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Spinocerebellar ataxia 27 B (SCA27B) is caused by the expansion of GAA repeats in the intron of the fibroblast growth factor 14 (FGF14) on chromosome 13 and is inherited dominantly. An 80‐year‐old male visited the hospital complaining of ataxic gait and harboring 229 pure GAA repeat units in the FGF14. Almost all the clinical features were similar to that of SCA27B. However, the patient initially presented with episodic grip myotonia, which has not been previously reported. [ABSTRACT FROM AUTHOR]

Introduction:- Friedreich’s ataxia is anautosomal recessive disease due to a mutationin gene X25. This gene codes for frataxin and itis located on chromosome 9. The disease iscaused by a triplet particular sequence of bases(GAA). Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich’sataxia, it can be repeated hundreds or even overthousand times.Objectives:To determine if there is a correlationbetween clinical and molecular findingsin our FRDA patients.Methods: Eleven patients with the typicalFriedreich´s ataxia phenotype were studied byPCR we determined the size of the GAA expansions,and analyzed the correlation of age at onset andrate of disease progression with the number ofGAA repetitions.Results and conclusions: Molecular analysisby PCR showed eight homozygous patientsfor the expansion and three negative. The averageof the size of the expansions in the allelewas of 622±5 with an average in the age ofbeginning of 13±8. For the sample size, therewas no significant statistical correlation betweenthe age of beginning of the disease and thenumber of repetitions, although there was likean inverse correlation.Besides understanding of FRDA physiology andthe Harding clinical inclusion criteria, moleculardiagnosis is an important step in the achievementof an optimal therapeutic treatment.

Friedreich's ataxia, an autosomal recessive disorder, is caused by tandem GAA nucleotide repeat expansions in intron 1 of the frataxin gene. The GAA repeats over 66 in number are considered as pathogenic, and commonly occurring pathogenic repeats are within a range of 600-1200. Clinically, the spectrum of features is confined mainly to neurological tissues; however, cardiomyopathy and diabetes mellitus have been reported in 60 and 30% of the subjects, respectively. The accurate detection of GAA repeat count is of utmost importance for clinical genetic correlation, and no study so far has attempted an approach that is of high-throughput nature and defines the exact sequence of GAA repeats. Largely, the method for detection of GAA repeats so far is either through the conventional polymerase chain reaction-based screening or Southern blot, which remains the gold standard method. We utilized an approach of long-range targeted amplification of FXN -GAA repeats using Oxford Nanopore Technologies MinION platform for accurate estimation of repeat length. We were able to achieve successful amplification of GAA repeats ranging from ∼120 to 1100 at ∼2600× mean coverage. The total throughput achievable through our protocol can allow for screening of up to 96 samples per flow cell in less than 24 h. The proposed method is clinically scalable and deployable for day-to-day diagnostics. In this paper, we demonstrate to resolve the genotype-phenotype correlation of Friedreich's ataxia patients with better accuracy., Competing Interests: No authors report competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination ofFXNtranscription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia. [ABSTRACT FROM PUBLISHER]

Friedreich's ataxia (FRDA) is the most common of the inherited ataxias and is associated with GAA trinucleotide repeat expansions within the first intron of the frataxin (FXN) gene. There are expanded FXN alleles from 66 to 1,700 GAA·TTC repeats in FRDA patients and correlations between number of GAA repeats and frataxin protein levels are assumed. Here, we present for the first time frataxin protein levels as well as analysis of GAA triplet repeats in the FXN gene in a population of 50 healthy Austrian people. Frataxin protein levels were measured in lymphocytes from blood samples by ELISA and GAA repeats were analyzed by capillary electrophoresis. Rather unexpectedly, we found a high variation of frataxin protein levels among the individuals. In addition, there was no correlation between frataxin levels, GAA repeats, age and sex in this group. However, these findings are of great importance for better characterization of the disease. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FRDA) is caused by expansion of GAA repeats in the frataxin ( FXN) gene on chromosome 9q13-q21.1. We analysed the origin of FRDA in 21 North Indian (NI) and eight South Indian (SI) families using five single nucleotide polymorphisms (SNPs) and a microsatellite marker spanning the GAA repeats. The NI and SI families were derived from Indo-European and Dravidian linguistic backgrounds respectively. The frequency of large normal (LNs) alleles of the GAA repeat correlate with the overall lower prevalence of FRDA in India compared to the European population. All of the expanded alleles in the Indian population share a common core haplotype suggesting a founder effect. The expanded alleles in the NI population demonstrate more similarity to those of Europeans in terms of age of GAA repeat expansion (15975 ± 2850 years) and association of LNs with expanded alleles. FRDA seems to have been introduced recently in the South Indian population since the average estimated age of the mutation in SI is 5425 ± 1750 years and unlike NI some of the haplotypes of LNs are not associated with the expanded alleles. [ABSTRACT FROM AUTHOR]

Friedreich's Ataxia (FRDA) is a very common cause of hereditary autosomal recessive ataxia among western Europeans. We aim to define the frequency of FRDA in Chinese Han population due to the lack of reports of FRDA in China. The GAA trinucleotide repeats in the FXN gene were analyzed by triplet repeat-primed PCR (TP-PCR) in 122 unrelated hereditary ataxia (HA) and 114 unrelated hereditary spastic paraplegia (HSP) patients. The GAA copy numbers in the FXN gene of all the subjects ranged from 5 to 16. There were no FRDA patients that could be diagnosed base on the results of TP-PCR. It suggests that FRDA is a very rare cause of inheritance ataxia and FRDA genetic analysis should not be used as a routine genetic diagnosis test in China. [ABSTRACT FROM AUTHOR]

Objectives – Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by expansion of GAA repeats in the frataxin gene. We have carried out the first molecular analysis at the Friedreich's ataxia locus in the Indian population. Materials and methods – Three families clinically diagnosed for Friedreich's ataxia were analyzed for GAA expansion at the FRDA locus. The distribution of GAA repeats was also estimated in normal individuals of Indian origin. Results – All patients clinically diagnosed for Friedreich's ataxia were found to be homozygous for GAA repeat expansion. The GAA repeat in the normal population show a bimodal distribution with 94% of alleles ranging from 7–16 repeats. Conclusion – Indian patients with expansion at the FRDA locus showed typical clinical features of Friedreich's ataxia. The low frequency of large normal alleles (6%) could indicate that the prevalence of this disease in the Indian population is likely to be low. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia is caused by large homozygous, intronic expansions of GAA repeats in the frataxin (FXN) gene, resulting in severe downregulation of its expression. Pathogenic repeats are located in intron one, hence patients express unaffected FXN protein, albeit in low quantities. Although FRDA symptoms typically afflict the nervous system, hypertrophic cardiomyopathy is the predominant cause of death. Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease. • Decreased frataxin expression in FRDA iPSC derived cardiomyocytes • Lipid droplet accumulation in FRDA cardiomyocytets • Cardiac hypertrophy expression signature FRDA cardiomyocytets • Frataxin deficiency alleviated by excision of expanded GAA repeats. • Reduced lipid droplet accumulation and reversal of gene expression changes upon correction of frataxin gene. [ABSTRACT FROM AUTHOR]