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1.
Cell Mol Life Sci ; 81(1): 347, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39136782

RESUMEN

CDKL5 Deficiency Disorder (CDD) is a debilitating epileptic encephalopathy disorder affecting young children with no effective treatments. CDD is caused by pathogenic variants in Cyclin-Dependent Kinase-Like 5 (CDKL5), a protein kinase that regulates key phosphorylation events in neurons. For therapeutic intervention, it is essential to understand molecular pathways and phosphorylation targets of CDKL5. Using an unbiased phosphoproteomic approach we identified novel targets of CDKL5, including GTF2I, PPP1R35, GATAD2A and ZNF219 in human iPSC-derived neuronal cells. The phosphoserine residue in the target proteins lies in the CDKL5 consensus motif. We validated direct phosphorylation of GTF2I and PPP1R35 by CDKL5 using complementary approaches. GTF2I controls axon guidance, cell cycle and neurodevelopment by regulating expression of neuronal genes. PPP1R35 is critical for centriole elongation and cilia morphology, processes that are impaired in CDD. PPP1R35 interacts with CEP131, a known CDKL5 phospho-target. GATAD2A and ZNF219 belong to the Nucleosome Remodelling Deacetylase (NuRD) complex, which regulates neuronal activity-dependent genes and synaptic connectivity. In-depth knowledge of molecular pathways regulated by CDKL5 will allow a better understanding of druggable disease pathways to fast-track therapeutic development.


Asunto(s)
Síndromes Epilépticos , Células Madre Pluripotentes Inducidas , Neuronas , Proteínas Serina-Treonina Quinasas , Espasmos Infantiles , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/citología , Neuronas/metabolismo , Neuronas/citología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Fosforilación , Síndromes Epilépticos/metabolismo , Síndromes Epilépticos/genética , Síndromes Epilépticos/patología , Espasmos Infantiles/metabolismo , Espasmos Infantiles/genética , Espasmos Infantiles/patología
2.
Hum Mol Genet ; 31(3): 362-375, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-34494102

RESUMEN

The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here, we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings' neurological disorder.


Asunto(s)
Discapacidad Intelectual , Microcefalia , Humanos , Discapacidad Intelectual/genética , Microcefalia/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética
3.
Clin Genet ; 105(2): 214-219, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37899549

RESUMEN

Critical genes involved in embryonic development are often transcription factors, regulating many downstream genes. LMX1B is a homeobox gene that is involved in formation of the limbs, eyes and kidneys, heterozygous loss-of-function sequence variants and deletions cause Nail-Patella syndrome. Most of the reported variants are localised within the gene's coding sequence, however, approximately 5%-10% of affected individuals do not have a pathogenic variant identified within this region. In this study, we present a family with four affected individuals across two generations with a deletion spanning a conserved upstream LMX1B-binding sequence. This deletion is de novo in the mother of three affected children. Furthermore, in this family, the manifestations appear limited to the nails and limbs, and therefore may reflect an attenuated phenotype of the classic Nail-Patella phenotype that includes ophthalmological and renal manifestations.


Asunto(s)
Genes Homeobox , Uñas , Niño , Humanos , Proteínas de Homeodominio/genética , Mutación , Rótula , Fenotipo , Factores de Transcripción/genética
4.
Int J Mol Sci ; 25(19)2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39409097

RESUMEN

Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD's antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids' pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid's potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid's therapeutic potential for CDD.


Asunto(s)
Cannabinoides , Síndromes Epilépticos , Espasmos Infantiles , Humanos , Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Síndromes Epilépticos/tratamiento farmacológico , Síndromes Epilépticos/genética , Animales , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/genética , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/farmacología , Cannabidiol/uso terapéutico , Cannabidiol/farmacología , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Epilepsia/metabolismo , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Síndrome de Lennox-Gastaut/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Modelos Animales de Enfermedad
5.
Am J Hum Genet ; 106(4): 559-569, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32197075

RESUMEN

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- ß1) and anchors it on the cell surface; this anchoring is required for activation of TGF-ß1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-ß1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-ß1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-ß1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-ß1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-ß1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.


