MSc (Med), Genetic Counselling, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are severe X-linked recessive, degenerative neuromuscular diseases. DMD/BMD are caused by deletions, duplications and point mutations in the DMD gene situated on the X-chromosome. Studies have shown that the risk of being a carrier for DMD/BMD has a psychosocial impact on individuals and affects their requests for DNA testing and their choices regarding reproduction. Very few articles have been published to date and this study is the first South African study to investigate the behaviours of individuals in DMD/BMD families. The study aimed to investigate why individuals attended genetic counselling and who referred them. It also aimed to identify factors that influence at-risk individuals‟ decisions regarding genetic counselling, carrier testing and reproduction. The study was retrospective and data were obtained by reviewing genetic counselling files at the Division of Human Genetics, National Health Laboratory Service and the University of the Witwatersrand. The sample consisted of 79 files of families seen for genetic counselling regarding DMD/BMD from 1995 to 2008. Subjects included the maternal female relatives of affected individuals, who were all of reproductive age (15-49 years); the total number of at-risk individuals identified was 237. Subjects were divided into three groups according to their assigned reproductive risks: low (0-9%), intermediate (10-24%) and high (>25%). The influence of reproductive risk and other identified variables on decisions to attend genetic counselling, have carrier testing and having children were analysed using chi-squared and logistic regression analysis. iii Reproductive risk and relationship to the affected individuals were shown to be significant predictors of individuals‟ decisions. Other factors that contributed significantly to the behaviour of at-risk individuals were ethnicity, age, whether a mutation was de novo and whether an individual had affected children.

Background: Duchenne and Becker muscular dystrophies, collectively referred to as dystrophinopathies, are recessive X-linked disorders characterized by progressive muscle weakness and ultimately cardiac and respiratory failure. Immediate family members are often primary caregivers of individuals with a dystrophinopathy. Methods: We explored the impact of this role by inviting primary caregivers (n = 209) of males diagnosed with childhood-onset dystrophinopathy who were identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) to complete a mailed questionnaire measuring perceived social support and stress, spirituality, and family quality of life (FQoL). Bivariate and multivariate analyses examined associations between study variables using the Double ABCX model as an analytic framework. Results: Higher stressor pile-up was associated with lower perceived social support (r = -0.29, p <.001), availability of supportive family (r = -0.30, p <.001) or non-family (r = -0.19, p <.01) relationships, and higher perceived stress (r = 0.33, p <.001); but not with spirituality (r = -0.14, p > 0.05). FQoL was positively associated with all support measures (correlations ranged from: 0.25 to 0.58, p-values 0.01-0.001) and negatively associated with perceived stress and control (r = -0.49, p <.001). The association between stressor pile-up and FQoL was completely mediated through global perceived social support, supportive family relationships, and perceived stress and control; supportive non-family relationships did not remain statistically significant after controlling for other mediators. Conclusions: Findings suggest caregiver adaptation to a dystrophinopathy diagnosis can be optimized by increased perceived control, supporting family resources, and creation of a healthy family identity. Our findings will help identify areas for family intervention and guide clinicians in identifying resources that minimize stress and maximize family adaptation.

Duchenne and Becker muscular dystrophies (DMD, BMD) are allelic X-linked diseases which affect approximately one in 3500 male newborns. They are caused by mutations in a gene positioned on the short arm of the X chromosome at Xp21. The first indication of the location of this gene was the description of rare females expressing DMD and who were found to have constitutional X;autosome translocations with an X chromosome breakpoint at this site. There are now 24 such females known worldwide. They express DMD as a consequence of preferential inactivation of the normal X chromosome. In order to contribute to the understanding of the aetiology of mutations causing DMD and the aetiology of constitutional translocations, two types of study have been performed here. Firstly, the detailed mapping of the X chromosome breakpoints of DMD-associated X;autosome translocations has been investigated. The results of this study have been compared with data on the physical distribution of mutations causing DMD in male patients. Secondly, one translocation, an X;l translocation with an autosomal breakpoint at Ip34, has been selected for more detailed investigation and the DNA sequence has been determined at the site of the rearrangement. Translocation breakpoint mapping studies were performed by somatic cell hybrid analysis. Hybrids were karyotyped and this information was used to construct a hybrid panel for the purpose of determining the autosomal localisations of anonymous DNA probes. The mapping of seven probes using this panel is described. The work described in this thesis revealed that the distribution of translocation breakpoints within the DMD gene appears to be random and may differ from the distribution of mutations in male patients. The X;l translocation whose breakpoints are cloned and sequenced was found to involve two expressed loci, one coding for dystrophin on the X chromosome and one for the leukocyte antigen related protein on chromosome 1. Sequence data revealed that a deletion of four to seven nucleotides from the X chromosome and a duplication of two to five nucleotides are associated with the translocation. The possible involvement of trinucleotides adjacent to the breakpoints, and of a LINE, a SINE and a stretch of potential Z-DNA within 1 kb of the X chromosome or the chromosome 1 breakpoint, is discussed.

