scholarly journals Friedreich's ataxia: clinical and molecular study of 25 Brazilian cases

2001 ◽  
Vol 56 (5) ◽  
pp. 143-148 ◽  
Author(s):  
Lilian M. J. Albano ◽  
Mayana Zatz ◽  
A. Kim Chong ◽  
Débora Bertola ◽  
Sofia M. M. Sugayama ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Age At Onset ◽  
Cranial Nerves ◽  
Autosomal Recessive Inheritance ◽  
Molecular Study ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Expansion ◽  
Neurologic Findings

INTRODUCTION: Friedreich's ataxia is a neurodegenerative disorder whose clinical diagnostic criteria for typical cases basically include: a) early age of onset (< 20 or 25 years), b) autosomal recessive inheritance, c) progressive ataxia of limbs and gait, and d) absence of lower limb tendon reflexes. METHODS: We studied the frequency and the size of expanded GAA and their influence on neurologic findings, age at onset, and disease progression in 25 Brazilian patients with clinical diagnosis of Friedreich's ataxia - 19 typical and 6 atypical - using a long-range PCR test. RESULTS: Abnormalities in cerebellar signs, in electrocardiography, and pes cavus occurred more frequently in typical cases; however, plantar response and speech were more frequently normal in this group when the both typical and atypical cases were compared. Homozygous GAA expansion repeats were detected in 17 cases (68%) - all typical cases. In 8 patients (32%) (6 atypical and 2 typical), no expansion was observed, ruling out the diagnosis of Friedreich's ataxia. In cases with GAA expansions, foot deformity, cardiac abnormalities, and some neurologic findings occurred more frequently; however, abnormalities in cranial nerves and in tomographic findings were detected less frequently than in patients without GAA expansions. DISCUSSION: Molecular analysis was imperative for the diagnosis of Friedreich's ataxia, not only for typical cases but also for atypical ones. There was no genotype-phenotype correlation. Diagnosis based only on clinical findings is limited; however, it aids in better screening for suspected cases that should be tested. Evaluation for vitamin E deficiency is recommended, especially in cases without GAA expansion.

scholarly journals Molecular Analysis of Friedreich's Ataxia in Macedonian Patients

2008 ◽  
Vol 11 (1) ◽  
pp. 61-64 ◽  
Author(s):  
S Kocheva ◽  
S Trivodalieva ◽  
S Vlaski-Jekic ◽  
M Kuturec ◽  
G Efremov
Keyword(s):  
Molecular Analysis ◽  
Early Onset ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Autosomal Recessive Inheritance ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
The Republic ◽  
Gaa Repeats ◽  
Frataxin Gene

Molecular Analysis of Friedreich's Ataxia in Macedonian PatientsFriedreich's ataxia (FRDA) is rare a progressive neurodegenerative disorder of autosomal recessive inheritance, which is associated with an unstable expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. We have performed molecular analyses of the frataxin gene of 40 patients with spinocerebellar ataxia from the Republic of Macedonia. Fifteen had early onset of progressive ataxia (before the age of 25), while the remainder were over 25 years old at the time of diagnosis. Only 14 patients had a mutation in the frataxin gene and all of these had early onset ataxia. The number of GAA repeats was in the normal range in 50 healthy individuals.

GAA expansion size and age at onset of Friedreich's ataxia

Neurology ◽  
2003 ◽  
Vol 61 (2) ◽  
pp. 274-275 ◽  
Author(s):  
I. Mateo ◽  
J. Llorca ◽  
V. Volpini ◽  
J. Corral ◽  
J. Berciano ◽  
...  
Keyword(s):  
Age At Onset ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Gaa Expansion

scholarly journals Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Dorra Hmida-Ben Brahim ◽  
Marwa Chourabi ◽  
Sana Ben Amor ◽  
Imed Harrabi ◽  
Saoussen Trabelsi ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Age At Onset ◽  
Specific Effect ◽  
Modifier Genes ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cag Expansion ◽  
Tunisian Patients