Asunto(s)
Encefalopatías/genética , Calcinosis/genética , Variación Genética/genética , Proteínas de Unión a TGF-beta Latente/genética , Enfermedades Neurodegenerativas/genética , Factor de Crecimiento Transformador beta1/genética , Alelos , Femenino , Células HEK293 , Humanos , Lactante , Macrófagos/patología , Masculino , Microglía/patología
6.
Int J Equity Health ; 22(1): 49, 2023 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-36932363

RESUMEN

As part of its commitment to advance health equity, the World Health Organization (WHO) has a developed area of work to promote and strengthen health inequality monitoring. This includes an emphasis on the collection, analysis and use of disaggregated health data, which are central to evidence-informed decision making. The aim of this paper is to review WHO's work on health inequality monitoring, namely the 2022-27 Inequality monitoring and analysis strategy and corresponding activities, resources and tools. The strategy has three goals pertaining to: strengthening capacity for health inequality monitoring; generating and disseminating the latest evidence on health inequality and supporting data disaggregation; and developing and refining health inequality monitoring methods, resources and best practices. In alignment with these goals, WHO has published reference materials focused on conceptual approaches to health inequality monitoring, which are applied in the global State of Inequality report series. The Health Inequality Monitoring eLearning channel on OpenWHO and capacity building workshops and webinars facilitate the uptake and application of inequality monitoring practices across diverse settings and stakeholders. A key tool available to support the analysis and reporting aspects of health inequality monitoring is the Health Equity Assessment Toolkit (HEAT) application, which allows users to explore data interactively. The Health Inequality Data Repository, a collection of the largest publicly available database of disaggregated data from around the globe, further enables inequality monitoring and analyses. This collection of resources is an important contribution to promote health inequality monitoring across diverse settings. The uptake of evidence from health inequality monitoring remains crucial to the advancement of equity as part of global health and development initiatives.


Asunto(s)
Equidad en Salud , Disparidades en el Estado de Salud , Humanos , Organización Mundial de la Salud , Salud Global , Bases de Datos Factuales
7.
Int J Mol Sci ; 24(4)2023 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-36834994

RESUMEN

We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.


Asunto(s)
Conmoción Encefálica , Encefalopatías Metabólicas , Hidroliasas , Adulto , Niño , Preescolar , Humanos , Hidroliasas/metabolismo , Mitocondrias/metabolismo , NAD/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Proteómica , Conmoción Encefálica/complicaciones , Conmoción Encefálica/genética , Encefalopatías Metabólicas/etiología , Encefalopatías Metabólicas/genética
8.
Biochem Soc Trans ; 50(4): 1207-1224, 2022 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-35997111

RESUMEN

CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.


Asunto(s)
Síndromes Epilépticos , Espasmos Infantiles , Niño , Preescolar , Síndromes Epilépticos/tratamiento farmacológico , Síndromes Epilépticos/terapia , Humanos , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Espasmos Infantiles/tratamiento farmacológico , Espasmos Infantiles/genética , Virulencia
9.
J Inherit Metab Dis ; 45(6): 1028-1038, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35866541

