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1.
Arnulf H. Koeppen Jennifer A. Morral Ashley N. Davis Jiang Qian Simone V. Petrocine Mitchell D. Knutson Walter M. Gibson Matthew J. Cusack Danhong Li 《Acta neuropathologica》2009,118(6):763-776
Atrophy of dorsal root ganglia (DRG) and thinning of dorsal roots (DR) are hallmarks of Friedreich’s ataxia (FRDA). Many previous
authors also emphasized the selective vulnerability of larger neurons in DRG and thicker myelinated DR axons. This report
is based on a systematic reexamination of DRG, DR and ventral roots (VR) in 19 genetically confirmed cases of FRDA by immunocytochemistry
and single- and double-label immunofluorescence with antibodies to specific proteins of myelin, neurons and axons; S-100α
as a marker of satellite and Schwann cells; laminin; and the iron-responsive proteins ferritin, mitochondrial ferritin, and
ferroportin. Confocal images of axons and myelin allowed the quantitative analysis of fiber density and size, and the extent
of DR and VR myelination. A novel technology, high-definition X-ray fluorescence (HDXRF) of polyethylene glycol-embedded fixed
tissue, was used to “map” iron in DRG. Unfixed frozen tissue of DRG in three cases was available for the chemical assay of
total iron. Proliferation of S-100α-positive satellite cells accompanied neuronal destruction in DRG of all FRDA cases. Double-label
visualization of peripheral nerve myelin protein 22 and phosphorylated neurofilament protein confirmed the known loss of large
myelinated DR fibers, but quantitative fiber counts per unit area did not change. The ratio of myelinated to neurofilament-positive
fibers in DR rose significantly from 0.55 to 0.66. In VR of FRDA patients, fiber counts and degree of myelination did not
differ from normal. Pooled histograms of axonal perimeters disclosed a shift to thinner fibers in DR, but also a modest excess
of smaller axons in VR. Schwann cell cytoplasm in DR of FRDA was depleted while laminin reaction product remained prominent.
Numerous small axons clustered around fewer Schwann cells. Ferritin in normal DRG localized to satellite cells, and proliferation
of these cells in FRDA caused wide rims of reaction product about degenerating nerve cells. Mitochondrial ferritin was not
detectable. Ferroportin was present in the cytoplasm of normal satellite cells and neurons, and in large axons of DR and VR.
In FRDA, some DRG neurons lost their cytoplasmic ferroportin immunoreactivity, whereas the cytoplasm of satellite cells remained
ferroportin positive. Ferroportin in DR axons disappeared in parallel with atrophy of large fibers. HDXRF of DRG detected
regional and diffuse increases in iron fluorescence that matched ferritin expression in satellite cells. The observations
support the conclusions that satellite cells and DRG neurons are affected by iron dysmetabolism; and that regeneration and
inappropriate myelination of small axons in DR are characteristic of the disease. 相似文献
2.
Koeppen AH Michael SC Knutson MD Haile DJ Qian J Levi S Santambrogio P Garrick MD Lamarche JB 《Acta neuropathologica》2007,114(2):163-173
Frataxin deficiency in Friedreich’s ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is
a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in
the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed
grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We
examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal
controls by biochemical and microscopic techniques. Total iron (1.53 ± 0.53 μmol/g wet weight) and ferritin (206.9 ± 46.6
μg/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 ± 0.88 μmol/g; ferritin: 210.9 ± 9.0 μg/g)
but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of
juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial
ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while
endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse
of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their
dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation
of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the
likely result of trans-synaptic degeneration. 相似文献
3.
Jennifer A. Morral Ashley N. Davis Jiang Qian Benjamin B. Gelman Arnulf H. Koeppen 《Acta neuropathologica》2010,120(1):97-108
Friedreich’s ataxia (FRDA) causes a complex neuropathological phenotype with characteristic lesions of dorsal root ganglia
(DRG); dorsal spinal roots; dorsal nuclei of Clarke; spinocerebellar and corticospinal tracts; dentate nuclei; and sensory
nerves. This report presents a systematic morphological analysis of sural nerves obtained by autopsy of six patients with
genetically confirmed FRDA. The outstanding lesion consisted of lack of myelinated fibers whereas axons were present in normal
numbers. On cross-sections, only 11% of all class III-β-tubulin-positive axons were myelinated in FRDA, contrasting with 36%
in normal control nerves. Despite their paucity, thin myelinated fibers assembled compact sheaths containing the peripheral
myelin proteins PMP-22, P0, and myelin basic protein. The nerves displayed major modifications in Schwann cells that were apparent by laminin 2 and
S100α immunocytochemistry. Few S100α-immunoreactive cells remained detectable whereas laminin 2 reaction product was abundant.
