Guía de Evaluación Diagnóstica y Discapacidad en Pacientes con Ataxias y Paraparesias Espásticas Hereditarias

Francisco Javier Arpa Gutiérrez, María José Abenza Abildúa, Idoia Rouco Axpe. Sociedad Española de Neurología (2022). ISBN: 978-84-124320-4-6 . https://www.edicionessen.es

El objetivo de este trabajo, dirigido a neurólogos en general y a otros facultativos de especialidades médicas como medicina física y rehabilitadora, atención primaria, medicina interna, medicina del trabajo, etc., es facilitar la correcta valoración diagnóstica y de la discapacidad en los pacientes con AH y PEH. Una gradación completa y homogénea de su situación clínica aumentaría la posibilidad de acceder a recursos sociales y legales adecuados a su situación.

The Use of Enhanced Recovery After Surgery Protocols and Sugammadex in a Friedreich Ataxia Patient Who Underwent Robotic Surgery: A Case Report of a Patient Who Required No Postoperative Opioids and Was Discharged Home Earlier Than Anticipated

Lori P. Russo, Daniel Haddad, Daniel Bauman, Mina M. Fam (September 26, 2022). Cureus 14(9): e29590. doi:10.7759/cureus.29590

Anesthesia in general must be carefully planned in FRDA patients to allow for the best possible recovery and minimize complications. Due to the underlying neuromuscular compromise seen in these patients, their ability to recover from the pharmacologic and physiologic changes associated with anesthesia can be more difficult. They are prone to sensitivity to opioids, sedatives, and neuromuscular blocking agents (NMBAs) and are less likely to tolerate hemodynamic changes. Our review revealed no literature to suggest the routine use of Enhanced Recovery After Surgery (ERAS) protocols in FRDA patients or in patients with neuromuscular disease in general. The use of sugammadex has also been shown to be safe, and literature suggests superiority in both the general population and those with neuromuscular conditions. Our understanding is that there is very limited literature in regard to the safe use of sugammadex in FRDA patients.

The inherited cerebellar ataxias: an update

Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M.; J Neurol. 2022 Sep 24. doi: 10.1007/s00415-022-11383-6. 

We describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.

Diagnostic Delay and Clinical Features in Friedreich’s Ataxia

Mehmet Fatih Yetkin, Murat Gültekin, Merve Akcakoyunlu, Recep Baydemir, Ayse Çağlar Sarılar, Mehmet Canpolat, Hüseyin Per; Turk Noroloji Dergisi, cilt.28, sa.2, ss.97-101, 2022 (Hakemli Dergi). DOI:10.4274/tnd.2022.26780

Conclusion: This study is the first study to evaluate the diagnosis delay in patients with FRDA in our country. Although FRDA was the most common hereditary ataxia, in our study, it was shown that there was a significant delay in diagnosis in patients with FRDA. There is a need for studies that will raise awareness of public and health professionals about FRDA.

FRIEDREICH'S ATAXIA AND ITS CARDIOVASCULAR MANIFESTATIONS

Bryam Esteban Coello Garcia, Karina Noemi Contreras Garcia, Priscila Jazmin Sarango Lapo, Tatiana Carolina Espinoza Coyago, Johanna Belen Illescas Aguilera, Bonny Maria Montalvan Nivicela, Karen Sofia Suscal Pelaez; EPRA International Journal of Multidisciplinary Research (IJMR) -Volume: 8, Issue: 9, September 2022, DOI:10.36713/epra11261 

 The aim of this bibliographic review is to inform the scientific community of the presence of systemic manifestations, especially cardiovascular, in Friedreich's Ataxia; since this disease is not only characterized by the presence of neurological alterations, but also of affections to different apparatuses and systems of the human body, such as the heart, due to the cellular alteration that Friedreich's Ataxia causes.

Gene Expression Quantification to Assess Frataxin Replacement Therapies in Friedreich’s Ataxia

M. Baile, D. Schecter, A. Miller, T. Galas, N. Scherer, R. Chen, N. Ruiz, D. Bettoun.; Mov Disord. 2022; 37 (suppl 1). Meeting: 2022 International Congress (September 15-18, 2022. Madrid, Spain) 

 Quantitation of expression levels of a small number of genes in buccal cells can be used to discriminate between healthy individuals and patients with FRDA. Treatment with CTI-1601 is effective in restoring the expression levels of 6 of those genes to levels similar to those observed in healthy individuals.

Tissue Frataxin Increases After Administration of CTI-1601, a Frataxin Replacement Therapy in Development for the Treatment of Friedreich’s Ataxia

D. Bettoun, T. Galas, D. Schecter, N. Ruiz, R. Clayton, J. Farmer.; Mov Disord. 2022; 37 (suppl 1).Meeting: 2022 International Congress (September 15-18, 2022. Madrid, Spain) 

In this first clinical study of CTI-1601, a therapy intended to increase FXN in patients with FRDA, increases in FXN levels were seen in multiple tissues. These observed increases in FXN after 7 days of QD dosing of 50 or 100 mg CTI-160 are potentially clinically relevant since 2- to 3-fold increases in FXN in patients with FRDA may achieve FXN levels observed in asymptomatic heterozygous carriers [1, 2]. CTI-1601 was generally well-tolerated. These data support the continued study of CTI-1601 as a treatment for patients with FRDA.