Introduction/Aims Duchenne and Becker muscular dystrophies (DBMD) are X-linked neuromuscular disorders characterized by progressive muscle weakness, leading to decreased mobility and multisystem complications. We estimate productivity costs attributable to time spent by a parent caring for a male child under the age of 18 y with DBMD, with particular focus on female caregivers of boys with Duchenne muscular dystrophy (DMD) who have already lost ambulation. Methods Primary caregivers of males with DBMD in the Muscular Dystrophy Surveillance and Research Tracking Network (MD STARnet) were surveyed during 2011–2012 on family quality of life measures, including labor market outcomes. Of 211 respondents, 96 female caregivers of boys with DBMD were matched on state, year of survey, respondent's age, child's age, and number of minor children with controls constructed from Current Population Survey extracts. Regression analysis was used to estimate labor market outcomes and productivity costs. Results Caregivers of boys with DBMD worked 296 h less per year on average than caregivers of unaffected children, translating to a $8816 earnings loss in 2020 U.S. dollars. Caregivers of boys with DMD with ≥4 y of ambulation loss had a predicted loss in annualized earnings of $23,995, whereas caregivers of boys with DBMD of the same ages who remained ambulatory had no loss of earnings. Discussion Female caregivers of non-ambulatory boys with DMD face additional household budget constraints through income loss. Failure to include informal care costs in economic studies could understate the societal cost-effectiveness of strategies for managing DMD that might prolong ambulation.

No description available.

No description available.

L'objectif de ce travail est de développer la partie clinique de la banque de données du gène DMD, afin d'étudier l'histoire naturelle des dystrophinopathies et les corrélations génotype–phénotype, et de faciliter la sélection des patients pour les futurs essais thérapeutiques. La méthodologie créée pour le gène DMD peut être généralisée et utilisée pour d'autres banques de données dédiées à des maladies génétiques. La collecte de 70 000 données cliniques chez 600 patients avec un suivi longitudinal moyen de 12 ans permet de décrire l'histoire naturelle des dystrophies musculaires de Duchenne et de Becker et des formes symptomatiques chez les femmes. Nous avons pu préciser l'hétérogénéité phénotypique sur le plan moteur, orthopédique et respiratoire (forme sévère et forme intermédiaire de la dystrophie musculaire de Duchenne), sur le plan cardiaque (absence de corrélation entre les atteintes motrice et cardiaque, variabilité de l'atteinte cardiaque), et sur le plan cérébral (atteinte intellectuelle chez les patients avec dystrophie musculaire de Becker, troubles psychologiques des dystrophinopathies). L'utilisation de cet outil par les cliniciens et les généticiens devrait faciliter le travail de recherche clinique et la réalisation des futurs essais cliniques. Ceci nécessite maintenant de développer l'accessibilité de la banque de données et d'envisager sa pérennisation. / The objective of this work is to develop the clinical part of the French dystrophinopathy data-base, in order to study the natural history and the genotype-phenotype correlations, and to facilitate the selection of the patients for the future therapeutic trials. The methodology developed for the DMD gene can be generalized and used for the other databases dedicated to genetic diseases. The collection of 70 000 clinical data for 600 patients with an average lon-gitudinal follow-up of 12 years allows to clarify the natural history of the muscular dystrophies of Duchenne and Becker and in symptomatic females. We were able to specify the pheno-typic heterogeneity of the motor, orthopaedic and respiratory involvements (severe form and intermediary form of the Duchenne muscular dystrophy), of the cardiac disorder (absence of correlation between motor and cardiac involvements, variability of the cardiomyopathy), and of the brain function (mental deficiency in the patients with Becker muscular dystrophy, psychological disorders in dystrophinopathies). The use of this tool by the clinicians and the ge-neticists should facilitate their clinical research work and the realization of the future clinical trials. This requires now to develop the accessibility of the database and to ensure its continued existence.

