Friedreich’s Ataxia: A New Mutation in Two Compound Heterozygous Siblings with Unusual Clinical Onset

Lamba, L. Doria; Ciotti, Paola; Giribaldi, Gaia; Maria, Emilio Di; Varese, Alessandra; Stadio, M. Di; Schenone, Angelo; Mandich, Paola; Bellone, Emilia

doi:10.1159/000198417

Cited by 5 publications

(2 citation statements)

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“…We examined 242 individuals with FRDA: 111 were compound heterozygous for a GAA expansion in intron 1 of FXN and a point/deletion/insertion mutation in the second FXN allele, and 131 were homozygous for a GAA expansion. We studied clinical outcome in each compound heterozygous individual, with data for 81 cases obtained from published literature . Information from an additional 30 unpublished cases confirmed as compound heterozygotes using standard diagnostic sequencing has been included in this study.…”

Section: Methodsmentioning

confidence: 99%

Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia

Galea

Huq

Lockhart

et al. 2016

Annals of Neurology

133

127

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Section: Methodsmentioning

confidence: 99%

Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia

Galea

Huq

Lockhart

et al. 2016

Annals of Neurology

133

127

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“…The repeats are located within the first intron of the nuclear FXN gene, and expansion above a certain threshold (above~60 repeats) causes inhibition of gene transcription, leading to lower levels of FXN mRNA and protein. Although~96-98% of FRDA patients are homozygous for the GAA•TTC triplet repeat expansion in the FXN gene [10], a small number of patients have one expanded allele and a second allele harboring either a premature stop codon, various point mutations, frameshift mutations, deletions, or splice site mutations [10][11][12][13][14]. Patient repeat alleles are most often between 600 and 900 repeats but repeats as long as 1700 have been reported (reviewed in [15]).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia

Gottesfeld

2019

Neurotherapeutics

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Friedreich ataxia (FRDA), the most common inherited ataxia, is caused by transcriptional silencing of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin. Currently, there is no approved therapy for this fatal disorder. Gene silencing in FRDA is due to hyperexpansion of the triplet repeat sequence GAA•TTC in the first intron of the FXN gene, which results in chromatin histone modifications consistent with heterochromatin formation. Frataxin is involved in mitochondrial iron homeostasis and the assembly and transfer of iron-sulfur clusters to various mitochondrial enzymes and components of the electron transport chain. Frataxin insufficiency leads to progressive spinocerebellar neurodegeneration, causing symptoms of gait and limb ataxia, slurred speech, muscle weakness, sensory loss, and cardiomyopathy in many patients, resulting in death in early adulthood. Numerous approaches are being taken to find a treatment for FRDA, including excision or correction of the repeats by genome engineering methods, gene activation with small molecules or artificial transcription factors, delivery of frataxin to affected cells by protein replacement therapy, gene therapy, or small molecules to increase frataxin protein levels, and therapies aimed at countering the cellular consequences of reduced frataxin. This review will summarize the mechanisms involved in repeat-mediated gene silencing and recent efforts aimed at development of therapeutics.

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