The normal honeycomb-like distribution of laminin 2 around myelinated fibers was replaced by confluent regions of reaction
product that enveloped clusters of closely apposed thin axons. Electron microscopy not only confirmed the lack of myelin but
also showed abnormal Schwann cells and axons. Ferritin localized to normal Schwann cell cytoplasm. In the sensory nerves of
patients with FRDA, the distribution of this protein strongly resembled laminin 2, but there was no net increase of the total
ferritin-reactive area. Ferroportin reaction product occurred in all axons of sural nerves in FRDA, which was at variance
with dorsal spinal roots. In the pathogenesis of sensory neuropathy in FRDA, two mechanisms are likely: hypomyelination due
to faulty interaction between axons and Schwann cells; and slow axonal degeneration. Neurons of DRG, satellite cells, Schwann
cells, and axons of sensory nerves and dorsal spinal roots derive from the neural crest, and hypomyelination in FRDA may be
attributed to defects of regulation or migration of shared precursor cells. Sural nerves in FRDA showed no convincing change
in ferritin and ferroportin, militating against local iron dysmetabolism. The result stands out in contrast to the previously
reported changes in dorsal spinal roots of patients with FRDA. 相似文献
4.
Michael S Petrocine SV Qian J Lamarche JB Knutson MD Garrick MD Koeppen AH 《Cerebellum (London, England)》2006,5(4):257-267
Hypertrophic cardiomyopathy is a common complication of Friedreich's ataxia (FRDA). Histological sections reveal abnormal cardiomyocytes, muscle fiber necrosis, reactive inflammation, and increased endomysial connective tissue. Scattered muscle fibers display perinuclear collections of minute iron-positive granules that lie in rows between myofibrils. Frataxin deficiency in FRDA causes mitochondrial iron dysmetabolism. We studied total iron and the iron-related proteins ferritin, mitochondrial ferritin, divalent metal transporter 1 (DMT1), and ferroportin in FRDA hearts by biochemical and histological techniques. Total iron in the left ventricular wall of FRDA patients (30.7+/-19.3 mg/100 g dry weight) was not significantly higher than normal (31.3+/-24.1 mg/100 g dry weight). Similarly, cytosolic holoferritin levels in FRDA hearts (230+/-172 microg/g wet weight) were not significantly elevated above normal (148+/-86 microg/g wet weight). The iron-positive granules exhibited immunoreactivity for cytosolic ferritin, mitochondrial ferritin, and ferroportin. Electron microscopy showed enhanced electron density of mitochondrial deposits after treatment with bismuth subnitrate supporting ferritin accumulation. The inflammatory cells in the endomysium were reactive for CD68, cytosolic ferritin, and the DMT1 isoform(s) translated from messenger ribonucleic acids containing iron-responsive elements (DMT1+). Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis. 相似文献
5.
AbstractThree cases of Friedreich’s ataxia were submitted to diverse neuroradiological procedures in order to determine the extent of atrophic processes in the central nervous system. All patients underwent computerized-tomography scan, Magnetic Resonance Imaging, and HMPA-single Photon emission computerized tomography studies, focusing in cerebellar lobes. A slight atrophy was observed in the vermis and the cerebellar lobes with CT scan and MRI. In contrast a significant decrease in cerebellar blood flow was shown by TC-HMPAE SPECT study. The significance of these findings in understanding physiopathological mechanisms in Friedreich’s ataxia is discussed. [Neurol Res 1994; 16: 342-344] 相似文献
6.
Hayer Stefanie Nicole Liepelt Inga Barro Christian Wilke Carlo Kuhle Jens Martus Peter Schöls Ludger 《Journal of neurology》2020,267(5):1420-1430
Journal of Neurology - To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich’s ataxia. Single molecule array measurements of neurofilament light (NfL)... 相似文献
7.
Lower limb spasticity compromises the independence of people with Friedreich’s ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n = 18) and non-ambulant (n = 13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function. 相似文献
8.
Giovanni Coppola Giuseppe De Michele Francesca Cavalcanti Luigi Pianese Anna Perretti Lucio Santoro Giuseppe Vita Antonio Toscano Marianna Amboni Giacinta Grimaldi Elena Salvatore Giuseppe Caruso A. Filla 《Journal of neurology》1999,246(5):353-357
Among 101 patients homozygous for GAA expansion within the X25 gene, 11 from 8 families had Friedreich’s ataxia with retained reflexes in the lower limbs (FARR). These patients had a lower
occurrence of decreased vibration sense, pes cavus, and echocardiographic signs of left ventricular hypertrophy than the 90
FA patients with areflexia. The mean age at onset was significantly later (26.6 ± 11.4 vs. 14.2 ± 6.9 years), and the mean
size of the smaller allele was significantly less (408 ± 252 vs. 719 ± 184 GAA triplets) in FARR patients. The neurophysiological
findings were consistent with milder peripheral neuropathy and milder impairment of the somatosensory pathways in FARR patients.
