Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso, Atención Primaria

Ismael Ejarque Doménech, Purificación Marín Reina, Sixto García-Miñaur Rica, Isabel Chirivella González, María Teresa Martínez Martínez, Ana María García Rodríguez, Sara Álvarez de Andrés, Juan José Tellería Orriols, Volume 54, Issue 12, 2022, 102501, doi:10.1016/j.aprim.2022.102501. La Atención Primaria (AP) es el primer contacto entre el paciente y el médico, por lo que es fundamental tener claro los criterios de sospecha de una enfermedad genética y dónde se debe remitir para su estudio. s Cuatro sociedades científicas: la Sociedad Española de Medicina Familiar y Comunitaria (semFYC), la Asociación Española de Genética Humana (AEGH), la Asociación Española de Pediatría (AEP) y la Sociedad Española de Oncología Médica (SEOM), han revisado los criterios de derivación a los servicios de genética clínica de las diferentes guías publicadas, con el objetivo de elaborar unas recomendaciones para AP.

De acuerdo con las recomendaciones internacionales, y teniendo siempre como objetivo fundamental la protección de los derechos del menor, se desaconseja el estudio genético de portadores (sanos) y de enfermedades de inicio en la edad adulta (sin posibilidad de intervención preventiva) en pacientes menores de edad. 

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Neuroinflammation: Implications for Neurodegenerative Disease Treatment

Katherine O. Kopp, Elliot J. Glotfelty, Yazhou Li, Nigel H. Greig; Pharmacological Research, 2022, 106550, DOI:10.1016/j.phrs.2022.106550. Abstract: Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation. 

 FRDA is a heritable neurodegenerative movement disorder fueled and exacerbated by neuroinflammation 290, 291, 292, which could make it a candidate for GLP-1R agonist treatment. Exenatide treatment was found to re-elevate reduced levels of frataxin, a critical mitochondrial protein, in FRDA patients, which can enhance mitochondrial health and function and could, by extension, reduce neuroinflammation and neurodegeneration characteristic of the disease [293]—again, providing a potentially fruitful area of future basic and clinical research. Similarly, studies by Meissner and colleagues [178] demonstrated the presence of impaired insulin/IGF-1 and IR in vulnerable brain regions of multiple system atrophy patients and a related transgenic mouse model, and their mitigation in the latter by exendin-4, likewise suggesting a promising area of future research.

Decreased mitochondrial respiration in cardiac fibers isolated from a mouse model of Friedreich’s ataxia

Peter Vitiello, Paul Pierce, Shirley/Xiu Wang, Alec Cooper, Aristides Rivera, Jared Ailts, Holly Van Remmen, Jacob Brown; Free Radical Biology and Medicine,Volume 192, Supplement 1, 2022, Page 75, doi:10.1016/j.freeradbiomed.2022.10.308.

Characterization of human mitochondrial aconitase and its interaction with frataxin

Santiago Mansilla, Verónica Tórtora, Florencia Pignataro, Santiago Sastre, Ignacio Castro, María Laura Chiribao, Carlos Robello, Ari Zeida, Javier Santos, Laura Castro; Free Radical Biology and Medicine, Volume 192, Supplement 1, 2022, Pages 86-87, doi:10.1016/j.freeradbiomed.2022.10.151.

RNA as a Major-Groove Ligand: RNA-RNA and RNA-DNA Triplexes Formed by GAA and UUC or TTC Sequences

Zhang J, Fakharzadeh A, Roland C, Sagui C.; ACS Omega. 2022 Nov;7(43):38728-38743. DOI: 10.1021/acsomega.2c04358. PMID: 36340174; PMCID: PMC9631886. 

 Friedreich's ataxia is associated with noncanonical nucleic acid structures that emerge when GAA:TTC repeats in the first intron of the FXN gene expand beyond a critical number of repeats. Specifically, the noncanonical repeats are associated with both triplexes and R-loops. Here, we present an in silico investigation of all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex, complementing previous DNA-based triplex studies. For both new triplexes results are similar. For a pyridimine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes. The presence of Mg2+ ions helps stabilize neutral, antiparallel GAA triplexes. These results (along with previous DNA-based studies) allow for the emergence of a complete picture of the stability and structural characteristics of triplexes based on the GAA and TTC/UUC sequences, thereby contributing to the field of trinucleotide repeats and the associated unusual structures that trigger expansion.