Friedreich's Ataxia Frequency in a Large Cohort of Genetically Undetermined Ataxia Patients

Brown AF, Parkinson MH, Garcia-Moreno H, Mudanohwo E, Labrum R, Sweeney M, Giunti P.; Front Neurol. 2021 Dec 9;12:736253. doi: 10.3389/fneur.2021.736253. PMID: 34956042; PMCID: PMC8697107. 

This study demonstrates that FRDA is very rare among patients who were referred purely for SCA testing without the clinical suspicion of FRDA. Such cases should be referred to specialist ataxia centres for more extensive testing to improve patient management and outcomes.

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, 2021, doi:10.1016/j.jare.2021.11.018.

CRISPR/Cas9, derived from the microbial innate immune system, is developed as a robust gene-editing tool and has been applied widely. Due to its high accuracy and efficiency, CRISPR/Cas9 techniques may provide a great chance to treat some gene-related diseases by disrupting, inserting, correcting, replacing, or blocking genes for clinical application with gene therapy.

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

The classification of neurodegenerative disease from acoustic speech data

Schultz B, Joukhadar Z, Quiroga MdM, Nattala U, Noffs G, Rojas S, Reece H, Walt Avd, Adam Vogel; Research Square; 2021. DOI: 10.21203/rs.3.rs-1029846/v1.

Neurodegenerative diseases often affect speech. Speech acoustics can be used as objective clinical markers of pathology. Previous investigations of pathological speech have primarily compared controls with one specific condition and excluded comorbidities. We broaden the utility of speech markers by examining how multiple acoustic features can delineate diseases. We used supervised machine learning with gradient boosting (CatBoost) to differentiate healthy speech and speech from people with multiple sclerosis or Friedreich ataxia.

Objective Assessment of Progression and Disease Characterization of Friedreich Ataxia via an Instrumented Drinking Cup: Preliminary Results

Krishna R, Pathirana PN, Horne MK, Szmulewicz DJ, Corben LA.; IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. 2021 ;29:2365-2377. DOI: 10.1109/tnsre.2021.3124869. PMID: 34727035. 

The monitoring of disease progression in certain neurodegenerative conditions can significantly be quantified with the help of objective assessments. The severity assessment of diseases like Friedreich ataxia (FRDA) are usually based on different subjective measures. The ability of a participant with FRDA to perform standard neurological tests is the most common way of assessing disease progression. In this feasibility study, an Ataxia Instrumented Measurement-Cup (AIM-C) is proposed to quantify the disease progression of 10 participants (mean age 39 years, onset of disease 16.3 years) in longitudinal timepoints. The device consists of a sensing system with the provision of extracting both kinetic and kinematic information while engaging in an activity closely associated with activities of daily living (ADL). A common functional task of simulated drinking was used to capture features that possesses disease progression information as well as certain other features which intrinsically correlate with commonly used clinical scales such as the modified Friedreich Ataxia Rating Scale (mFARS), the Functional Staging of Ataxia score and the ADL scale. Frequency and time-frequency domain features allowed the longitudinal assessment of participants with FRDA. Furthermore, both kinetic and kinematic measures captured clinically relevant features and correlated 85% with clinical assessments.

Conformational stability, dynamics and function of human frataxin: Tryptophan side chain interplay

Espeche LD, Sewell KE, Castro IH, Capece L, Pignataro MF, Dain L, Javier Santos; Archives of Biochemistry and Biophysics. 2021 Nov;715:109086. DOI: 10.1016/j.abb.2021.109086. PMID: 34801473. 

In humans, the loss of frataxin results in Friedreich's Ataxia, a neurodegenerative disease, in which a deficit in the iron–sulfur cluster assembly is observed. In this work, we analyzed three frataxin variants in which one tryptophan was replaced by a glycine: W155G, W168G and W173G. As expected, given its localization in the assembly site, W155G was not able to activate the desulfurase activity of the supercomplex for iron–sulfur cluster assembly. In turn, W168G, which was significantly more unstable than W155G, was fully active. W173G, which was highly unstable as W168G, showed a significantly decreased activity, only slightly higher than W155G. As W168G and W173G were highly sensitive to proteolysis, we investigated the protein motions by molecular dynamic simulations. We observed that W173G may display altered motions at the Trp155 site. Furthermore, we revealed a H-bond network in which Trp155 takes part, involving residues Gln148, Asn151, Gln153 and Arg165. We suggest that this motion modulation that specifically alters the population of different Trp155 rotamers can be directly transferred to the assembly site, altering the dynamics of the ISCU His137 key residue. This hypothesis was also contrasted by means of molecular dynamic simulations of frataxin in the context of the complete supercomplex. We propose that the supercomplex requires very definite motions of Trp155 to consolidate the assembly site.