Received: 25 May 1998 Received in revised form: 11 September 1998 Accepted: 26 September 1998 相似文献
9.
Friedreich’s ataxia (FRDA) affects very young persons. In a large series, the mean ages of onset and death were 11 and 38 years,
respectively. The clinical spectrum of FRDA has expanded after genetic confirmation of the mutation became a routine laboratory
test. The main cause of death in juvenile-onset FRDA is cardiomyopathy whereas patients with late-onset are more likely to
succumb to neurological disability or an intercurrent illness. Many patients with early onset now survive for 20 years or
longer. This study made a systematic comparison of the neuropathology in 14 patients with juvenile onset and long survival,
and five patients with late onset and long survival. Mean ages of onset (± standard deviation) were 10 ± 5 and 28 ± 13 years,
respectively. Disease durations were 33 ± 11 and 47 ± 11 years, respectively. Cross-sectional areas of the thoracic spinal
cord were greatly reduced from the normal state but did not differ between the two groups. Similarly, the neurons of dorsal
root ganglia were significantly reduced in size in both juvenile- and late-onset cases of FRDA. The dentate nucleus showed
severe loss of neurons as well as modification and destruction of corticonuclear terminals in all FRDA patients. Delayed atrophy
of the dentate nucleus is the likely cause of the ataxic phenotype of FRDA in late-onset cases, but the reason for the delay
is unknown. Frataxin levels in the dentate nucleus of two patients with late onset were similar to those of seven patients
with juvenile onset. 相似文献
10.
11.
Marcondes C. França Jr Anelyssa D’Abreu Clarissa L. Yasuda Luciana Cardoso Bonadia Marilza Santos da Silva Anamarli Nucci Iscia Lopes-Cendes Fernando Cendes 《Journal of neurology》2009,256(7):1114-1120
Friedreich’s ataxia (FA) is the most frequent autosomal recessive ataxia and essentially considered a disease of the dorsal
root ganglia and spinal cord. It is caused by homozygous GAA expansions in the Frataxin gene in most cases. Although only a few studies have addressed cerebral involvement in FA, cognitive symptoms have lately
been emphasized. To evaluate brain damage in vivo, we employed whole-brain VBM and analysis of pre-defined regions of interest
(ROIs) over the cerebellum to compare 24 patients with 24 age-and-sex-matched normal controls. 1H-MRS of deep cerebral white matter (WM) was subsequently performed. Mean age of patients was 28 years (range 14–45), mean
duration of disease was 14 years (range 5–28) and 11 were men. Mean length of shorter (GAA1) and longer (GAA2) alleles were
735 and 863, respectively. VBM analysis identified WM atrophy in the posterior cyngulate gyrus, paracentral lobule and middle
frontal gyrus. ROIs over the infero-medial cerebellar hemispheres and dorsal brainstem presented gray matter atrophy, which
correlated with duration of disease (r = −0.4). NAA/Cr ratios were smaller among patients (P = 0.006), but not Cho/Cr (P = 0.08). Our results provide evidence of axonal damage in the cerebellum, brainstem and subcortical WM in FA. This suggests
that neuronal dysfunction is more widespread than previously thought in FA. 相似文献
12.
Schur Gayatri Maria Dunn Julia Nguyen Sara Dedio Anna Wade Kristin Tamaroff Jaclyn Mitta Nithya Wilson Neil Reddy Ravinder Lynch David R. McCormack Shana E. 《Journal of neurology》2022,269(5):2527-2538
Journal of Neurology - Friedreich’s ataxia (FRDA) is a neurodegenerative disease caused by decreased expression of frataxin, a protein involved in many cellular metabolic processes, including... 相似文献
13.
Schöls L Zange J Abele M Schillings M Skipka G Kuntz-Hehner S van Beekvelt MC Colier WN Müller K Klockgether T Przuntek H Vorgerd M 《Journal of neural transmission (Vienna, Austria : 1996)》2005,112(6):789-796
Summary. Impaired oxidative phosphorylation is a crucial factor in the pathogenesis of Friedreichs ataxia (FA). L-carnitine and creatine are natural compounds that can enhance cellular energy transduction. We performed a placebo-controlled triple-phase crossover trial of L-carnitine (3g/d) and creatine (6.75g/d) in 16 patients with genetically confirmed FA. Primary outcome measures were mitochondrial ATP production measured as phosphocreatine recovery by 31Phosphorus magnetic resonance spectroscopy, neurological deficits assessed by the international co-operative ataxia rating scale and cardiac hypertrophy in echocardiography. After 4 months on L-carnitine phosphocreatine recovery was improved compared to baseline (p<0.03, t-test) but comparison to placebo and creatine effects did not reach significance (p=0.06, F-test). Ataxia rating scale and echocardiographic parameters remained unchanged. Creatine had no effect in FA patients. L-carnitine is a promising substance for the treatment of FA patients, and larger trials are warranted.Both authors contributed equally to this work 相似文献
14.
