Friedreich’s Ataxia Misdiagnosed as Lumbar Disc Prolapse: Case Report

Naglaa Hussein, Matthew Bartels, Mohammad Dwary; Int J Phys Med Rehabil, Vol.9 Iss.5 No:1000614

Chronic low back pain not responding to the usual treatment, particularly associated with balance and gait disturbance, could be, although rarely, a presenting feature of Friedreich’s ataxia and full clinical and electrophysiological examination should be conducted to prove or disprove such diagnosis.

TQS-168: ALS and exploratory development ongoing in Friedreich’s Ataxia and other indications

Tranquis Therapeutics, Inc., 01/10/2022; 

Our initial therapeutic candidates have been designed to cross the blood brain barrier and modulate microglia in the brain to treat a range of immune-mediated and mitochondrial diseases, starting with amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, and other indications (e.g. Frontotemporal Dementia (FTD), Huntington’s Disease, Friedreich’s Ataxia, Muscular Dystrophy, Parkinson’s, and Alzheimer’s disease). 

Because our platform targets such fundamental cell energy modulators, like PGC1α, present in all mammalian cells, it appears to have clinical utility across a broad range of immune-mediated and mitochondrial diseases—beyond the CNS. 

TQS-168 ALS and exploratory development ongoing in Frontotemporal Dementia, Huntington’s Disease, Muscular Dystrophy, Friedreich’s Ataxia and other indications

Magnetic resonance imaging evaluation of spinal cord lesions: what can we find? - Part 1. Neoplastic, vascular, metabolic, and traumatic injuries

Pereira RG, Ribeiro BNF, Pereira TRGC, Bahia PRV, Marchiori E.; Radiologia Brasileira. 2021 Nov-Dec;54(6):406-411. DOI: 10.1590/0100-3984.2020.0127. PMID: 34866701; PMCID: PMC8630944. 

Friedreich ataxia: On MRI, the spinal cord may show a reduction in its anteroposterior diameter, together with changes in signal intensity in its posterior and lateral columns.

Transcriptional Analysis of Nuclear-Encoded Mitochondrial Genes in Eight Neurodegenerative Disorders: The Analysis of Seven Diseases in Reference to Friedreich's Ataxia

Elsadany M, Elghaish RA, Khalil AS, Ahmed AS, Mansour RH, Badr E, Elserafy M.; Front Genet. 2021 Dec 20;12:749792. doi: 10.3389/fgene.2021.749792. PMID: 34987545; PMCID: PMC8721009. 

In this study, we analyzed the transcriptional changes of nuclear-encoded mitochondrial (NEM) genes in eight NDDs to specifically address the association of these genes with the diseases. Previous studies show strong links between defects in NEM genes and neurodegeneration, yet connecting specific genes with NDDs is not well studied. Friedreich's ataxia (FRDA) is an NDD that cannot be treated effectively; therefore, we focused first on FRDA and compared the outcome with seven other NDDs, including Alzheimer's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease, multiple sclerosis, and Parkinson's disease.

The dynamin-related protein 1 is decreased and the mitochondrial network is altered in Friedreich’s ataxia cardiomyopathy

Bojjibabu Chidipi, Mariana Burgos Angulo, Syed Islamuddin Shah, Michelle Rieser, Ganim Ullah, Thomas V. McDonald, Sami F. Noujaim; The International Journal of Biochemistry & Cell Biology, Volume 143, 2022, 106137, doi:10.1016/j.biocel.2021.106137. 

 We found a significantly higher mitochondrial footprint, decreased mitochondrial fission protein dynamin-related protein, and mitochondrial fission rate over fusion with more giant mitochondrial clusters in human induced pluripotent stem cell derived cardiomyocytes from a patient with Friedreich ataxia hypertrophic cardiomyopathy, compared to an unaffected individual. We also found significantly depolarized mitochondrial membrane potential and higher reactive oxygen species levels in Friedreich ataxia human induced pluripotent stem cell cardiomyocytes. Our results show that frataxin's depletion may dampen the mitochondrial fission machinery by reducing dynamin-related protein1. The loss of mitochondrial fission might lead to elevated reactive oxygen species and depolarized mitochondrial membrane potential, which may cause oxidative damage in Friedreich ataxia hypertrophic cardiomyopathy. Further investigations are needed to identify the mechanism of downregulating dynamin-related protein1 due to the frataxin deficiency in Friedreich ataxia hypertrophic cardiomyopathy.

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.