Combined Therapy with Idebenone and Deferiprone in Patients with Friedreich��s Ataxia

Iron chelators are a new therapeutical approach for patients with Friedreich??s ataxia, on the basis that oxidative cell damage that occurs in these patients is due to the increasing deposits of mitochondrial iron pools. The objective of the study was to evaluate the effects of the combined therapy of idebenone and low oral doses of deferiprone on the neurological signs and cardiac function parameters. This study was designed as a prospective open-label single-arm study. Twenty Friedreich??s ataxia patients were treated with idebenone (20?mg/kg/day) and deferiprone (20?mg/kg/day) for 11?months. Patients were evaluated before the start and throughout the study with the International Cooperative Ataxia Rating Scale (ICARS) scores, echocardiographic measurements and MRI (magnetic resonance imaging) techniques to asses brain iron deposits in the dentate nucleus. No significant differences were observed in total ICARS scores when comparing baseline status and the end of the study in the whole group of patients. Posture and gait scores increased significantly after 11?months of therapy (Wilcoxon??s test, p?=?0.04) and kinetic function improved significantly (Wilcoxon??s test, p?=?0.015). Echocardiography data showed a significant reduction of the interventricular septum thickness (Wilcoxon??s test, p?=?0.04) and in the left ventricular mass index (Wilcoxon??s test, p?=?0.038) after the start of the therapy. The MRI values in the dentate nucleus showed a statistically significant reduction (Wilcoxon??s test p?=?0.007) between baseline conditions and after 11?months of the therapy. Combined therapy with idebenone and deferiprone in patients with FDRA indicates a stabilizing effect in neurologic dysfunctions due to an improvement in the kinetic functions, with a worsening of gait and posture scores. Heart hypertrophy parameters and iron deposits in dentate nucleus improved significantly. Combined therapy was well tolerated with mild side effects, apart from the risk of neutropenia and progressive reduction of plasma iron parameters.     

Superior Cerebellar Peduncle Atrophy in Friedreich��s Ataxia Correlates with Disease Symptoms

Friedreich’s ataxia (FRDA) is the most common early onset inherited ataxia with clinical manifestations, including gradual progression of unremitting cerebellar–sensory ataxia, peripheral sensory loss, loss of lower limb tendon reflexes and hypertrophic cardiomyopathy. Although atrophy of the superior cerebellar peduncle (SCP) has been reported in several magnetic resonance imaging (MRI) studies of FRDA, the relationship of SCP changes to genetic and clinical features of FRDA has not been investigated. We acquired T1-weighted MRI scans in 12 right-handed individuals with FRDA, homozygous for a GAA expansion in intron 1 of FXN, as well as 13 healthy age-matched controls. The corrected cross-sectional areas of the right (left) SCP in the individuals with FRDA (R, 20 ± 7.9 mm²; L, 25 ± 5.6 mm²) were significantly smaller than for controls (R, 68 ± 16 mm²; L, 78 ± 17 mm²) (p < 0.001). The SCP volumes of individuals with FRDA were negatively correlated with Friedreich’s ataxia rating scale score (r = −0.553) and disease duration (r = −0.541), and positively correlated with the age of onset (r = 0.548) (p < 0.05). These findings suggest that structural MR imaging of the SCP can provide a surrogate marker of disease severity in FRDA and support the potential role of structural MRI as a biomarker in the evaluation of neurodegenerative diseases and therapies.     

Restless Legs and Substantia Nigra Hypoechogenicity are Common Features in Friedreich��s Ataxia

Friedreich’s ataxia (FA) is a multisystemic degenerative disease, but the prevalence of restless legs syndrome (RLS) is unknown. FA patients might be particularly susceptible to develop RLS as FA presents with features commonly associated with RLS, e.g. multisystemic network dysfunction, peripheral neuropathy and disturbances in subcellular brain iron homeostasis. In this work, we assessed the following: (1) the prevalence of RLS; (2) the prevalence of sonographic hypoechogenicity of the substantia nigra (SN), which is known to be associated with idiopathic RLS; and (3) the relation between both in 28 FA patients. Thirty-two percent of the patients suffered from RLS, thus clearly exceeding the prevalence rate in the general population. SN hypoechogenicity was more frequent in FA patients (61%) compared to healthy controls (7%) and was significantly associated with RLS. However, as SN echogenicity also correlated inversely with disease severity, it seems to be related not only to RLS, but also to the neurodegenerative process in FA itself. The high prevalence of RLS in FA patients warrants specific assessment by neurologists involved in the care of FA patients as treatments are readily available. Similar to patients with idiopathic RLS, reduced SN echogenicity is a frequent finding in FA, possibly indicating regional changes in subcellular brain iron regulation in FA.     

