Friedreich's Ataxia: Clinical Aspects and Pathogenesis

Abstract

Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.

Assessment of Whole-Brain White Matter by DTI in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

“…These features can also contribute to differentiation of ARSACS from other degenerative diseases of mainly axonal neuropathy, such as Friedreich ataxia. 25 In our study, a widespread WM abnormality is being documented first in ARSACS, in contrast to more localized involvement of WM in the superior cerebellar peduncles and peridentate area in Friedreich ataxia. 26,27 Iron deposition in the basal ganglia and thalami and lipofuscin-like dens material within the lysosomes of swollen thalamic and cerebellar cortical neurons were suggested to cause T2 hypointensity in the pons and middle cerebellar peduncles.…”

Iron, Aging, and Neurodegeneration

“…Friedreich's Ataxia is the most common of the ataxias and affects adolescents [27]. The disease is caused by mutations in the gene for frataxin, a protein found in the mitochondria that is associated with the assembly of Fe-S clusters and may act as an iron chaperone [28].…”

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

“…However, the ability of the brain to withstand oxidative stress is limited because of: (a) a high content of easily oxidizable substrates, such as polyunsaturated fatty acids and catecholamines; (b) relatively low levels of antioxidants such as glutathione and vitamin E and antioxidant enzymes (such as glutathione peroxidase, catalase and superoxide dismutase); (c) the endogenous generation of reactive oxygen free radicals via several specific reactions; (d) the elevated content of iron in specific areas of the human brain, such as globus pallidus and substantia nigra (SN), while cerebrospinal fluid has very little iron-binding capacity owing to its low content of transferrin; (e) CNS contains non-replicating neuronal cells which, once damaged, may be permanently dysfunctional or committed to programmed cell death (apoptosis). Moreover, it is becoming increasingly clear that the mitochondrial genome may play an essential role in neurodegenerative diseases, such as FRDA [9]. It is generally recognized that, in addition to the nuclear genome, each human cell contains multiple copies of a small double-stranded mitochondrial genome.…”