A Distrofia Muscular de Duchenne/Becker (DMD/BMD) é a doença neuromuscular mais freqüente em crianças, afetando uma em cada 3.500 nascidos vivos do sexo masculino (DMD), e um em cada 20.000 (BMD). A criança nasce aparentemente saudável, com o aparecimento gradual e progressivo dos sintomas desde o primeiro ano de vida. A perda da habilidade de caminhar se dá entre os sete e 12 anos de idade, com sobrevivência rara acima dos 30 anos; e a BMD, de forma mais amena, com os mesmos sintomas aparecendo mais tardiamente. O diagnóstico se baseia nas características clínicas e na investigação genética de deleções e duplicações no gene da distrofina. Um teste preciso ainda é necessário para a identificação de mulheres portadoras. O PCR quantitativo em tempo real seria um bom ensaio para a determinação deste status.O objetivo deste trabalho foi identificar as mulheres portadoras de deleções no gene da distrofina através de PCR quantitativo em tempo real e apresentar informações diagnósticas sobre a população de meninos com DMD/BMD do RS. Informações pertinentes a 123 meninos com diagnostico clínico foram incluídos neste estudo. Após análise dos exames de DNA nos meninos estudados, os exons 47, 48 e 50 se mostraram mais frequentemente deletados na nossa população, confirmando que o segundo "hotspot" gênico é o que mais sofre alterações. Cinco mulheres com filhos com deleções nos exons 45, 47 e 51 foram testadas para estabelecimento do seu status de portadora ou não-portadora. A comparação direta dos exons específicos em relação aos mesmos em outras mulheres, determinou, com uma fácil visualização, a confirmação de três mulheres portadoras e duas não-portadoras, sendo um método preciso e efetivo. É uma abordagem prática e importante para uma utilização em casos de duplicações neste mesmo gene e em outros que necessitem deste tipo de quantificação exata. / Duchenne/Becker Muscular dystrophy (DMD/BMD) is the most frequent neuromuscular disorder in children, affecting one in every 3,500 born male boys (DMD), and one in every 20,000 (BMD). The child is born apparently healthy, with a gradual and progressive appearance of the symptoms during the first year of life. Between the ages of seven to 12, the child demonstrates a loss of the ability to walk, with rare survival above 30 years; and BMD, a milder form, with similar symptoms delayed. The diagnosis is based on the clinical characteristics and a genetic investigation of deletions and duplications in the dystrophin gene. A precise test is still necessary for the identification of carrier women. A quantitative real-time PCR would be a good assay for the determination of this status. The main goals of this study were to identify the carrier women of deletions in the dystrophin gene through the quantitative real-time PCR and to present the diagnostic information available for the population of boys with DMD/BMD in RS. Information pertaining to 123 boys with a clinical diagnosis was included in this study. After the analysis of the boy´s DNA exams, exons 47, 48, and 50 were the most frequently deleted in our population, confirming that the second genetic hospot suffers most of the alterations. Five women that bore children with deletions in exons 45, 47, and 51 were tested for the establishment of their carrier or non-carrier status. A direct comparison of the specific exons to the same ones in other women determined, with an easy visualization, the confirmation of three carrier women and two non-carrier, being a precise and effective method. It is a practical and important approach for the use in cases of duplication in this same gene and in others that may need an exact quantification.

A Distrofia Muscular de Duchenne/Becker (DMD/BMD) é a doença neuromuscular mais freqüente em crianças, afetando uma em cada 3.500 nascidos vivos do sexo masculino (DMD), e um em cada 20.000 (BMD). A criança nasce aparentemente saudável, com o aparecimento gradual e progressivo dos sintomas desde o primeiro ano de vida. A perda da habilidade de caminhar se dá entre os sete e 12 anos de idade, com sobrevivência rara acima dos 30 anos; e a BMD, de forma mais amena, com os mesmos sintomas aparecendo mais tardiamente. O diagnóstico se baseia nas características clínicas e na investigação genética de deleções e duplicações no gene da distrofina. Um teste preciso ainda é necessário para a identificação de mulheres portadoras. O PCR quantitativo em tempo real seria um bom ensaio para a determinação deste status.O objetivo deste trabalho foi identificar as mulheres portadoras de deleções no gene da distrofina através de PCR quantitativo em tempo real e apresentar informações diagnósticas sobre a população de meninos com DMD/BMD do RS. Informações pertinentes a 123 meninos com diagnostico clínico foram incluídos neste estudo. Após análise dos exames de DNA nos meninos estudados, os exons 47, 48 e 50 se mostraram mais frequentemente deletados na nossa população, confirmando que o segundo "hotspot" gênico é o que mais sofre alterações. Cinco mulheres com filhos com deleções nos exons 45, 47 e 51 foram testadas para estabelecimento do seu status de portadora ou não-portadora. A comparação direta dos exons específicos em relação aos mesmos em outras mulheres, determinou, com uma fácil visualização, a confirmação de três mulheres portadoras e duas não-portadoras, sendo um método preciso e efetivo. É uma abordagem prática e importante para uma utilização em casos de duplicações neste mesmo gene e em outros que necessitem deste tipo de quantificação exata. / Duchenne/Becker Muscular dystrophy (DMD/BMD) is the most frequent neuromuscular disorder in children, affecting one in every 3,500 born male boys (DMD), and one in every 20,000 (BMD). The child is born apparently healthy, with a gradual and progressive appearance of the symptoms during the first year of life. Between the ages of seven to 12, the child demonstrates a loss of the ability to walk, with rare survival above 30 years; and BMD, a milder form, with similar symptoms delayed. The diagnosis is based on the clinical characteristics and a genetic investigation of deletions and duplications in the dystrophin gene. A precise test is still necessary for the identification of carrier women. A quantitative real-time PCR would be a good assay for the determination of this status. The main goals of this study were to identify the carrier women of deletions in the dystrophin gene through the quantitative real-time PCR and to present the diagnostic information available for the population of boys with DMD/BMD in RS. Information pertaining to 123 boys with a clinical diagnosis was included in this study. After the analysis of the boy´s DNA exams, exons 47, 48, and 50 were the most frequently deleted in our population, confirming that the second genetic hospot suffers most of the alterations. Five women that bore children with deletions in exons 45, 47, and 51 were tested for the establishment of their carrier or non-carrier status. A direct comparison of the specific exons to the same ones in other women determined, with an easy visualization, the confirmation of three carrier women and two non-carrier, being a precise and effective method. It is a practical and important approach for the use in cases of duplication in this same gene and in others that may need an exact quantification.

