Friedreich Ataxia: Clinical Features and New Developments

Keita, Medina; McIntyre, Kellie; Rodden, Layne N.; Schadt, Kim; Lynch, David R.

doi:10.2217/nmt-2022-0011

Cited by 31 publications

(27 citation statements)

References 172 publications

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“…There is a compelling need for protein biomarkers to monitor the natural history of diseases as well as the effect of therapeutic interventions on protein targets involved in the disease. This is particularly relevant to genetic diseases where it is necessary to increase, replace, or remove the dysregulated protein. ,,, There are >7000 rare diseases with dysregulated protein expression that affect >30 million people in the US population . There is also accumulating evidence that dysregulated protein expression is responsible for neurodegenerative diseases such as Alzheimer’s disease, which has been estimated to affect 13.8 million people in the United States by 2050 and 152.8 million worldwide .…”

Section: Discussionmentioning

confidence: 99%

Liquid Chromatography–Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich’s Ataxia

Rojsajjakul

Grady

et al. 2023

Anal. Chem.

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Friedreich’s ataxia (FRDA) is caused primarily by expanded GAA repeats in intron 1 of both alleles of the FXN gene, which causes transcriptional silencing and reduced expression of frataxin mRNA and protein. FRDA is characterized by slowly progressive ataxia and cardiomyopathy. Symptoms generally appear during adolescence, and patients slowly progress to wheelchair dependency usually in the late teens or early twenties with death on average in the 4th decade. There are two known mature proteoforms of frataxin. Mitochondrial frataxin (frataxin-M) is a 130-amino acid protein with a molecular weight of 14,268 Da, and there is an alternatively spliced N-terminally acetylated 135-amino acid form (frataxin-E) with a molecular weight of 14,953 Da found in erythrocytes. There is reduced expression of frataxin in the heart and brain, but frataxin is not secreted into the systemic circulation, so it cannot be analyzed in serum or plasma. Blood is a readily accessible biofluid that contains numerous different cell types that express frataxin. We have found that pig blood can serve as an excellent surrogate matrix to validate an assay for frataxin proteoforms because pig frataxin is lost during the immunoprecipitation step used to isolate human frataxin. Frataxin-M is expressed in blood cells that contain mitochondria, whereas extra-mitochondrial frataxin-E is found in erythrocytes. This means that the analysis of frataxin in whole blood provides information on the concentration of both proteoforms without having to isolate the individual cell types. In the current study, we observed that the distributions of frataxin levels for a sample of 25 healthy controls and 50 FRDA patients were completely separated from each other, suggesting 100% specificity and 100% sensitivity for distinguishing healthy controls from FRDA cases, a very unusual finding for a biomarker assay. Additionally, frataxin levels were significantly correlated with the GAA repeat length and age of onset with higher correlations for extra-mitochondrial frataxin-E than those for mitochondrial frataxin-M. These findings auger well for using frataxin levels measured by the validated stable isotope dilution ultrahigh-performance liquid chromatography–multiple reaction monitoring/mass spectrometry assay to monitor therapeutic interventions and the natural history of FRDA. Our study also illustrates the utility of using whole blood for protein disease biomarker discovery and validation.

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Section: Discussionmentioning

confidence: 99%

Liquid Chromatography–Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich’s Ataxia

Rojsajjakul

Grady

et al. 2023

Anal. Chem.

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“…FRDA, a multi-system, autosomal recessive neurodegenerative disorder and is the most abundantly existing type of hereditary ataxia ( Keita et al, 2022 ). This illness usually starts before the age of 25 with subsequent disease progression including dorsal root ganglia, sensory peripheral nerves, corticospinal tracts, and dentate nuclei of the cerebellum ( Santos et al, 2010 ).…”

Section: The Enigmatic Connection Between Circrnas Autophagy and Neur...mentioning

confidence: 99%

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

Basri

Awan²,

Yang³

et al. 2023

Front. Mol. Neurosci.

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Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich’s ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.

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“…Az ebbe a csoportba tartozó Friedreich-ataxia egy autoszomális recesszív betegség, amelynek oka az FRDA-gén első intronjában található GAA-ismétlődés hosszának növekedése. A tünetek általában fiatal felnőtt korban kezdődnek járászavarral és végtagügyetlenséggel, amelyhez a későbbiekben diabétesz, gerincdeformitás és kardiomiopátia is társulhat (Keita et al, 2022). A kezelésére sajnos csak rendkívül szerény lehetőségek állnak rendelkezésünkre, és azok is elsősorban tüneti hatásúak.…”

Section: Magyar Tudomány 184(2023)1unclassified

Extrapiramidális kórképek • Movement Disorders

Klivényi¹,

Vécsei²

2023

Ma.Tud.

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Az extrapiramidális betegségek vagy más néven neurológia eredetű mozgászavarok az öregedő társadalomban egyre nagyobb kihívást jelentenek. Annak ellenére, hogy ritka betegségnek számítanak, az előfordulási gyakoriságuk alapján a legtöbb egészségügyi szolgáltató praxisa során találkozni fog velük. A kórképek felismerése számos differenciáldiagnosztikai és terápiás nehézséget okozhat, és a páciensek ellátása legtöbb esetben multidiszciplináris megközelítést és speciális tudást igényel. Ezt a munkát segítik a folyamatosan fejlesztett szakmai irányelvek, nemzetközi konzorciumok és különböző szakmai szervezetek által szervezett folyamatos továbbképzések. Jelen összeállításban a leggyakoribb kórképek kerülnek ismertetésre.

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Friedreich Ataxia: Clinical Features and New Developments

Cited by 31 publications

References 172 publications

Liquid Chromatography–Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich’s Ataxia

Liquid Chromatography–Mass Spectrometry Analysis of Frataxin Proteoforms in Whole Blood as Biomarkers of the Genetic Disease Friedreich’s Ataxia

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

Extrapiramidális kórképek • Movement Disorders

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