Gene Expression Profiling in Limb-Girdle Muscular Dystrophy 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that β-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies

Gerri distrofia muskularra Gipuzkoan

Gracias a los avances producidos en la genética molecular, el concepto de Distro a Muscular Lumbar (LGMD) está cambiando rápidamente. Se han descrito diferentes loci y ha quedado probado que el síndrome de Distro a muscular Lumbar es heterogéneo. Hemos realizado un examen epidemiológico en Gipuzkoa y hemos encontrado la prevalencia mayor de LGMD descrita hasta la fecha: 69/106. La mutación en el gen Kalpaina3 que evidencian los afectados muestra características clínicas similares que son distintas a las características de otros grupos, lo cual posibilita un diagnóstico clínico preciso.Genetika molekularrean egindako aurrerapausoeri esker, Gerri Distro a muskularren (LGMD) kontzeptua azkar ari da aldatzen. Loci desberdinak deskribatu dira Gerri Distro muskularra sindrome heterogeneoa dela frogatuz. Azterketa epidemiologikoa burutu dugu Gipuzkoan eta gaurdaino deskribaturiko LGMD-en prebalentzirik altuena aurkitu dugu: 69/106. Kalpaina3 genean mutazioa duten gaisoek, antzeko ezaugarri klinikoak agertzen dituzte beste taldeen ezaugarriekiko desberdinak direlarik, horrela diagnostiko kliniko zehatza baimenduz.Grâce aux progrès qui ont été fait dans le domaine de la génétique moléculaire, le concept de Dystrophie Musculaire Lombaire (LGMC) est en train de changer rapidement. On a décrit différents loci et il a été prouvé que le syndrome de Dystrophie musculaire Lombaire est hétérogène. Nous avons réalisé un examen épidémiologique en Gipuzkoa et nous avons trouvé la plus importante prévalence de LGMD décrite jusqu'à cette date: 69/106. La mutation dans le gène Kalpaina3 que les personnes affectées mettent en évidence montre des caractéristiques cliniques similaires qui sont différentes des caractéristiques d'autres groupes, ce qui permet un diagnostique clinique précis.Thanks to the advances that have taken place in molecular genetics, the concept of Limb-Girdle Muscular Dystrophy (LGMD) is rapidly changing. Various loci have been described and it has been proved that the Limb-Girdle Muscular Dystrophy syndrome is heterogeneous. We have carried out an epidemiological examination in Gipuzkoa and we have found the highest LGMD prevalence described up to the present: 69/106. The mutation in gen Kalpaina3 displayed by those affected shows similar clinical characteristics to those of other groups, which makes a precise clinical diagnosis possible

Epilepsia eta Genetika

El aislamiento de determinados genes que intervienen en el origen de la epilepsia idiopática ha permitido una mejor clasi cación de la epilepsia. En el presente trabajo se da cuenta del examen clínico de dos familias con síndrome epiléptico. La primera muestra una epilepsia nocturna asociada al cromosoma 20q, que presenta una mutación en el gen (CHRNA4) de la subunidad 4 del receptor nicotínico de la acetilcolina. La segunda muestra una epilepsia lateral temporal autosómica dominante asociada al cromosoma 10q.Epilepsia idiopatikoen sorreran parte hartzen duten zenbait geneen isolaketak epilepsiaren sailkapena hobetzea baimendu du. Lan honetan sindrome epileptikoa duten bi sendiren ikerketa kliniko eta genetikoa aurkezten da. Lehenak, 20q kromosomari loturiko gau epilepsia frontala agertzen du, azetil kolinaren errezeptore nikotinikoaren 4 azpiunitatearen genean (CHRNA4) mutazio bat agertzen duelarik. Bigarrenak, 10q kromosomari loturiko autosomiko gainartzailea den epilepsia albo-tenporala agertzen du.L'isolement de certains gènes qui interviennent dans l'origine de l'épilepsie idiopathique a permis une meilleure classi cation de l'épilepsie. Dans ce travail on rend compte de l'examen clinique de deux familles qui souffrent du syndrome épileptique. La première montre une épilepsie nocturne associée au chromosome 20q, qui présente une mutation dans le gène (CHRNA4) de la sous-unité 4 du récepteur nicotinique de l'acétylcholine. La seconde montre une épilepsie latérale temporelle autosomique dominante associée au chromosome 10q.The isolating of certain genes that intervene in the origin of idiopathic epilepsy has allowed for a better classification of epilepsy as a whole. This work is about the clinical analysis of two families with an epileptic syndrome. The first family displays a nocturnal epilepsy associated to chromosome 20q, which has a mutation in gen (CHRNA4) of sub-unit á4 of the acetylcoline nicotinic receptor. The second family displays a dominant lateral temporal lobe and autosomal epilepsy associated to chromosome 10q

