Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a severe autosomal recessive genetic disorder of the central nervous (CNS) and peripheral nervous system (PNS), affecting children and young adults. Its onset is before 25 years of age, with mean ages of onset and death between 11 and 38 years, respectively. The incidence is 1 in 30,000–50,000 persons. It is caused, in 97% of cases, by a homozygous guanine-adenine-adenine (GAA) trinucleotide mutation in the first intron of the frataxin (FXN) gene on chromosome 9 (9q13–q1.1). The mutation of this gene causes a deficiency of frataxin, which induces an altered inflow of iron into the mitochondria, increasing the nervous system’s vulnerability to oxidative stress. The main clinical signs include spinocerebellar ataxia with sensory loss and disappearance of deep tendon reflexes, cerebellar dysarthria, cardiomyopathy, and scoliosis. Diabetes, hearing loss, and pes cavus may also occur, and although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.
Highlights
Overview of Friedreich Ataxia DiseaseWithin the spinocerebellar ataxias, Friedreich’s ataxia (FRDA) is the most common autosomal recessive hereditary form [1,2]
In 60% of FRDA patients, nystagmus caused by horizontal gaze occurs [44] [44], and spontaneous vertical nystagmus in the dark was observed in 45% of the patients studied that correlated with the duration of the disease [44]
FRDA patients have a severe two-sided Vestibulo-Ocular Reflexes (VOR) impairment and normal saccadic velocity, which is a clinical hallmark of FRDA and distinguishes it from several spinocerebellar ataxias of dominant inheritance; these eye movements could be used as biomarkers for this disease [44,47]
Summary
Friedreich’s ataxia (FRDA) is the most common autosomal recessive hereditary form [1,2]. The FXN gene encodes frataxin (FXN), a small, long mitochondrial protein that, in the human body, is found in high concentrations in the cells of the heart, spinal cord, liver, pancreas, and voluntary movement muscles [10]. The mutation in this gene causes a deficiency of FXN, which leads to (i) insufficient biosynthesis of iron-sulfur (Fe-S) groups that are necessary for mitochondrial electron transport and the functional assembly of aconitase, and (ii) impaired iron metabolism in the cell [8]. The effect of the FXN mutation leads to an altered iron supply to the mitochondria, increasing the vulnerability of the nervous system to oxidative stress, including the visual pathway [11,12,13]
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