Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy

Salinas L, Montgomery CB, Figueroa F, Thai PN, Chiamvimonvat N, Cortopassi G, Dedkova EN. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy. Commun Biol. 2024 Oct 3;7(1):1250. doi: 10.1038/s42003-024-06962-4. PMID: 39363102; PMCID: PMC11449905. 

 The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses

Lee L, Flach S, Xue H, Arivelu L, Golden L, Kong R, Darpo B. Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses. Clin Pharmacol Drug Dev. 2024 Nov;13(11):1227-1238. doi: 10.1002/cpdd.1476. Epub 2024 Oct 17. PMID: 39415654. 

 No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level.

Friedreich Ataxia

Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich Ataxia. 1998 Dec 18 [updated 2024 Oct 31]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301458. 

 Review (Last Update: October 31, 2024.)

Efficacy of Stabilometric Platform to Improve Standing Balance in Patients with Friedreich's Ataxia

ClinicalTrials.gov ID NCT06692296. Sponsor IRCCS Eugenio Medea. Last Update Posted 2024-11-21

The primary objective is to evaluate the potential effectiveness of an individualized intensive rehabilitation intervention using the "Prokin 252" stabilometric platform in the treatment of adolescent and adult patients with Friedreich's Ataxia. The secondary objective is to assess the retention of the rehabilitation treatment effects over time.

Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives

Naghipour S, Corben LA, Hulme AJ, Dottori M, Delatycki MB, Lees JG, Lim SY. Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives. Mov Disord. 2024 Nov 19. doi: 10.1002/mds.30070. Epub ahead of print. PMID: 39559924. 

The scarcity literature addressing the cardiovascular effects omaveloxolone in FRDA is concerning, especially considering that cardiomyopathy is the primary cause of mortality in affected individuals. Furthermore, the reported potential of omaveloxolone to induce mil elevations in B-natriuretic peptide (BNP), a known marker of heart failure, adds to this concern. Thus, those individuals with FRDA who have cardiomyopathy are advised to monitor BNP levels while using omaveloxolone. In this viewpoint, we examine the current literature on the efficacy and safety of omaveloxolone in treating FRDA, with a focus on its potential impact on cardiovascular health.

Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN

Gerhart BJ, Pellerin D, Danzi MC, Zuchner S, Brais B, Matos-Rodrigues G, Nussenzweig A, Usdin K, Park CC, Napierala JS, Lynch DR, Napierala M. Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN. Neurol Genet. 2024 Nov 20;10(6):e200210. doi: 10.1212/NXG.0000000000200210. PMID: 39574782; PMCID: PMC11581763.

Despite both molecular and clinical similarities between FRDA and SCA27B, the length of the GAA repeats in the FGF14 gene, including potentially pathogenic alleles, did not influence the clinical presentation of FRDA.

Recurrent DNA nicks drive massive expansions of (GAA)n repeats

Li L, Scott WS, Khristich AN, Armenia JF, Mirkin SM. Recurrent DNA nicks drive massive expansions of (GAA)n repeats. Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2413298121. doi: 10.1073/pnas.2413298121. Epub 2024 Nov 25. PMID: 39585990.

 We found that DNA nicks 5' of the (GAA)100 run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)n repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3' of the (GAA)100 repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5' GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.

Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex

Steinhilper R, Boß L, Freibert SA, Schulz V, Krapoth N, Kaltwasser S, Lill R, Murphy BJ. Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex. Nat Commun. 2024 Dec 4;15(1):10559. doi: 10.1038/s41467-024-54585-4. PMID: 39632806; PMCID: PMC11618653.  

The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex.