Very-late-onset Friedreich’s ataxia: diagnosis in a kindred with late-onset cerebellar ataxia

Fearon, Conor; Lonergan, Roisin; Ferguson, Damien; Byrne, Susan; Bradley, David; Langan, Yvonne; Redmond, Janice

doi:10.1136/practneurol-2019-002368

Cited by 9 publications

(8 citation statements)

References 15 publications

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“…9 For late-onset FRDA, 10 qualitative phenotypic differences appear 11,12 using AOO thresholds of 25 years 13 and even 40 years. 14 Based on these findings, a 4-group stratification might prove useful: early-onset (0-7 years), typical Onset (8-14 years), intermediate-onset (15-24 years), and late-onset FRDA (older than 24 years). While transitions will always be fluid and might imperfectly represent the continuous nature of the causal defect, such grouping can help to identify subgroups with more homogeneous progression and support the understanding of clinical cohort structures beyond simple summary statistics.…”

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confidence: 99%

Natural History of Friedreich Ataxia

et al. 2022

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Background– The understanding of the natural history of Friedreich's ataxia has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this work was to acknowledge the broad genetic diversity of the population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies.Methods– Based on a large natural history study, the Friedreich’s Ataxia Clinical Outcome Measures study (FACOMS) that at the current data cut enrolled 1115 participants, followed up for 5287 yearly visits, we present results from the modified Friedreich’s Ataxia Rating Scale and its sub scores. Secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk and the 9-hole peg test. Long-term progression was modeled using slope analyses within Early, Typical, Intermediate and Late Onset Friedreich's Ataxia. To reflect recruitment in clinical trials, short term changes were analyzed within age-based sub-populations. All analyses were stratified by ambulation status.Findings– Long term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages of onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability sub score of the mFARS. The analyses of short-term changes showed slower progression with increasing population age, as a result of decreasing genetic severity. Future clinical studies could reduce population diversity, inter-patient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification.Interpretation– Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.

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confidence: 99%

Natural History of Friedreich Ataxia

et al. 2022

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“…The frequency and severity of cardiomyopathy was found to be related to the length of the GAA repeat expansion, 8,9,16 young age at onset of FRDA, 5 angiotensin II type 1 receptor polymorphism, 17 but not to neurological involvement or severity 5,9,18 . Patients with delayed‐onset FRDA (≥25 years) do not commonly exhibit typical clinical features of cardiac disease 10,12,19–22 . Likewise, compound heterozygous patients (approximately 4% of FRDA cases) are less likely to present cardiomyopathy than homozygous GAA expansion carriers 23 …”

Section: Resultsmentioning

confidence: 99%

“…5,9,18 Patients with delayed-onset FRDA (≥25 years) do not commonly exhibit typical clinical features of cardiac disease. 10,12,[19][20][21][22] Likewise, compound heterozygous patients (approximately 4% of FRDA cases) are less likely to present cardiomyopathy than homozygous GAA expansion carriers. 23 The pathogenesis of cardiomyopathy in FRDA involves a severe reduction of cardiac frataxin levels, failure to clear iron from myocytes, ferroptosis (a recently identified pathway of regulated, iron-dependent cell death, distinct from apoptosis), lack of oxidative phosphorylation, reduced adenosine triphosphate production, chronic inflammation, and disorganization of intercalated discs (plasma membrane specializations that connect heart fibers end to end and provide mechanical cohesion and ionic coupling).…”

