Friedreich Ataxia: Neuropathology Revised

and Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (JEM).
Journal of neuropathology and experimental neurology 02/2013; 72(2):78-90. DOI: 10.1097/NEN.0b013e31827e5762
Source: PubMed


Friedreich ataxia is an autosomal recessive disorder that affects children and young adults. The mutation consists of a homozygous guanine-adenine-adenine trinucleotide repeat expansion that causes deficiency of frataxin, a small nuclear genome-encoded mitochondrial protein. Low frataxin levels lead to insufficient biosynthesis of iron-sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase, and iron dysmetabolism of the entire cell. This review of the neuropathology of Friedreich ataxia stresses the critical role of hypoplasia and superimposed atrophy of dorsal root ganglia. Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal columns, transsynaptic atrophy of nerve cells in Clarke column and dorsal spinocerebellar fibers, atrophy of gracile and cuneate nuclei, and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain γ-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second intrinsic CNS lesion. In light of the selective vulnerability of organs and tissues to systemicfrataxin deficiency, many questions about the pathogenesis of Friedreich ataxia remain.

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    • "This observation may be the result of anomalies at the neuromuscular synapse. Normal pain sensitivity exhibited by Fxn KO/Mck mice on the hotplate test was expected on the basis of lemniscal not extralemniscal pathways being mostly affected in Friedreich ataxia (Koeppen and Mazurkiewicz, 2013). "
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    ABSTRACT: Friedreich ataxia is the most common autosomal recessive disorder of the cerebellum, causing degeneration of spinal sensory neurons and spinocerebellar tracts. The disease is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron metabolism. An experimental model has been generated by crossing mice homozygous for a conditional allele of the Fxn gene with mice heterozygous for a deleted exon 4 of Fxn carrying a tissue-specific Cre transgene under control of the muscle creatine kinase promoter. Relative to wild-type, Fxn null mutants were impaired on tests of motor coordination comprising horizontal bar, vertical pole, and the rotorod as well as displaying gait anomalies and the hindlimb clasping response. The Fxn KO/Mck model reproduces some key features of patients with Friedreich ataxia and provides an opportunity of ameliorating their symptoms with experimental therapies. Copyright © 2015. Published by Elsevier B.V.
    Brain Research 03/2015; 1608. DOI:10.1016/j.brainres.2015.03.001 · 2.84 Impact Factor
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    • "Thus, IRP1 activation may be the link between inhibition of complex I and iron accumulation, two hallmarks of idiopathic PD. 5.5. Mitochondrial dysfunction and iron accumulation in FA FA is an autosomal recessive mitochondrial disorder characterized by progressive cardiologic and neurological degeneration that affects mainly the dorsal root ganglia, the spinal cord, and the cerebellum (Harding, 1981; Hughes et al., 1968; Koeppen and Mazurkiewicz, 2013; Lamarche et al., 1984). FA is usually caused by a homozygous GAA repeat expansion mutation in intron 1 of FXN (Campuzano et al., 1996; Pandolfo, 2002; Rotig et al., 1997). "
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    ABSTRACT: Synthesis of the iron-containing prosthetic groups-heme and iron-sulfur clusters-occurs in mitochondria. The mitochondrion is also an important producer of reactive oxygen species (ROS), which are derived from electrons leaking from the electron transport chain. The coexistence of both ROS and iron in the secluded space of the mitochondrion makes this organelle particularly prone to oxidative damage. Here, we review the elements that configure mitochondrial iron homeostasis and discuss the principles of iron-mediated ROS generation in mitochondria. We also review the evidence for mitochondrial dysfunction and iron accumulation in Alzheimer's disease, Huntington Disease, Friedreich's ataxia, and in particular Parkinson's disease. We postulate that a positive feedback loop of mitochondrial dysfunction, iron accumulation, and ROS production accounts for the process of cell death in various neurodegenerative diseases in which these features are present. Copyright © 2015. Published by Elsevier B.V.
    Mitochondrion 02/2015; 21. DOI:10.1016/j.mito.2015.02.001 · 3.25 Impact Factor
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    • "Until the 20th century, FA was classified as a disorder of the spinal cord, and only in 1957 was the considerable involvement of the DN and, to a lesser extent, of the cerebellum appreciated (Urich et al., 1957; Wüllner et al., 1993; Huang et al., 1993; Ormerod et al., 1994). In histopathological studies the DN is severely atrophic with neuronal loss of large neurons and proliferation of synaptic terminals (Koeppen and Mazurkiewicz, 2013). Atrophy of the cerebellum appears late and is commonly minor. "
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    ABSTRACT: Background In Friedreich’s ataxia (FA) the genetically decreased expression of the mitochondrial protein frataxin leads to disturbance of the mitochondrial iron metabolism. Within the cerebellum the dentate nuclei (DN) are primarily affected. Histopathological studies show atrophy and accumulation of mitochondrial iron in DN. Dentate iron content has been suggested as a biomarker to measure the effects of siderophores/antioxidant treatment of FA. We assessed the iron content and the volume of DN in FA patients and controls based on ultra-high-field MRI (7 Tesla) images. Methods Fourteen FA patients (mean age 38.1 yrs) and 14 age- and gender-matched controls participated. Multi-echo gradient echo and susceptibility weighted imaging (SWI) sequences were acquired on a 7 T whole-body scanner. For comparison SWI images were acquired on a 1.5 T MR scanner. Volumes of the DN and cerebellum were assessed at 7 and 1.5 T, respectively. Parametric maps of T2 and T2* sequences were created and proton transverse relaxation rates were estimated as a measure of iron content. Results In FA, the DN and the cerebellum were significantly smaller compared to controls. However, proton transverse relaxation rates of the DN were not significantly different between both groups. Conclusions Applying in vivo MRI methods we could demonstrate significant atrophy of the DN in the presence of normal iron content. The findings suggest that relaxation rates are not reliable biomarkers in clinical trials evaluating the potential effect of FA therapy.
    Clinical neuroimaging 12/2014; 6. DOI:10.1016/j.nicl.2014.08.018 · 2.53 Impact Factor
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