiles can be effected with very modest inroads on memory and storage resources. The computerized diagnostic aid which resulted from this thesis, has been demonstrated to be successful in both the Department of Human Genetics of the University of Cape Town and the Department of Paediatrics of the Johannes Gutenberg University in Mainz. Evaluated both in terms of efficiency and utility, the system provides an enhancement to the specialist genetic diagnostician. These achievements have been effected by means of a unique newly developed application of compressed bit-mapping, attained by writing the applicable programs in Turbo Pascal and 8086- assembler languages. Calculations indicate that much larger data bases may possibly be implemented on present-day microcomputers by means of the methods developed in this project.
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    A molecular investigation of the novel gene underlying autosomal dominant retinitis pigmentosa in a South African family
    (1999) Bardien-Kruger, Soraya; Greenberg, Jacquie; Beighton, Peter; Ramesar, Rajkumar
    The inherited retinal degenerative disorders are a common cause of severe visual handicap in the W estem world. Retinitis pigmentosa (RP) is a group of retinopathies in which a primary feature is a progressive loss of photoreceptor and retinal pigment epithelium function. Over the last decade, investigations into the patho-physiology of RP have identified numerous disease-causing genes and loci (for a current listing refer to the web site http://www.sph.uth.tmc.edu/Retnet/). A study of a South African family with an autosomal dominant form of RP (adRP) forms the basis of this dissertation. In this family, comprising 44 individuals, the first manifestation of visual disturbance is usually evident between 20 and 30 years of age. Subsequently, another South African adRP family, consisting of 25 members, was also incorporated into this investigation. Genetic linkage analysis facilitated the mapping of the disease phenotype in the two South African adRP families to a 10 cM interval on chromosome 17q22. This novel locus, designated RP17, is the eighth identified for adRP. Haplotype construction in the two kindreds, in conjunction with multipoint analyses subsequently fine mapped RP17 to a 1 cM region between microsatellite markers D17S1604 and D17S948. Although the two families are from ethnically diverse population groups, they share the same disease-associated haplotype spanning 12 cM, which suggests that the disorder may be caused by the same pathogenic mutation in the same gene. The positional cloning approach was utilised in an endeavour to identify the RP17 gene and an attempt was made to construct a physical map of the 1 cM critical region. A contig consisting of seven yeast artificial chromosome (YAC) clones was assembled using sequence-tagged-site (STS) content mapping. In order to close a gap in the YAC contig, a bacterial artificial chromosome (BAC) library was screened and the vectorette PCR technique was used to verify overlapping sequences. This contig should provide a useful tool for the purpose of isolating genes or transcription units within the RP17 critical interval. In this regard, purified YAC DNA was isolated using pulsed-field gel electrophoresis and the cDNA selection technique was employed to generate a transcription map. This approach was applied to YAC 75Ic12 using a foetal brain cDNA library, and two rounds of selection were performed to create a sub-library for enriched cDNAs derived from this clone. Screening for the presence of contaminating sequences in the 480 transformants revealed that (i) approximately 7% of the selected clones contain COT-1 DNA and (ii) none of the clones were contaminated with yeast AB1380 DNA. Ten randomly chosen clones were sequenced and subjected to BLASTN analysis, which revealed the presence of a 23 bp contaminant, known genes as well as novel transcripts. In order to optimise efforts to isolate the adRP gene, four positional candidates residing on 17q were screened for evidence implicating them in the adRP phenotype in the two 17q22-linked families. The genes investigated were: PDEG (gamma subunit of rod phosphodiesterase), TIMP2 (tissue inhibitor of metalloproteinases-2), PKCA (protein kinase C alpha) and retinal fascin. These candidates were chosen on the basis of (i) mapping to 17q, (ii) expression in the retina and/or (iii) potential involvement in the rod phototransduction pathway. Recombination events between the adRP locus and a single strand conformation polymorphism (SSCP) in PDEG, and a restriction fragment length polymorphism (RFLP) in TIMP2 provided evidence for the exclusion of these candidate genes. A novel SSCP detected in the promoter region of retinal fascin was genotyped in the two adRP families and showed a lack of co-segregation with the disease locus. Furthermore, direct DNA sequencing of the coding regions as well as the promoter region of retinal fascin in RP affected family members did not reveal any pathogenic mutations. In addition, data is provided which suggests that PKCA does not reside on any of the YACs and BACs encompassing the RP17 critical interval. This gene is therefore unlikely to be responsible for the adRP phenotype in the two RP17-linked families. Ultimately, the work reported in this thesis may contribute to the body of knowledge on inherited retinal degenerative disorders. Moreover, this investigation should provide the basis for further study of the aetiology of RP in all families linked to the RP17 locus on chromosome 17q22. The immediate application of these molecular findings is the potential for pre-symptomatic testing of at-risk members from the two adRP kindreds.
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    Orthodontic management of achondroplasia in South Africa
    (2005) Stephen, Lawrence; Holmes, Haly; Roberts, Tina; Fieggen, Karen; Beighton, Peter
    Achondroplasia is a relatively common genetic skeletal dysplasia that manifests with stunted stature and disproportionate limb shortening. Characteristic craniofacial features include a prominent forehead, depressed nasal bridge and maxillary hypoplasia. It is probable that there are between 500 and 1 000 persons with achondroplasia in South Africa, and it is inevitable that they will seek consultation and care in general and specialised dental practices. In this context, it is relevant that dental and orthodontic management is constrained by practical problems associated with upper airway obstruction and other primary and secondary syndromic components. In order to provide a perspective on the situation in South Africa, we assessed the special oro-dental needs of 10 affected children. Our findings are presented here.
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    Towards identifying the ADRP gene in a large South African family with retinitis pigmentosa
    (2000) Goliath, René; Greenberg, Jacquie; Ramesar, Rajkumar; Beighton, Peter
    The present study was initiated with the aim of elucidating the molecular genetic basis of the RP phenotype segregating in a large SA family of British origin. The family is one of the largest pedigrees from which DNA is archived in the Department, and the pedigree structure and ADRP phenotype will be discussed in detail in chapter two.