RESUMEN

The central cofactors NAD(P)H are prone to damage by hydration, resulting in formation of redox-inactive derivatives designated NAD(P)HX. The highly conserved enzymes NAD(P)HX dehydratase (NAXD) and NAD(P)HX epimerase (NAXE) function to repair intracellular NAD(P)HX. Recently, pathogenic variants in both the NAXD and NAXE genes were associated with rapid deterioration and death after an otherwise trivial fever, infection, or illness in young patients. As more patients are identified, distinct clinical features are emerging depending on the location of the pathogenic variant. In this review, we carefully catalogued the clinical features of all published NAXD deficiency patients and found distinct patterns in clinical presentations depending on which subcellular compartment is affected by the enzymatic deficiency. Exon 1 of NAXD contains a mitochondrial propeptide, and a unique cytosolic isoform is initiated from an alternative start codon in exon 2. NAXD deficiency patients with variants that affect both the cytosolic and mitochondrial isoforms present with neurological defects, seizures and skin lesions. Interestingly, patients with NAXD variants exclusively affecting the mitochondrial isoform present with myopathy, moderate neuropathy and a cardiac presentation, without the characteristic skin lesions, seizures or neurological degeneration. This suggests that cytosolic NAD(P)HX repair may protect from neurological damage, whereas muscle fibres may be more sensitive to mitochondrial NAD(P)HX damage. A deeper understanding of the clinical phenotype may facilitate rapid identification of new cases and allow earlier therapeutic intervention. Niacin-based therapies are promising, but advances in disease modelling for both NAXD and NAXE deficiency may identify more specific compounds as targeted treatments. In this review, we found distinct patterns in the clinical presentations of NAXD deficiency patients based on the location of the pathogenic variant, which determines the subcellular compartment that is affected by the enzymatic deficiency.


Asunto(s)
Enfermedades Metabólicas , NAD , Humanos , NAD/metabolismo , Racemasas y Epimerasas/metabolismo , Mitocondrias/metabolismo , Enfermedades Metabólicas/metabolismo , Convulsiones/metabolismo
10.
Int J Equity Health ; 21(Suppl 3): 158, 2022 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-36357891

RESUMEN

BACKGROUND: The coronavirus pandemic has exposed existing social inequalities in relation to disease preventive behaviors, risk of exposure, testing and healthcare access, and consequences as a result of illness and containment measures across different population groups. However, due to a lack of data, to date there has been limited evidence of the extent of such within-country inequalities globally. METHODS: We examined education-related inequalities in four COVID-19 prevention and testing indicators within 90 countries, using data from the University of Maryland Social Data Science Center Global COVID-19 Trends and Impact Survey, in partnership with Facebook, over the period 1 June 2021 to 31 December 2021. The overall level of education-related inequalities, as well as how they differ across country income groups and how they have changed over time were analyzed using the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII). We also assessed whether these education-related inequalities were associated with government policies and responses. RESULTS: Education-related inequalities in beliefs, mask wearing, social distancing and testing varied across the study countries. Mask wearing and beliefs in the effectiveness of social distancing and mask wearing were overall more common among people with a higher level of education. Even after controlling for other sociodemographic and health-related factors, social distancing practice was higher among the most educated in low/lower middle income countries, but was higher overall among the least educated in high income countries. Overall there were low education-related inequalities in COVID-19 testing, though there was variation across countries. CONCLUSIONS: The study highlights important within-country education-related differences in COVID-19 beliefs, preventive behaviors and testing, as well as differing trends across country income groups. This has implications for considering and targeting specific population groups when designing public health interventions and messaging during the COVID-19 pandemic and future health emergencies.


Asunto(s)
COVID-19 , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Pandemias/prevención & control , Prueba de COVID-19 , Escolaridad , Factores Socioeconómicos
11.
Int J Equity Health ; 21(1): 133, 2022 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-36100901

RESUMEN

BACKGROUND: Health inequality monitoring can generate important evidence to inform and motivate changes to policy, programmes and practices. However, the potential of health inequality monitoring practices to quantify inequalities between population subgroups and track progress on the advancement of health equity is under-realized. Capacity strengthening on health inequality monitoring can play an important role in enhancing political will for the generation and use of disaggregated data and for wider adoption of this practice to inform health decision-making. There is a lack of widely available and accessible training materials related to health inequality monitoring that may be used by a range of stakeholders. OBJECTIVE: In this paper, we describe the design, development and implementation of the Health Inequality Monitoring channel on the OpenWHO eLearning platform. We discuss the anticipated impact and potential opportunities for these eLearning courses to contribute to strengthened health inequality monitoring practices. RESULTS: The Health Inequality Monitoring channel on the OpenWHO platform is a self-directed learning environment, designed to meet the immediate learning needs of users. The channel contains three series of courses: health inequality monitoring foundations courses; topic-specific health inequality monitoring courses; and health inequality monitoring skill building courses. Courses are primarily targeted to monitoring and evaluation officers, data analysts, academics and researchers, public health professionals, medical and public health students, and others with a general interest in health data and inequality monitoring. CONCLUSIONS: WHO eLearning courses on health inequality monitoring are addressing the need for capacity strengthening in the collection, analysis and reporting of inequality data. They introduce learners to the foundational concepts, best practices, tools and skills required to conduct health inequality monitoring. The courses on the Health Inequality Monitoring channel demonstrate how technical information can be simplified and presented to broad audiences in a manner that is highly accessible to learners. The Health Inequality Monitoring channel on OpenWHO is an innovative and necessary addition to existing tools and resources to support the advancement of health equity.


