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Friedreich ataxia (FRDA) is an autosomal recessive disorder defined by progressive motor incoordination. FRDA results from reduced expression of the protein, frataxin, which is involved in cellular iron homeostasis and metabolism, antioxidant protection, and iron-sulfur cluster biogenesis. Disruption of one or more of these processes putatively underpins the pathophysiology of FRDA, which manifests in cell death preferentially targeted to tissues with high rates of frataxin transcription.1
In the brain, accumulation or redistribution of iron within, and atrophy of, the cerebellar dentate nuclei have been reported.1–3 The dentate nuclei are iron-laden structures pivotal to movement coordination. However, basal ganglia and midbrain structures also have high iron content, express high levels of frataxin, and play key roles in motor regulation. Furthermore, the dentate nuclei directly innervate the thalamus and red nuclei, and indirectly project to the striatum. This biology motivates the hypothesis that iron-related pathology and/or degeneration within these extrapyramidal stations may also feature in FRDA. To test this hypothesis, we analysed tissue volume and iron concentration within the dentate nuclei, midbrain (red nuclei, substantia nigra), basal ganglia (caudate, putamen and pallidum), and thalami in individuals with FRDA and healthy controls using magnetic resonance imaging (MRI).
Whole-brain 3 T MRI were acquired from 30 individuals with genetically-confirmed FRDA (35.7±12.2 years; 17 males) and 33 healthy controls (36.9±13.1 years; 18 males; see online supplementary table S1): (1) dual-echo gradient-echo (GRE) images: TA=11.5 min; TR=30 ms, TE1=7.38 ms, …
Contributors IHH and PR conducted statistical analyses and wrote the paper; MBD, LAC, ES, NG-K, and GFE conceptualised the project and edited the paper; MRS conducted data collection and edited the paper.
Funding National Health and Medical Research Council (grant no. 1046037).
Competing interests None declared.
Ethics approval Monash Health Human Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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