Substantia Nigra Echogenicity in Friedreich’s Ataxia Patients

The aim of this study is to assess the presence of substantia nigra (SN) hypoechogenicity in a cohort of Friedreich’s ataxia (FRDA) patients and its possible association with restless syndrome (RLS). Fourteen genetically confirmed FRDA patients and 14 sex- and age-matched healthy controls underwent transcranial sonography examination to evaluate the area of echogenicity of the SN. Both groups were clinically assessed with the essential and additional diagnostic criteria for RLS established by the International RLS Study Group. Ataxia was evaluated using the Scale for the Assessment and Rating of Ataxia. We did not find significant differences between the mean sum area of SN echogenicity in FRDA patients and in controls. Only one patient in the FDRA group and two control subjects showed SN hypoechogenicity. Two out of the 14 FDRA patients and one of the controls fulfilled diagnostic criteria for RLS. The areas of SN echogenicity in the two FRDA patients with RLS were the lowest found in this group. We conclude that our data do not support the notion that SN hypoechogenicity is related to FRDA itself, although it might be associated with RLS.     

The cerebellar component of Friedreich’s ataxia

Lack of frataxin in Friedreich’s ataxia (FRDA) causes a complex neurological and pathological phenotype. Progressive atrophy of the dentate nucleus (DN) is a major intrinsic central nervous system lesion. Antibodies to neuron-specific enolase (NSE), calbindin, glutamic acid decarboxylase (GAD), and vesicular glutamate transporters 1 and 2 (VGluT1, VGluT2) allowed insight into the disturbed synaptic circuitry of the DN. The available case material included autopsy specimens of 24 patients with genetically defined FRDA and 14 normal controls. In FRDA, the cerebellar cortex revealed intact Purkinje cell somata and dendrites as assessed by calbindin immunoreactivity. The DN, however, displayed severe loss of large NSE-reactive neurons. Small neurons remained intact. Labeling of Purkinje cells, basket fibers, Golgi neurons, and Golgi axonal plexuses with antibodies to GAD indicated normal intrinsic circuitry of the cerebellar cortex involving γ-aminobutyric acid (GABA). In contrast, the DN displayed severe loss of GABA-ergic terminals and formation of GAD- and calbindin-reactive grumose degeneration. The surviving small GAD-positive DN neurons provided normal GABA-ergic terminals to intact inferior olivary nuclei. The olives also received normal glutamatergic terminals as shown by VGluT2-reactivity. VGluT1-immunocytochemistry of the cerebellar cortex confirmed normal glutamatergic input to the molecular layer by parallel fibers and the granular layer by mossy fibers. VGluT2-immunoreactivity visualized normal climbing fibers and mossy fiber terminals. The DN, however, showed depletion of VGluT1- and VGluT2-reactive terminals arising from climbing and mossy fiber collaterals. The main functional deficit underlying cerebellar ataxia in FRDA is defective processing of inhibitory and excitatory impulses that converge on the large neurons of the DN. The reason for the selective vulnerability of these nerve cells remains elusive.     

A Collaborative-Filtering-Based Data Collection Strategy for Friedreich’s Ataxia

Cognitive Computation - Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disorder with the prevalence of 2–4 in every 100,000 Caucasian population. Since 2010, the European...     

Emotion Recognition and Psychological Comorbidity in Friedreich’s Ataxia

Friedreich’s ataxia (FRDA) is an autosomal recessive disease presenting with ataxia, corticospinal signs, peripheral neuropathy, and cardiac abnormalities. Little effort has been made to understand the psychological and emotional burden of the disease. The aim of our study was to measure patients’ ability to recognize emotions using visual and non-verbal auditory hints, and to correlate this ability with psychological, neuropsychological, and neurological variables. We included 20 patients with FRDA, and 20 age, sex, and education matched healthy controls (HC). We measured emotion recognition using the Geneva Emotion Recognition Test (GERT). Neuropsychological status was assessed measuring memory, executive functions, and prosopagnosia. Psychological tests were Patient Health Questionnaire-9 (PHQ-9), State Trait Anxiety Inventory–state/?trait (STAI-S/?T), and Structured Clinical Interview for DSM Disorders II. FRDA patients scored worse at the global assessment and showed impaired immediate visuospatial memory and executive functions. Patients presented lower STAI-S scores, and similar scores at the STAI-T, and PHQ-9 as compared to HC. Three patients were identified with personality disorders. Emotion recognition was impaired in FRDA with 29% reduction at the total GERT score (95% CI ??44.8%, ??12.6%; p?<?0.001; Cohen’s d?=?1.2). Variables associated with poor GERT scores were the 10/36 spatial recall test, the Ray Auditory Verbal Learning Test, the Montreal Cognitive Assessment, and the STAI-T (R²?=?0.906; p?<?0.001). FRDA patients have impaired emotion recognition that may be secondary to neuropsychological impairment. Depression and anxiety were not higher in FRDA as compared to HC and should not be considered as part of the disease.     