Asunto(s)
Instrucción por Computador , Equidad en Salud , Salud Global , Disparidades en el Estado de Salud , Humanos , Salud Pública
12.
Int J Mol Sci ; 23(2)2022 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-35055180

RESUMEN

Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein's precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child's clinical presentation.


Asunto(s)
Enfermedad de Leigh/diagnóstico por imagen , Mutación Missense , Proteínas Supresoras de Tumor/genética , Resultado Fatal , Humanos , Lactante , Enfermedad de Leigh/genética , Imagen por Resonancia Magnética , Masculino , Proteínas Mitocondriales/metabolismo , Modelos Moleculares , Proteómica , Análisis de Secuencia de ARN , Proteínas Supresoras de Tumor/química , Secuenciación Completa del Genoma
13.
Neurobiol Dis ; 155: 105370, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33905871

RESUMEN

CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting in dysfunctional CDKL5 protein. It predominantly affects females and causes seizures in the first few months of life, ultimately resulting in severe intellectual disability. In the absence of targeted therapies, treatment is currently only symptomatic. CDKL5 is a serine/threonine kinase that is highly expressed in the brain, with a critical role in neuronal development. Evidence of mitochondrial dysfunction in CDD is gathering, but has not been studied extensively. We used human patient-derived induced pluripotent stem cells with a pathogenic truncating mutation (p.Arg59*) and CRISPR/Cas9 gene-corrected isogenic controls, differentiated into neurons, to investigate the impact of CDKL5 mutation on cellular function. Quantitative proteomics indicated mitochondrial defects in CDKL5 p.Arg59* neurons, and mitochondrial bioenergetics analysis confirmed decreased activity of mitochondrial respiratory chain complexes. Additionally, mitochondrial trafficking velocity was significantly impaired, and there was a higher percentage of stationary mitochondria. We propose mitochondrial dysfunction is contributing to CDD pathology, and should be a focus for development of targeted treatments for CDD.


Asunto(s)
Metabolismo Energético/fisiología , Síndromes Epilépticos/genética , Síndromes Epilépticos/metabolismo , Dinámicas Mitocondriales/fisiología , Neuronas/metabolismo , Espasmos Infantiles/genética , Espasmos Infantiles/metabolismo , Adolescente , Diferenciación Celular/fisiología , Línea Celular Tumoral , Células Cultivadas , Preescolar , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Lactante , Masculino , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Proteómica/métodos
14.
Bull World Health Organ ; 99(9): 627-639, 2021 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-34475600

RESUMEN

OBJECTIVE: To analyse subnational inequality in diphtheria-tetanus-pertussis (DTP) immunization dropout in 24 African countries using administrative data on receipt of the first and third vaccine doses (DTP1 and DTP3, respectively) collected by the Joint Reporting Process of the World Health Organization and the United Nations Children's Fund. METHODS: Districts in each country were grouped into quintiles according to the proportion of children who dropped out between DTP1 and DTP3 (i.e. the dropout rate). We used six summary measures to quantify inequalities in dropout rates between districts and compared rates with national dropout rates and DTP1 and DTP3 immunization coverage. FINDINGS: The median dropout rate across countries was 2.4% in quintiles with the lowest rate and 14.6% in quintiles with the highest rate. In eight countries, the difference between the highest and lowest quintiles was 14.9 percentage points or more. In most countries, underperforming districts in the quintile with the highest rate tended to lag disproportionately behind the others. This divergence was not evident from looking only at national dropout rates. Countries with the largest inequalities in absolute subnational dropout rate tended to have lower estimated national DTP1 and DTP3 immunization coverage. CONCLUSION: There were marked inequalities in DTP immunization dropout rates between districts in most countries studied. Monitoring dropout at the subnational level could help guide immunization interventions that address inequalities in underserved areas, thereby improving overall DTP3 coverage. The quality of administrative data should be improved to ensure accurate and timely assessment of geographical inequalities in immunization.