Activation of a type I interferon response associated with acute frataxin knockdown in iPSC-derived cardiomyocytes

Cotticelli MG, Xia S, Truitt R, Doliba NM, Rozo AV, Tobias JW, Lee T, Chen J, Napierala JS, Napierala M, Yang W, Wilson RB.; Dis Model Mech. 2022 Sep 15:dmm.049497. doi: 10.1242/dmm.049497 

We confirmed that in iPSC-derived cardiomyocytes, loss of frataxin leads to mitochondrial dysfunction. The type I interferon response was activated in multiple cell types following acute frataxin knockdown and was caused, at least in part, by release of mitochondrial DNA into the cytosol, activating the cGAS-STING sensor pathway.

The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy

Ning Guo, Ji-Bin Liu, Wen Li, Yu-Shui Ma, Da Fu; Journal of Advanced Research, Volume 40, 2022, Pages 135-152, doi:10.1016/j.jare.2021.11.018. 

CRISPR/Cas9 also provides a possible therapeutic strategy for Friedreich's ataxia (FRDA). For example, removing the GAA expansions of the frataxin gene (FXN) in vitro and in vivo alleviates related symptoms dramatically but with some unexpected side effects like p53-mediated cell proliferation delay.

A Study to Assess the Safety and Efficacy of Vatiquinone in Participants With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT05515536

The primary objective of this study is to assess the long-term safety of vatiquinone in participants with Friedreich ataxia (FA) previously exposed to vatiquinone in Study PTC743-NEU-003-FA (NCT04577352) or Study PTC743-NEU-005-FA

Phase 3 

Study Type : Interventional (Clinical Trial) 

Estimated Enrollment : 140 participants 

Allocation: N/A 

Intervention Model: Single Group Assignment 

Masking: None (Open Label) 

Primary Purpose: Treatment 

Official Title: Long-Term Open-Label Study to Assess the Safety and Efficacy of Vatiquinone in Patients With Friedreich Ataxia 

Estimated Study Start Date : November 1, 2022 

Estimated Primary Completion Date : December 31, 2027 

Estimated Study Completion Date : December 31, 2027

Consideration of oral health in rare disease expertise centres: a retrospective study on 39 rare diseases using text mining extraction method

Friedlander, L., Vincent, M., Berdal, A. et al.; Orphanet J Rare Dis 17, 317 (2022). doi:10.1186/s13023-022-02467-7 

Five networks we studied fill in the patient database while their phenotypes predict that dental and oral phenotypes may raise difficulties. The analysis of the collected data suggests a lack of connection with oral professionals during early childhood and adult transition. These networks are BRAIN-TEAM with Friedreich ataxia (Rare diseases with motor or cognitive expression of the central nervous system)......

Resveratrol from Dietary Supplement to a Drug Candidate: An Assessment of Potential

Khattar, Shivani, Sauban Ahmed Khan, Syed Amir Azam Zaidi, Mahdi Darvishikolour, Uzma Farooq, Punnoth Poonkuzhi Naseef, Mohamed Saheer Kurunian, Mohammed Zaafar Khan, Athar Shamim, Mohd Masih Uzzaman Khan, Zeenat Iqbal, and Mohd. Aamir Mirza. 2022.; Pharmaceuticals 15, no. 8: 957. doi:10.3390/ph15080957

In Australia, RVT as an option for the treatment of Friedreich ataxia was assessed ( NCT01339884, A Study of Resveratrol as Treatment for Friedreich Ataxia, Phase 1, Phase 2)

Perspectives on current models of Friedreich's ataxia

Kelekçi S, Yıldız AB, Sevinç K, Çimen DU, Önder T. Perspectives on current models of Friedreich's ataxia. Frontiers in Cell and Developmental Biology. 2022 ;10:958398. DOI: 10.3389/fcell.2022.958398 

We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages

Fichera M, Castaldo A, Mongelli A, Marchini G, Gellera C, Nanetti L, Mariotti C.; Neurol Sci. 2022 Sep 2. doi: 10.1007/s10072-022-06360-w 

 Incidence of FA-related medical conditions varies according to disease duration. In patients with very long disease duration, we observed an unexpectedly high incidence of visual and auditory pseudo-hallucinations that were not previously reported in FA patients. We hypothesized that these late complications may be possibly related to the severe sensory deafferentation syndrome observed in the advanced stages of FA disease.

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

Hanaford A, Johnson SC. Orphanet Journal of Rare Diseases. 2022 Sep;17(1):335. DOI: 10.1186/s13023-022-02495-3.