Neuroanatomical Correlates of Depression in Friedreich’s Ataxia: a Voxel-Based Morphometry Study

Affective disorders have been increasingly recognized in neurodegenerative diseases and often result in poor quality of life. However, the frequency, clinical relevance, and anatomical substrate of depression in Friedreich’s ataxia were not yet evaluated. We assessed 22 patients with Friedreich’s ataxia for major depression using Beck Depression Inventory and cerebral 3 T MRI scans. We then employed whole-brain voxel-based morphometry analyses on volumetric T1 datasets to compare tissue loss between patients with and without major depression. Patients (36.3 %) fulfilled criteria for major depression (8/22). Mean Beck Depression Inventory (BDI) score was 9.63?±?8.95 and the depressive group had significantly higher score compared to non-depressive group (18.5?±?8.6 vs 4.4?±?2.9, p?<?0.001). There was no correlation between Beck Depression Inventory score and age of patients, ataxia severity, age at onset, or duration of the disease. The comparison between patient groups found no significant differences of white matter volumes. In contrast, we found reduction of gray matter volumes in the depressive group in medial and orbital region of frontal lobe and anterior cingulate gyri (p?<?0.001). Regression analyses have shown that BDI scores were inversely correlated with gray matter volume at right superior frontal gyrus. Major depression is frequent in Friedreich’s ataxia and possibly under recognized. Our results strongly suggest that this may not be a simply reactive phenomenon, but rather associated to structural abnormalities.     

Routine Clinical Testing Underestimates Proprioceptive Deficits in Friedreich’s Ataxia

Friedreich’s ataxia (FA) is the most common recessive ataxia in the Western world with degeneration of dorsal root ganglia neurons as its major neuropathological hallmark. The sensitivity of clinical tools commonly used for the assessment of the proprioceptive component of FA is currently unknown. We hypothesised that current clinical testing underestimates proprioceptive deficits in FA patients. Such an underestimation would hamper our understanding of the components of FA, the monitoring of disease progression, and the detection of deficits in the current advent of drug trials. We compared clinical tests for joint position sense (JPS) and vibration sense (VS) to a test of spatial position sense (SPS) that examines localisation of both hands across a horizontal 2D space. We tested 22 healthy controls to derive a cut-off for the SPS. Eleven patients with genetically confirmed FA participated in this study. All 11 FA patients were impaired in the SPS test. Two patients showed unimpaired JPS and VS. Two additional patients showed unimpaired JPS, while two other patients unimpaired VS. The SPS test was more sensitive and revealed deficits potentially earlier than clinical screening tests. Only the SPS showed a positive correlation with ataxia severity. The SPS was more sensitive than the commonly used JPS and VS. Thus, our results indicate that proprioceptive deficits in FA start earlier and are more severe than indicated by routine standard clinical testing. The contribution of proprioceptive deficits to the impairment of FA patients might therefore indeed be underestimated today.     

Spinal Cord Atrophy Correlates with Disability in Friedreich’s Ataxia

Although Friedreich’s ataxia is characterized by spinal cord atrophy, it remains to be investigated the possible correlation of such atrophy with clinical disability and genetic parameters. Thirty-three patients with Friedreich’s ataxia and 30 healthy controls underwent MRI on a 3 T scanner. We used T1-weighted 3D images to estimate spinal cord area and eccentricity at C2/C3 level based on a semi-automatic image segmentation protocol. We quantified severity of ataxia with the Friedreich ataxia rating scale (FARS). Mean cord area in Friedreich’s ataxia was smaller than in controls (38 vs 67.9 mm², p?<?0.001). In contrast, mean cord eccentricity was significantly higher in Friedreich’s ataxia when compared to the controls (0.82 vs 0.76, p?<?0.001). There was a significant correlation between cord areas and the FARS scores (r?=??0.53, p?=?0.002). Cord damage in Friedreich’s ataxia results in atrophy combined with flattening. Cord area is associated to clinical disability and might be useful as a biomarker in the disease.     

Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich’s Ataxia

Friedreich’s ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (¹H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and ¹H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) values were calculated for the same ¹H-MRS VOI. Clinical severity was evaluated using the International Cooperative Ataxia Rating Scale (ICARS). FRDA patients showed a significant reduction of N-acetyl-aspartate (NAA), a neuroaxonal marker, and choline (Cho), a membrane marker, both expressed relatively to creatine (Cr), and increased MD values. In FRDA patients NAA/Cr negatively correlated with MD values (r?=??0.396, p?=?0.037) and with ICARS score (r?=??0.669, p?<?0.001). Age-normalized NAA/Cr loss correlated with the GAA expansion (r?=??0.492, p?=?0.008). The reduced cerebellar NAA/Cr in FRDA suggests that neuroaxonal loss is related to the microstructural changes determining higher MD values. The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.     