Characterizing cardiac phenotype in Friedreich's ataxia: The CARFA study

Lise Legrand, Jonathan W. Weinsaft, Francoise Pousset, Claire Ewenczyk, Perrine Charles, Stéphane Hatem, Anna Heinzmann, Marie Biet, Alexandra Durr, Alban Redheuil, Volume 1267, Issue 1, 11/2021, Pages 1-73, ISSN 1875-2136, doi:10.1016/j.acvd.2021.10.010 

The multivariable characterization of the cardiac phenotype of patients with Friedreich's ataxia was significantly different from controls at baseline. Over 1 year there were no clinically significant changes in patients with Friedreich's ataxia compared with healthy controls, whereas the neurological severity score increased modestly.

Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children

Anwar Baban, Valentina Lodato, Giovanni Parlapiano, Corrado di Mambro, Rachele Adorisio, Enrico Silvio Bertini, Carlo Dionisi-Vici, Fabrizio Drago, and Diego Martinelli; Biomolecules. 2021 Oct;11(11). DOI: 10.3390/biom11111578. PMID: 34827576; PMCID: PMC8615674. 

Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich’s Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies.

Friedreich cardiomyopathy is a secondary desminopathy

Koeppen, A., Rafique, R., Mazurkiewicz, J., Pelech, S., Sutter, C., Lin, Q., & Qian, J. (2021). Free Neuropathology, 2, 34. doi:10.17879/freeneuropathology-2021-3679 

A proteomic analysis of heart proteins in FA cardiomyopathy by antibody microarray, Western blots, immunohistochemistry, and double-label laser scanning confocal immunofluorescence microscopy revealed upregulation of desmin and its chaperone protein, αB-crystallin. In normal hearts, these two proteins are co-localized at intercalated discs and Z discs. In FA, desmin and αB-crystallin aggregate, causing chaotic modification of intercalated discs, clustering of mitochondria, and destruction of the contractile apparatus of cardiomyocytes. Western blots of tissue lysates in FA cardiomyopathy reveal a truncated desmin isoprotein that migrates at a lower molecular weight range than wild type desmin. While desmin and αB-crystallin are not mutated in FA, the accumulation of these proteins in FA hearts allows the conclusion that FA cardiomyopathy is a desminopathy akin to desmin myopathy of skeletal muscle.

Epigenetic Heterogeneity in Friedreich Ataxia Underlies Variable FXN Reactivation

Rodden LN, Gilliam KM, Lam C, Lynch DR and Bidichandani SI (2021); Front. Neurosci. 15:752921. doi: 10.3389/fnins.2021.752921 

Treatment of the same PBMCs from this cohort with HDACi-109 significantly increased FXN transcript to levels seen in asymptomatic heterozygous carriers, albeit with the expected inter-individual variability. Response to HDACi-109 correlated significantly with the prevalence of unmethylated and partially methylated FXN molecules, supporting the model that FXN reactivation involves a proportion of genes that are amenable to correction in non-dividing somatic cells, and that heavily methylated FXN molecules are relatively resistant to reactivation. FXN reactivation is a promising therapeutic strategy in FRDA, and inter-individual variability is explained, at least in part, by somatic epigenetic heterogeneity.

Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia

CHICAGO & CAMBRIDGE, Mass., December 10, 2021--(BUSINESS WIRE)--Exicure, Inc.® (NASDAQ: XCUR) announced the results of its previously disclosed independent internal investigation and a number of strategic actions aimed to reduce cash spend and prioritize the Company’s therapeutic pipeline

The results of the investigation are summarized below.

• Beginning in the autumn of 2020, Dr. Corbett misreported raw data from certain research and development experiments related to XCUR-FXN;

• Dr. Corbett misreported the results of at least three different experiments that were conducted through at least February 2021;

• The misreported data related solely to efficacy rather than safety of XCUR-FXN;

• The misreported data was included in various public presentations and SEC filings from as early as January 7, 2021 through as late as August 12, 2021;

Directors has implemented the following approved plan:

• Indefinite suspension of further development of the Company’s XCUR-FXN program for the treatment of Friedreich’s ataxia

• Douglas Feltner, M.D., the Company’s Chief Medical Officer, has agreed to assist in the wind down of the cavrotolimod and XCUR-FXN programs and will depart the Company on January 31, 2022.