ENTIRE CAPN3 GENE DELETION IN A PATIENT WITH LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 2A

International audienceLimb-girdle muscular dystrophy type 2A (LGMD2A) due to mutations in the CAPN3 gene is one of the most common of autosomal recessive limb-girdle muscular dystrophies. We describe a patient who had a typical LGMD2A phenotype and posterior compartment involvement on MRI. Different genetic analyses were performed, including microarray analysis. There was an apparently homozygous mutation in exon 24, c.2465G>T, p.(*822Leuext62*), and a lack of correlation in the disease segregation analyses. This suggested the presence of a genomic rearrangement. In fact, a heterozygous deletion of the entire CAPN3 gene was found. This novel deletion comprised the terminal region of the GANC gene and the entire CAPN3 gene. This finding points out the need to reconsider and adapt our current strategy of molecular diagnosis in order to detect these types of genomic rearrangements that escape standard mutation screening procedures

Reducing child mental health inequities through parental mental health and preschool attendance

Background Prevention is key to reducing socioeconomic inequities in children’s mental health problems, especially given limited availability and accessibility of services supporting treatment. We investigated the potential to reduce these inequities for disadvantaged children by improving parental mental health and preschool attendance in early childhood. Methods Data from the nationally representative birth cohort of the Longitudinal Study of Australian Children (N=5107, commencing in 2004) were used to examine the impact of socioeconomic disadvantage (0-1 year) on children’s mental health problems (10-11 years). Using an interventional effects approach, we estimated the extent to which inequities in children’s mental health problems could be reduced by improving disadvantaged children’s parental mental health (4-5 years) and their preschool attendance (4-5 years). Results Disadvantaged children had a higher prevalence of elevated mental health symptoms (32.8%) compared with their non-disadvantaged peers (18.7%): confounder-adjusted difference in prevalence=11.6% (95% CI: 7.7%-15.4%). Improving disadvantaged children’s parental mental health and their preschool attendance to the level of their non-disadvantaged peers could reduce 6.5% and 0.3% of socioeconomic differences in child mental health problems, respectively (equivalent to 0.8% and 0.04% absolute reductions). If these interventions were delivered in combination, a 10.8% (95% CI: 6.9% to 14.7%) higher prevalence of elevated symptoms would remain for disadvantaged children. Conclusions Targeted policy interventions that improve parent mental health and preschool attendance for disadvantaged children are potential opportunities to reduce socioeconomic inequities in children’s mental health problems. Such interventions should be considered within a broader, sustained, and multipronged approach that includes addressing socioeconomic disadvantage itself.</p

Reducing child mental health inequities through parental mental health and preschool attendance

Background Prevention is key to reducing socioeconomic inequities in children’s mental health problems, especially given limited availability and accessibility of services supporting treatment. We investigated the potential to reduce these inequities for disadvantaged children by improving parental mental health and preschool attendance in early childhood. Methods Data from the nationally representative birth cohort of the Longitudinal Study of Australian Children (N=5107, commencing in 2004) were used to examine the impact of socioeconomic disadvantage (0-1 year) on children’s mental health problems (10-11 years). Using an interventional effects approach, we estimated the extent to which inequities in children’s mental health problems could be reduced by improving disadvantaged children’s parental mental health (4-5 years) and their preschool attendance (4-5 years). Results Disadvantaged children had a higher prevalence of elevated mental health symptoms (32.8%) compared with their non-disadvantaged peers (18.7%): confounder-adjusted difference in prevalence=11.6% (95% CI: 7.7%-15.4%). Improving disadvantaged children’s parental mental health and their preschool attendance to the level of their non-disadvantaged peers could reduce 6.5% and 0.3% of socioeconomic differences in child mental health problems, respectively (equivalent to 0.8% and 0.04% absolute reductions). If these interventions were delivered in combination, a 10.8% (95% CI: 6.9% to 14.7%) higher prevalence of elevated symptoms would remain for disadvantaged children. Conclusions Targeted policy interventions that improve parent mental health and preschool attendance for disadvantaged children are potential opportunities to reduce socioeconomic inequities in children’s mental health problems. Such interventions should be considered within a broader, sustained, and multipronged approach that includes addressing socioeconomic disadvantage itself.</p

Supplementary information files for article Addressing child mental health inequities through parental mental health and preschool attendance

Supplementary information files for article Addressing child mental health inequities through parental mental health and preschool attendance   Background Prevention is key to reducing socioeconomic inequities in children’s mental health problems, especially given limited availability and accessibility of services supporting treatment. We investigated the potential to reduce these inequities for disadvantaged children by improving parental mental health and preschool attendance in early childhood. Methods Data from the nationally representative birth cohort of the Longitudinal Study of Australian Children (N=5107, commencing in 2004) were used to examine the impact of socioeconomic disadvantage (0-1 year) on children’s mental health problems (10-11 years). Using an interventional effects approach, we estimated the extent to which inequities in children’s mental health problems could be reduced by improving disadvantaged children’s parental mental health (4-5 years) and their preschool attendance (4-5 years). Results Disadvantaged children had a higher prevalence of elevated mental health symptoms (32.8%) compared with their non-disadvantaged peers (18.7%): confounder-adjusted difference in prevalence=11.6% (95% CI: 7.7%-15.4%). Improving disadvantaged children’s parental mental health and their preschool attendance to the level of their non-disadvantaged peers could reduce 6.5% and 0.3% of socioeconomic differences in child mental health problems, respectively (equivalent to 0.8% and 0.04% absolute reductions). If these interventions were delivered in combination, a 10.8% (95% CI: 6.9% to 14.7%) higher prevalence of elevated symptoms would remain for disadvantaged children. Conclusions Targeted policy interventions that improve parent mental health and preschool attendance for disadvantaged children are potential opportunities to reduce socioeconomic inequities in children’s mental health problems. Such interventions should be considered within a broader, sustained, and multipronged approach that includes addressing socioeconomic disadvantage itself.</p

Inequities in children's reading skills: the role of home reading and preschool attendance

ObjectiveChildren from socioeconomically disadvantaged backgrounds have poorer learning outcomes. These inequities are a significant public health issue, tracking forward to adverse health outcomes in adulthood. We examined the potential to reduce socioeconomic gaps in children's reading skills through increasing home reading and preschool attendance among disadvantaged children.MethodsWe drew on data from the nationally representative birth cohort of the Longitudinal Study of Australian Children (N = 5107) to examine the impact of socioeconomic disadvantage (0–1 year) on children's reading skills (8–9 years). An interventional effects approach was applied to estimate the extent to which improving the levels of home reading (2–5 years) and preschool attendance (4–5 years) of socioeconomically disadvantaged children to be commensurate with their advantaged peers, could potentially reduce socioeconomic gaps in children's reading skills.ResultsSocioeconomically disadvantaged children had a higher risk of poor reading outcomes compared to more advantaged peers: absolute risk difference = 20.1% (95% confidence interval [CI]: 16.0%–24.2%). Results suggest that improving disadvantaged children's home reading and preschool attendance to the level of their advantaged peers could eliminate 6.5% and 2.1% of socioeconomic gaps in reading skills, respectively. However, large socioeconomic gaps would remain, with disadvantaged children maintaining an 18.3% (95% CI: 14.0%–22.7%) higher risk of poor reading outcomes in absolute terms.ConclusionThere are clear socioeconomic disparities in children's reading skills by late childhood. Findings suggest that interventions that improve home reading and preschool attendance may contribute to reducing these inequities, but alone are unlikely to be sufficient to close the equity gap.</div

Household income supplements in early childhood to reduce inequities in children's development

Background: Early childhood interventions have the potential to reduce children's developmental inequities. We aimed to estimate the extent to which household income supplements for lower-income families in early childhood could close the gap in children's developmental outcomes and parental mental health. Methods: Data were drawn from a nationally representative birth cohort, the Longitudinal Study of Australian Children (N = 5107), which commenced in 2004 and conducted follow-ups every two years. Exposure was annual household income (0–1 year). Outcomes were children's developmental outcomes, specifically social-emotional, physical functioning, and learning (bottom 15% versus top 85%) at 4–5 years, and an intermediate outcome, parental mental health (poor versus good) at 2–3 years. We modelled hypothetical interventions that provided a fixed-income supplement to lower-income families with a child aged 0–1 year. Considering varying eligibility scenarios and amounts motivated by actual policies in the Australian context, we estimated the risk of poor outcomes for eligible families under no intervention and the hypothetical intervention using marginal structural models. The reduction in risk under intervention relative to no intervention was estimated. Results: A single hypothetical supplement of AU$26,000 (equivalent to ∼USD$17,350) provided to lower-income families (below AU$56,137 (∼USD$37,915) per annum) in a child's first year of life demonstrated an absolute reduction of 2.7%, 1.9% and 2.6% in the risk of poor social-emotional, physical functioning and learning outcomes in children, respectively (equivalent to relative reductions of 12%, 10% and 11%, respectively). The absolute reduction in risk of poor mental health in eligible parents was 1.0%, equivalent to a relative reduction of 7%. Benefits were similar across other income thresholds used to assess eligibility (range, AU$73,329-$99,864). Conclusions: Household income supplements provided to lower-income families may benefit children's development and parental mental health. This intervention should be considered within a social-ecological approach by stacking complementary interventions to eliminate developmental inequities.</p