How does performance of the Friedreich Ataxia Functional Composite compare to rating scales?

Progression of Friedreich ataxia (FRDA) is often measured using neurological rating scales such as the Friedreich Ataxia Rating Scale (FARS). Performance scales comprising functional measures have been used in other conditions due to their increased sensitivity and reproducibility and may replace examination-based measures. The aims of this study were to examine the relationship between the Friedreich Ataxia Functional Composite (FAFC) measures and characteristics of FRDA to determine if the FAFC is more sensitive to clinical change over time compared to its components. One hundred and twenty-two individuals completed the timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT) and the low-contrast letter acuity (LCLA) test at baseline, 63 at year 1, 34 at year 2 and 25 at year 3. Composite scores, Z2 (T25FW and 9HPT) and Z3 (T25FW, 9HPT and LCLA) were created. Correlation analyses were conducted. Change in FAFC components were examined over 1, 2, and 3 years. The FARS, Z2, Z3 and 9HPT showed significant change over all time points compared to baseline. The T25FW only demonstrated significant change over 3 years. The LCLA demonstrated no significant change over any of the time points. The FAFC shows significant change over time and indicates disease progression, however, this may result from individual components driving the differences. The LCLA showed no change over time, rendering Z3 redundant. The FAFC is of limited value in cohorts with non-ambulant individuals as it leads to skewing of the dataset and is better suited to less affected populations.     

The dorsal root ganglion in Friedreich’s ataxia

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.     

The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins

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.     

Human Mesenchymal Stem Cells Increase Anti-oxidant Defences in Cells Derived from Patients with Friedreich’s Ataxia

Friedreich??s ataxia (FRDA) is a progressive neurodegenerative disorder which is, at present, incurable. Oxidative damage and inhibition of mitochondrial function are key determinants of cellular damage in FRDA, since there is greater sensitivity to oxidative stress in cells with frataxin deficiency. In addition, frataxin-deficient cells have an impaired ability to recruit antioxidant defences against endogenous oxidative stress. We have recently shown that factors derived from bone marrow-derived mesenchymal stem cells (MSCs) increase hydrogen peroxide scavenging enzymes and offer protection against hydrogen peroxide-mediated injury in cells derived from patients with FRDA. Here we extend these studies and have performed a series of experiments showing that expression of superoxide dismutase (1 and 2) enzymes is reduced in FRDA cells but can be restored by treatment with conditioned medium from human MSCs. Furthermore, we have demonstrated that exposure to factors secreted by MSCs increases resistance to nitric oxide-induced oxidative stress in FRDA fibroblasts through, at least in part, restoring the expression of the superoxide dismuting enzymes and via modulation of PI₃ kinase/Akt pathways. These findings suggest that MSCs secrete factors that improve the cellular homeostasis of cells derived from FRDA patients and provide suitable support for their enhanced survival. This study further suggests the potential therapeutic use of MSCs in patients with FRDA.     

Triple Therapy with Darbepoetin Alfa, Idebenone, and Riboflavin in Friedreich’s Ataxia: an Open-Label Trial

Minimal objective evidence exists regarding management of Friedreich’s ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy—darbepoetin alfa, idebenone, and riboflavin—in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28?±?8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7?±?8.3) on the scale for the assessment and rating of ataxia and 94.3?±?27.2 g/m² in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 μg darbepoetin alfa every 2 or 3 weeks, 10–20 mg/kg/day idebenone, and 10–15 mg/kg/day riboflavin for 32?±?19.4 months (range of 8–56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.     

The effects of aging and Alzheimer��s disease on associative recognition memory

We investigated the effects of aging and Alzheimer's disease (AD) on item and associative recognition memory. Three groups of participants (younger adults, elderly adults, and AD patients) studied photographs of common objects that were located on either the left or the right side of a black computer screen inside either a red or a blue square. In a subsequent old/new recognition memory test, the participants were presented with four kinds of stimuli: "intact" stimuli, which were presented as they were during the study phase; "location-altered" stimuli, which were presented in a different location; "color-altered" stimuli, which were presented with a different surrounding color; and "new" stimuli, which consisted of photographs that had not been presented during the study phase. Compared with younger adults, the older adults showed equivalent performance in simple item recognition but worse performance in discriminating location-altered and color-altered stimuli. Compared with older adults, the AD patients showed equivalent performance in discriminating color-altered stimuli but worse performance in simple item recognition and the discrimination of location-altered stimuli. We speculate that distinct structural and functional changes in specific brain regions that are caused by aging and AD are responsible for the different patterns of memory impairment.     

Pathology and pathogenesis of sensory neuropathy in Friedreich’s ataxia

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.