15.
T. Klopstock S. Chahrokh-Zadeh E. Holinski-Feder A. Meindl T. Gasser D. Pongratz W. Müller-Felber 《Acta neuropathologica》1999,97(2):139-142
Friedreich’s ataxia (FA) is most frequently caused by intronic trinucleotide repeat expansions in the frataxin gene on chromosome
9. The broad clinical spectrum includes late-onset FA (LOFA) and FA with retained reflexes (FARR). The size of the GAA expansions
accounts for most, but not all, of the clinical variability. We report the unusual occurrence of LOFA and FARR in two siblings
of patients with classical early-onset FA in two families. In spite of the markedly different course of the disease, the respective
siblings harboured GAA repeat expansions of similar size in leucocytes. Since haplotype-related variability is not likely
among siblings, we suppose that this intrafamilial phenotype variability is due to somatic mosaicism, with the more severely
affected siblings harbouring the larger expansions in spinal cord and other affected tissues. In view of these results, genetic
counseling and predictions on the course of FA are particularly difficult, even if an expansion mutation is found.
Received: 5 May 1998 / Revised, accepted: 15 July 1998 相似文献
16.
17.
Beate Diehl Michael S. Lee Janet R. Reid Craig D. Nielsen Marvin R. Natowicz 《Neurogenetics》2010,11(2):261-265
Friedreich ataxia (FRDA) is typically characterized by slowly progressive ataxia, depressed tendon reflexes, dysarthria, pyramidal
signs, and loss of position and vibration sense with onset before 25 years. While several atypical forms of FRDA are recognized,
profound vision deficit is rare. We describe here a 41-year-old man with profound vision deficit and episodic complete blindness
associated with marked optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia whose diagnostic evaluation
revealed compound heterozygosity for two frataxin mutations, a 994 GAA repeat intronic expansion and c.389G > T (p.G130V)
missense mutation. This case emphasizes that FRDA should be considered for individuals with significant vision deficit with
optic atrophy and sensory neuropathy, even in the absence of ataxia. This case also raises the additional, related concern
that prior studies may underestimate the frequency and varieties of variant forms of FRDA. 相似文献
18.
Among the hereditary cerebellar ataxias (CAs), there are at least 36 different forms of autosomal dominant cerebellar ataxia (ADCAs), 20 autosomal recessive cerebellar ataxias (ARCAs), two X-linked ataxias, and several forms of ataxia associated with mitochondrial defects. Despite the steady increase in the number of newly discovered CA genes, patients, especially those with putative ARCAs, cannot yet be genotyped. Moreover, in daily clinical practice, ataxia may present as an isolated cerebellar syndrome or, more often, it is associated with a broad spectrum of neurological manifestations including pyramidal, extrapyramidal, sensory, and cognitive dysfunction. Furthermore, non-neurological symptoms may also coexist. A close integration between clinical records, neurophysiological, neuroradiological and, in some instances, biochemical findings will help physicians in the diagnostic work-up (including selection of the correct genetic tests) and may lead to timely therapy. Some inherited CAs are in fact potentially treatable, and the efficacy of the therapy is directly related to the severity of the cerebellar atrophy and to the time of onset of the disease. Most cases of CA are sporadic, and the diagnostic work-up remains a challenge. Detailed anamnesis and deep investigation of the family pedigree are usually enough to discriminate between acquired and genetic conditions. In the case of ADCA, molecular testing should be guided by taking into account the main associated symptoms. In sporadic cases, a multi-disciplinary approach is needed and should consider the following points: (1) onset and clinical course; (2) associated features; (3) neurophysiological parameters, with special attention to the occurrence of peripheral neuropathy; (4) neuroimaging results; and (5) laboratory findings. A late-onset sporadic ataxia, in which other possible causes have been excluded by following the proposed steps, might be attributable to metabolic disorders, which in some instances may be treatable. In this review, we will guide the reader through the labyrinth of CAs, and we propose a diagnostic flow chart. 相似文献
19.
Friedreich ataxia—update on pathogenesis and possible therapies 总被引:1,自引:0,他引:1
Friedreich ataxia is the most-common inherited ataxia. Since the causative genetic basis was described in 1996, much has been learnt about the pathogenesis from human, animal, and yeast studies. This has led to the development of rational therapeutic approaches. In this review, the current state of knowledge regarding the pathogenesis of Friedreich ataxia is presented and possible therapeutic strategies based on this knowledge are discussed.None of the authors has any conflicts of interest. 相似文献
20.
J. Cohnheim 《European archives of psychiatry and clinical neuroscience》1879,9(2):447-448
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