Inflammation appears to play a role in the pathogenesis of the mitochondria-associated iron accumulation disease Friedreich ataxia (FRDA). Microgliosis has been reported in the dorsal root ganglia of FRDA patients, a known site of FRDA neuropathology. Microglial activation has also been reported in FRDA patients in brain regions associated with neuropathology using PET scanning for 18F-FEMPA, a high-affinity ligand for the microglia-specific 18-kDa Translocator protein (TPSO). 18F-FEMPA signal intensity correlates with age of disease onset, supporting a causal role for neuroinflammation in FRDA symptoms. FRDA patients also show elevated plasma IL-6, and FRDA patient blood transcriptomic profiles show upregulated innate immune responses.

Identifying project topics and requirements in a citizen science project in rare diseases: a participative study

Michaela Neff, Holger Storf, Jessica Vasseur, Jörg Scheidt, Thomas Zerr, Andreas Khouri & Jannik Schaaf. Orphanet J Rare Dis 17, 357 (2022). doi:10.1186/s13023-022-02514-3 

Due to their low prevalence (< 5 in 10,000), rare diseases are an important area of research, with the active participation of those affected being a key factor. In the Citizen Science project “SelEe” (Researching rare diseases in a citizen science approach), citizens collaborate with researchers using a digital application, developed as part of the project together with those affected, to answer research questions on rare diseases. The aim of this study was to define the rare diseases to be considered, the project topics and the initial requirements for the implementation in a digital application.

Advancing qualitative rare disease research methodology: a comparison of virtual and in-person focus group formats

Andrew A. Dwyer, Melissa Uveges, Samantha Dockray & Neil Smith; Orphanet J Rare Dis 17, 354 (2022). doi:10.1186/s13023-022-02522-3 

Geographically dispersed patients have posed significant roadblocks for rare disease research resulting in small sample sizes and underpowered studies. As rare disease patients have been referred to as internet “power users”, web-enabled technologies hold promise for reaching dispersed rare disease patients and surmounting geographic barriers for many. To our knowledge, the present study is the first to support the validity of virtual focus groups for qualitative rare disease research. Moreover, the present findings suggest the anonymity afforded by the internet can facilitate discussion of highly sensitive and intimate topics. This observation is important as feelings of stigma and shame are frequently experienced by patients living with a rare disease—particularly in a condition like CHH that has a psychosexual/sexual health component. The present findings support methodologic rigor of using web-enabled technologies for qualitative research using focus groups in rare diseases.

A promissing mouse model for Friedreich Ataxia progressing like human patients

Catherine Gérard, Annabelle Fortin Archambault, Camille Bouchard, Jacques P. Tremblay; Behavioural Brain Research, 2022, 114107, doi:10.1016/j.bbr.2022.1141

Jackson Laboratories Inc. developed a new mouse model that has 800 GAA repeats. We demonstrate here that these mice accurately reflect the human disease with a progressive neuromuscular degeneration highlighted by the two beam tests and the beginning of heart hypertrophy at 26 weeks. YG8-800 mice are thus currently a promising mouse model for FRDA.

Larimar Therapeutics Announces FDA Clearance to Initiate the 25 mg Cohort of a Phase 2 Dose Exploration Trial of CTI-1601 in Friedreich’s Ataxia Patients

BALA CYNWYD, Pa., Sept. 14, 2022 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) today announced that the U.S. Food and Drug Administration (FDA) has cleared the initiation of the 25 mg cohort of a Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in Friedreich’s ataxia (FA) patients. In a written communication to Larimar, the FDA indicated it was lifting its full clinical hold on the CTI-1601 program and imposing a partial hold. The design of the upcoming Phase 2 trial is identical to the design proposed by Larimar, with the exception of a requirement for the FDA to review data from the 25 mg cohort prior to escalating the dose in the second cohort. Larimar expects to begin the Phase 2 trial in Q4 2022, with top-line data expected in 2H 2023.

The C-Terminal Cross-linked Telopeptide of Type I Collagen (CTX-I) as a Potential Cardiomyopathy Biomarker in Friedreich Ataxia Patients

Chiara Pane, Assunta Trinchillo, Andrea Salzano, Angela Marsili, Giorgia Puorro, Antonio Cittadini, Francesco Saccà & Cinzia Valeria Russo; Cerebellum (2022). doi:10.1007/s12311-022-01475-4 

CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients.

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

Rodden LN, Rummey C, Dong YN, Lagedrost S, Regner S, Brocht A, Bushara K, Delatycki MB, Gomez CM, Mathews K, Murray S, Perlman S, Ravina B, Subramony SH, Wilmot G, Zesiewicz T, Bolotta A, Domissy A, Jespersen C, Ji B, Soragni E, Gottesfeld JM and Lynch DR; (2022). Front. Mol. Biosci. 9:933788. doi: 10.3389/fmolb.2022.933788

People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.