Rad9-mediated checkpoint activation is responsible for elevated expansions of GAA repeats in CST-deficient yeast

Spivakovsky-Gonzalez E, Polleys EJ, Masnovo C, Cebrian J, Molina-Vargas AM, Freudenreich CH, Mirkin SM.; Genetics. 2021 Oct 2;219(2):iyab125. doi: 10.1093/genetics/iyab125. 

 Large-scale expansion of (GAA)n repeats in the first intron of the FXN gene is responsible for the severe neurodegenerative disease, Friedreich's ataxia in humans. We have previously conducted an unbiased genetic screen for GAA repeat instability in a yeast experimental system. The majority of genes that came from this screen encoded the components of DNA replication machinery, strongly implying that replication irregularities are at the heart of GAA repeat expansions. This screen, however, also produced two unexpected hits: members of the CST complex, CDC13 and TEN1 genes, which are required for telomere maintenance. To understand how the CST complex could affect intra-chromosomal GAA repeats, we studied the well-characterized temperature-sensitive cdc13-1 mutation and its effects on GAA repeat instability in yeast. We found that in-line with the screen results, this mutation leads to ∼10-fold increase in the rate of large-scale expansions of the (GAA)100 repeat at semi-permissive temperature. Unexpectedly, the hyper-expansion phenotype of the cdc13-1 mutant largely depends on activation of the G2/M checkpoint, as deletions of individual genes RAD9, MEC1, RAD53, and EXO1 belonging to this pathway rescued the increased GAA expansions. Furthermore, the hyper-expansion phenotype of the cdc13-1 mutant depended on the subunit of DNA polymerase δ, Pol32. We hypothesize, therefore, that increased repeat expansions in the cdc13-1 mutant happen during post-replicative repair of nicks or small gaps within repetitive tracts during the G2 phase of the cell cycle upon activation of the G2/M checkpoint.

Longitudinal Assessment Using Optical Coherence Tomography in Patients with Friedreich’s Ataxia

Bogdanova-Mihaylova, P.; Plapp, H.M.; Chen, H.; Early, A.; Cassidy, L.; Walsh, R.A.; Murphy, S.M.; Tomography 2021, 7, 915-931. doi:10.3390/tomography7040076 

Ocular abnormalities occur frequently in Friedreich’s ataxia (FRDA), although visual symptoms are not always reported. We evaluated a cohort of patients with FRDA to characterise the clinical phenotype and optic nerve findings as detected with optical coherence tomography (OCT). A total of 48 patients from 42 unrelated families were recruited. Mean age at onset was 13.8 years (range 4–40), mean disease duration 19.5 years (range 5–43), mean disease severity as quantified with the Scale for the Assessment and Rating of Ataxia 22/40 (range 4.5–38). All patients displayed variable ataxia and two-thirds had ocular abnormalities. Statistically significant thinning of average retinal nerve fibre layer (RNFL) and thinning in all but the temporal quadrant compared to controls was demonstrated on OCT. Significant RNFL and macular thinning was documented over time in 20 individuals. Disease severity and visual acuity were correlated with RNFL and macular thickness, but no association was found with disease duration. Our results highlight that FDRA is associated with subclinical optic neuropathy. This is the largest longitudinal study of OCT findings in FRDA to date, demonstrating progressive RNFL thickness decline, suggesting that RNFL thickness as measured by OCT has the potential to become a quantifiable biomarker for the evaluation of disease progression in FRDA.

The Responsiveness of Gait and Balance Outcomes to Disease Progression in Friedreich Ataxia

Sarah C. Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli, Eppie M. Yiu, Nellie Georgiou-Karistianis, Geneieve Tai, Theresa Zesiewicz, Martin B. Delatycki & Louise A. Corben. Cerebellum (2021). doi:10.1007/s12311-021-01348-2 

In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

Nuclear Factor Erythroid-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Bianca Seminotti1, Mateus Grings, Paolo Tucci, Guilhian Leipnitz1, Luciano Saso; Front. Cell. Neurosci., 26 November 2021 doi:10.3389/fncel.2021.785057 

We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.