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO) of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

scholarly journals New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Alessandra Bolotta ◽  
Provvidenza Maria Abruzzo ◽  
Vito Antonio Baldassarro ◽  
Alessandro Ghezzo ◽  
Katia Scotlandi ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Neurodegenerative Disorder ◽  
Cell Types ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cardiac Cells ◽  
Cardiac Differentiation ◽  
Specific Cell ◽  
Differentiation Markers ◽  
Cardiac Iron

Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich’s ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis.

scholarly journals Complex I and ATP Content Deficiency in Lymphocytes from Friedreich's Ataxia

2009 ◽  
Vol 36 (1) ◽  
pp. 26-31 ◽  
Author(s):  
Mohammad Mehdi Heidari ◽  
Massoud Houshmand ◽  
Saman Hosseinkhani ◽  
Shahriar Nafissi ◽  
Mehri Khatami
Keyword(s):  
Respiratory Chain ◽  
Complex I ◽  
Age Of Onset ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Iron Accumulation ◽  
Atp Content ◽  
Respiratory Chain Complexes ◽  
Intracellular Atp ◽  
Complex I Activity

Background:Friedreich's ataxia (FRDA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. A deficiency in the protein frataxin causes this disease. Frataxin deficiency leads to progressive iron accumulation in mitochondria, excessive free radical production and dysfunction of respiratory chain complexes. The expansion (GAA) repeat in the first intron causes decreased frataxin expression by interfering with transcription.Methods:Activity of mitochondrial respiratory chain complex I (measured as NADH ferricyanide reductase) and intracellular ATP measurement was performed on lymphocyte of FRDA patients (n=12) and control subjects (n=25).Results:Our findings showed that complex I activity and intracellular ATP were significantly reduced (P=0.001) in patients compared with controls and we found strong correlation between complex I activity and intracellular ATP content in FRDA patients (r = 0.93; P<0.002). 8.6 and 9.0 kb deletion in mtDNA was detected in 9 patients out of 12 (75%) by multiplex polymerase chain reaction (PCR) and Southern blot analysis.Conclusions:This study suggested that a biochemical defect in complex I activity and ATP production, which may be due to iron accumulation in mitochondria, can be involved in age of onset of FRDA.

scholarly journals The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals

2010 ◽  
Vol 432 (1) ◽  
pp. 165-172 ◽  
Author(s):  
René Thierbach ◽  
Gunnar Drewes ◽  
Markus Fusser ◽  
Anja Voigt ◽  
Doreen Kuhlow ◽  
...  
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Disorder ◽  
Excision Repair ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Liver Tumours ◽  
Dna Repair Mechanisms ◽  
Dna Base ◽  
Repair Mechanisms ◽  
Base Excision

DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.

scholarly journals Late-onset Huntington’s disease with 40–42 CAG expansion

2019 ◽  
Vol 41 (4) ◽  
pp. 869-876 ◽  
Author(s):  
Elisa Capiluppi ◽  
Luca Romano ◽  
Paola Rebora ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Cag Repeats ◽  
Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

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

Tomography ◽  
2021 ◽  
Vol 7 (4) ◽  
pp. 915-931
Author(s):  
Petya Bogdanova-Mihaylova ◽  
Helena Maria Plapp ◽  
Hongying Chen ◽  
Anne Early ◽  
Lorraine Cassidy ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Disease Severity ◽  
Disease Duration ◽  
Age At Onset ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Optical Coherence ◽  
Longitudinal Assessment ◽  
Ocular Abnormalities ◽  
Rnfl Thickness

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.

scholarly journals The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

2020 ◽  
Vol 21 (3) ◽  
pp. 916 ◽  
Author(s):  
Piergiorgio La Rosa ◽  
Enrico Silvio Bertini ◽  
Fiorella Piemonte
Keyword(s):  
Cellular Response ◽  
Iron Homeostasis ◽  
Nuclear Translocation ◽  
Neurodegenerative Disorder ◽  
Mitochondrial Protein ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Signaling Network ◽  
Related Factor ◽  
Clinical Biomarkers

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

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