Asunto(s)
Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Difteria/prevención & control , Programas de Inmunización/estadística & datos numéricos , Tétanos/prevención & control , Cobertura de Vacunación/estadística & datos numéricos , Tos Ferina/prevención & control , África , Niño , Femenino , Disparidades en Atención de Salud , Humanos , Inmunización , Lactante , Masculino , Pobreza , Factores Socioeconómicos
15.
Brain ; 143(1): 112-130, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31794024

RESUMEN

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.


Asunto(s)
Autofagia/genética , Anomalías Craneofaciales/genética , Fibroblastos/metabolismo , Proteínas del Tejido Nervioso/genética , Trastornos del Neurodesarrollo/genética , Proteínas de Transporte Vesicular/genética , Atrofia , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Niño , Preescolar , Anomalías Craneofaciales/diagnóstico por imagen , Sordera/genética , Sordera/fisiopatología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Microcefalia/genética , Microcefalia/fisiopatología , Microscopía Fluorescente , Espasticidad Muscular/genética , Espasticidad Muscular/fisiopatología , Trastornos del Neurodesarrollo/fisiopatología , Linaje , Cuadriplejía/genética , Cuadriplejía/fisiopatología , Sitios de Empalme de ARN/genética , Síndrome
16.
Hum Mutat ; 41(10): 1761-1774, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32652677

RESUMEN

Defects in the motor domain of kinesin family member 1A (KIF1A), a neuron-specific ATP-dependent anterograde axonal transporter of synaptic cargo, are well-recognized to cause a spectrum of neurological conditions, commonly known as KIF1A-associated neurological disorders (KAND). Here, we report one mutation-negative female with classic Rett syndrome (RTT) harboring a de novo heterozygous novel variant [NP_001230937.1:p.(Asp248Glu)] in the highly conserved motor domain of KIF1A. In addition, three individuals with severe neurodevelopmental disorder along with clinical features overlapping with KAND are also reported carrying de novo heterozygous novel [NP_001230937.1:p.(Cys92Arg) and p.(Pro305Leu)] or previously reported [NP_001230937.1:p.(Thr99Met)] variants in KIF1A. In silico tools predicted these variants to be likely pathogenic, and 3D molecular modeling predicted defective ATP hydrolysis and/or microtubule binding. Using the neurite tip accumulation assay, we demonstrated that all novel KIF1A variants significantly reduced the ability of the motor domain of KIF1A to accumulate along the neurite lengths of differentiated SH-SY5Y cells. In vitro microtubule gliding assays showed significantly reduced velocities for the variant p.(Asp248Glu) and reduced microtubule binding for the p.(Cys92Arg) and p.(Pro305Leu) variants, suggesting a decreased ability of KIF1A to move along microtubules. Thus, this study further expanded the phenotypic characteristics of KAND individuals with pathogenic variants in the KIF1A motor domain to include clinical features commonly seen in RTT individuals.


Asunto(s)
Cinesinas , Mutación Missense , Familia , Femenino , Heterocigoto , Humanos , Cinesinas/genética , Mutación , Trastornos del Neurodesarrollo/genética , Síndrome de Rett/genética
17.
Brain ; 142(1): 50-58, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30576410

RESUMEN

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.