A Distrofia Muscular de Duchenne/Becker (DMD/BMD) é a doença neuromuscular mais freqüente em crianças, afetando uma em cada 3.500 nascidos vivos do sexo masculino (DMD), e um em cada 20.000 (BMD). A criança nasce aparentemente saudável, com o aparecimento gradual e progressivo dos sintomas desde o primeiro ano de vida. A perda da habilidade de caminhar se dá entre os sete e 12 anos de idade, com sobrevivência rara acima dos 30 anos; e a BMD, de forma mais amena, com os mesmos sintomas aparecendo mais tardiamente. O diagnóstico se baseia nas características clínicas e na investigação genética de deleções e duplicações no gene da distrofina. Um teste preciso ainda é necessário para a identificação de mulheres portadoras. O PCR quantitativo em tempo real seria um bom ensaio para a determinação deste status.O objetivo deste trabalho foi identificar as mulheres portadoras de deleções no gene da distrofina através de PCR quantitativo em tempo real e apresentar informações diagnósticas sobre a população de meninos com DMD/BMD do RS. Informações pertinentes a 123 meninos com diagnostico clínico foram incluídos neste estudo. Após análise dos exames de DNA nos meninos estudados, os exons 47, 48 e 50 se mostraram mais frequentemente deletados na nossa população, confirmando que o segundo "hotspot" gênico é o que mais sofre alterações. Cinco mulheres com filhos com deleções nos exons 45, 47 e 51 foram testadas para estabelecimento do seu status de portadora ou não-portadora. A comparação direta dos exons específicos em relação aos mesmos em outras mulheres, determinou, com uma fácil visualização, a confirmação de três mulheres portadoras e duas não-portadoras, sendo um método preciso e efetivo. É uma abordagem prática e importante para uma utilização em casos de duplicações neste mesmo gene e em outros que necessitem deste tipo de quantificação exata. / Duchenne/Becker Muscular dystrophy (DMD/BMD) is the most frequent neuromuscular disorder in children, affecting one in every 3,500 born male boys (DMD), and one in every 20,000 (BMD). The child is born apparently healthy, with a gradual and progressive appearance of the symptoms during the first year of life. Between the ages of seven to 12, the child demonstrates a loss of the ability to walk, with rare survival above 30 years; and BMD, a milder form, with similar symptoms delayed. The diagnosis is based on the clinical characteristics and a genetic investigation of deletions and duplications in the dystrophin gene. A precise test is still necessary for the identification of carrier women. A quantitative real-time PCR would be a good assay for the determination of this status. The main goals of this study were to identify the carrier women of deletions in the dystrophin gene through the quantitative real-time PCR and to present the diagnostic information available for the population of boys with DMD/BMD in RS. Information pertaining to 123 boys with a clinical diagnosis was included in this study. After the analysis of the boy´s DNA exams, exons 47, 48, and 50 were the most frequently deleted in our population, confirming that the second genetic hospot suffers most of the alterations. Five women that bore children with deletions in exons 45, 47, and 51 were tested for the establishment of their carrier or non-carrier status. A direct comparison of the specific exons to the same ones in other women determined, with an easy visualization, the confirmation of three carrier women and two non-carrier, being a precise and effective method. It is a practical and important approach for the use in cases of duplication in this same gene and in others that may need an exact quantification.