Section: Frda (Or Atx-fxn)mentioning

confidence: 99%

Cardiac Involvement in Movement Disorders

Rossi

Wainsztein

Merello

2021

Movement Disord Clin Pract

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BackgroundBackground: Several conditions represented mainly by movement disorders are associated with cardiac disease, which can be overlooked in clinical practice in the context of a prominent primary neurological disorder. Objectives Objectives: To review neurological conditions that combine movement disorders and primary cardiac involvement. Methods Methods: A comprehensive and structured literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was conducted to identify disorders combining movement disorders and cardiac disease. ResultsResults: Some movement disorders are commonly or prominently associated with cardiac disease. Neurological and cardiac symptoms may share underlying physiopathological mechanisms in diseases, such as Friedreichʼs ataxia and Wilsonʼs disease, and in certain metabolic disorders, including Refsum disease, Gaucher disease, a congenital disorder of glycosylation, or cerebrotendinous xanthomatosis. In certain conditions, such as Sydenhamʼs chorea or dilated cardiomyopathy with ataxia syndrome (ATX-DNAJC19), heart involvement can present early in the course of disease, whereas in others such as Friedreichʼs ataxia or Refsum disease, cardiac symptoms tend to present in later stages. In another 68 acquired or inherited conditions, cardiac involvement or movement disorders are seldom reported. Conclusions Conclusions: As cardiac disease is part of the phenotypic spectrum of several movement disorders, heart involvement should be carefully investigated and increased awareness of this association encouraged as it may represent a leading cause of morbidity and mortality.Cardiac abnormalities may be a significant source of morbidity and premature mortality [1][2][3][4] and can occur in numerous neurological diseases, manifesting as cardiomyopathy, arrhythmias, conduction defects, structural malformations, coronary disease, valvulopathies, or cardiac autonomic dysfunction. In neurological conditions mainly manifested by movement disorders, cardiac disease can be a frequent and predominant clinical feature, or only be reported in isolated cases, and can be of early presentation, or occur only during later stages of disease. 5,6 In diseases such as Friedreichʼs ataxia (FRDA), where the need for heart monitoring is well established, a cross-sectional healthcare resource study revealed that recommended annual cardiac evaluations had not been conducted in up to 23% of patients with FRDA in the United States and 14% in Canada. 7 These figures may be even higher in other parts of the world.In this educational review, we describe and list movement disorders with cardiac involvement as part of the clinical picture. MethodsA comprehensive and structured search in PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (http://www.prismastatement.org) was conducted.

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“…Our shFXN model may be considered a mild knockdown due to the retention of 61% of protein expression in the shFXN hBMVEC compared to EVEC, whereas classical FRDA patients retain on average only 30%. It should be noted that while the GAA-expansion mutation in teenage years is the most common FRDA cause, ∼2-5% of patients develop disease due to a single-allele point mutation (pFA), and “late onset Friedreich’s Ataxia” (LOFA) represents about 25% of the disease cohort 74, 75 . Residual FXN protein levels vary in these cases, with 33% FXN retention in pFA, and 65.6% in LOFA 75 .…”

Section: Discussionmentioning

confidence: 99%

Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable –implications for blood-brain barrier integrity in Friedreich’s Ataxia

Smith

Kosman

2023

Preprint

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Friedreich's Ataxia (FRDA) is the most prevalent inherited ataxia; the disease results from loss of Frataxin, an essential mitochondrial iron trafficking protein. FRDA presents as neurodegeneration of the dorsal root ganglion and cerebellar dentate nuclei, followed by brain iron accumulation in the latter. End stage disease includes cardiac fibrosis that contributes to hypertrophic cardiomyopathy. The microvasculature plays an essential barrier role in both the brain and heart, thus an investigation of this tissue system in FRDA is essential to the delineation of the cellular dysfunction in this genetic disorder. Here, we investigate brain microvascular endothelial cell integrity in FRDA in a model of the blood-brain barrier (BBB). We used lentiviral mediated shRNA delivery to generate a novel FRDA model in immortalized human brain microvascular endothelial cells (hBMVEC) that compose the microcapillaries of the BBB. We verified known cellular pathophysiologies of FXN knockdown including increased oxidative stress, loss of energy metabolism, and increased cell size. Furthermore, we investigated cytoskeletal architecture including the abundance and organization of filamentous actin, and barrier physiology via transendothelial electrical resistance and fluorescent tracer flux. shFXN hBMVEC display the known FRDA cell morbidity including increased oxidative stress, decreased energy metabolism, and an increase in cell size. We demonstrate that shFXN hBMVEC have less overall filamentous actin, and that filamentous actin is lost at the cell membrane and cortical actin ring. Consistent with loss of cytoskeletal structure and anchorage, we found decreased barrier strength and increased paracellular tracer flux in the shFXN hBMVEC transwell model. We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and increased barrier permeability, cell pathologies that may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Our findings implicate other barrier cells, e.g., the cardiac microvasculature, likely contributory also to disease pathology in FRDA.

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Very-late-onset Friedreich’s ataxia: diagnosis in a kindred with late-onset cerebellar ataxia

Cited by 9 publications

References 15 publications

Natural History of Friedreich Ataxia

Natural History of Friedreich Ataxia

Cardiac Involvement in Movement Disorders

Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable –implications for blood-brain barrier integrity in Friedreich’s Ataxia

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