Asunto(s)
Hidroliasas/deficiencia , Enfermedades Neurodegenerativas/genética , Preescolar , Simulación por Computador , Femenino , Fiebre/complicaciones , Fiebre/metabolismo , Fibroblastos/metabolismo , Vectores Genéticos , Humanos , Hidroliasas/genética , Lactante , Cinética , Lentivirus , Masculino , Mitocondrias/metabolismo , Mutación , NAD/análogos & derivados , NAD/metabolismo , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/metabolismo , Cultivo Primario de Células , Secuenciación Completa del Genoma
19.
BMC Public Health ; 20(1): 1593, 2020 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-33092565

RESUMEN

BACKGROUND: Maternity waiting homes (MWHs), residential spaces for pregnant women close to obstetric care facilities, are being used to tackle physical barriers to access. However, their effectiveness has not been rigorously assessed. The objective of this cluster randomized trial was to evaluate the effectiveness of functional MWHs combined with community mobilization by trained local leaders in improving institutional births in Jimma Zone, Ethiopia. METHODS: A pragmatic, parallel arm cluster-randomized trial was conducted in three districts. Twenty-four primary health care units (PHCUs) were randomly assigned to either (i) upgraded MWHs combined with local leader training on safe motherhood strategies, (ii) local leader training only, or (iii) usual care. Data were collected using repeat cross-sectional surveys at baseline and 21 months after intervention to assess the effect of intervention on the primary outcome, defined as institutional births, at the individual level. Women who had a pregnancy outcome (livebirth, stillbirth or abortion) 12 months prior to being surveyed were eligible for interview. Random effects logistic regression was used to evaluate the effect of the interventions. RESULTS: Data from 24 PHCUs and 7593 women were analysed using intention-to-treat. The proportion of institutional births was comparable at baseline between the three arms. At endline, institutional births were slightly higher in the MWH + training (54% [n = 671/1239]) and training only arms (65% [n = 821/1263]) compared to usual care (51% [n = 646/1271]). MWH use at baseline was 6.7% (n = 256/3784) and 5.8% at endline (n = 219/3809). Both intervention groups exhibited a non-statistically significant higher odds of institutional births compared to usual care (MWH+ & leader training odds ratio [OR] = 1.09, 97.5% confidence interval [CI] 0.67 to 1.75; leader training OR = 1.37, 97.5% CI 0.85 to 2.22). CONCLUSIONS: Both the combined MWH+ & leader training and the leader training alone intervention led to a small but non-significant increase in institutional births when compared to usual care. Implementation challenges and short intervention duration may have hindered intervention effectiveness. Nevertheless, the observed increases suggest the interventions have potential to improve women's use of maternal healthcare services. Optimal distances at which MWHs are most beneficial to women need to be investigated. TRIAL REGISTRATION: The trial was retrospectively registered on the Clinical Trials website ( https://clinicaltrials.gov ) on 3rd October 2017. The trial identifier is NCT03299491 .


Asunto(s)
Accesibilidad a los Servicios de Salud , Servicios de Salud Materna , Estudios Transversales , Etiopía , Femenino , Instituciones de Salud , Humanos , Embarazo
20.
Qual Health Res ; 30(5): 783-792, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31830860

RESUMEN

Many qualitative research studies acknowledge the possibility of social desirability bias (a tendency to present reality to align with what is perceived to be socially acceptable) as a limitation that creates complexities in interpreting findings. Drawing on experiences conducting interviews and focus groups in rural Ethiopia, this article provides an empirical account of how one research team developed and employed strategies to detect and limit social desirability bias. Data collectors identified common cues for social desirability tendencies, relating to the nature of the responses given and word choice patterns. Strategies to avoid or limit bias included techniques for introducing the study, establishing rapport, and asking questions. Pre-fieldwork training with data collectors, regular debriefing sessions, and research team meetings provided opportunities to discuss social desirability tendencies and refine approaches to account for them throughout the research. Although social desirability bias in qualitative research may be intractable, it can be minimized.


Asunto(s)
Relaciones Interpersonales , Deseabilidad Social , Sesgo , Etiopía , Humanos , Investigación Cualitativa
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