Determinant of the Cerebellar cognitive affective syndrome in Friedreich Ataxia

destrebecq, comet, deveylder, alaerts, naeije.; Research Square; 2022. DOI: 10.21203/rs.3.rs-2279266/v1. 

CCAS is highly prevalent in adult individuals with FRDA. CCAS is predicted by ataxic motor symptoms severity. This finding supports common core cerebellar pathophysiology in both cognitive and motor symptoms in FRDA and warrants screening for CCAS, especially in patients with SARA > 20.

Harmonizing results of ataxia rating scales: mFARS, SARA, and ICARS

Rummey C, Harding IH, Delatycki MB, Tai G, Rezende T, Corben LA.; Ann Clin Transl Neurol. 2022 Nov 16. doi: 10.1002/acn3.51686. Epub ahead of print. PMID: 36394163. 

 The ever-increasing body of ataxia research provides opportunities for large-scale meta-analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression.

Cerebellar impulsivity–compulsivity assessment scale

Lin, C.-Y.R., Amokrane, N., Chen, S., Chen, T.X., Lai, R.-Y., Trinh, P., Minyetty, M.J., Emmerich, H., Pan, M.-K., Claassen, D.O. and Kuo, S.-H. (2022); Ann Clin Transl Neurol. doi.:10.1002/acn3.51698

Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test–retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity.

Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)

Kemper C, Benham D, Brothers S, Wahlestedt C, Volmar CH, Bennett D, Hayward M.; AAPS Open. 2022;8(1):11. doi: 10.1186/s41120-022-00058-1. Epub 2022 Jun 30. PMID: 35789594; PMCID: PMC9243782. 

 Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer's disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; "Jupiter") is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich's ataxia, and Alzheimer's disease/mild cognitive impairment.

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Juan Benito-Lozano, Blanca López-Villalba, Greta Arias-Merino, Manuel Posada de la Paz & Verónica Alonso-Ferreira; Orphanet J Rare Dis 17, 418 (2022). doi:10.1186/s13023-022-02530-3 

This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

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.