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.

1 Follower
16 Reads
  • Source
    • "Histological studies of post-mortem cerebellar tissue show clear differences between SCA6 on the one hand and Friedreich's ataxia and SCA3 on the other. There is marked reduction of the cerebellar cortex in SCA6 with predominant loss of Purkinje cells, whereas the cerebellar cortex is largely preserved in Friedreich's ataxia and SCA3 (Sasaki et al., 1998; Koeppen, 2005; Scherzed et al., 2012; Koeppen and Mazurkiewicz, 2013). On the level of the cerebellar nuclei, the opposite appears to be the case. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich's ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich's ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Full-text · Article · Mar 2015 · Brain
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2015 · Brain Research
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2015 · Mitochondrion
Show more