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The cognitive control of movement suppression, including performance monitoring, is one of the core properties of the executive system. A complex cortical and subcortical network involving cerebral cortex, thalamus, subthalamus, and basal ganglia has been regarded as the neural substrate of inhibition of programmed movements. Using the countermanding task, a suitable tool to explore behavioral components of movement suppression, the contribution of the cerebellum in the proactive control and monitoring of voluntary action has been recently described in patients affected by focal lesions involving in particular the cerebellar dentate nucleus. Here, we evaluated the performance on the countermanding task in a group of patients with cerebellar degeneration, in which the cerebellar cortex was diffusely affected, and showed that they display additionally a longer latency in countermanding engaged movements. Overall, the present data confirm the role of the cerebellum in executive control of action inhibition by extending the contribution to reactive motor suppression.

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.

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-beta-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, P(0), and myelin basic protein. The nerves displayed major modifications in Schwann cells that were apparent by laminin 2 and S100alpha immunocytochemistry. Few S100alpha-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.

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 mumol/g wet weight) and ferritin (206.9 +/- 46.6 mug/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 +/- 0.88 mumol/g; ferritin: 210.9 +/- 9.0 mug/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.

Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence. Patients have progressive neurodegeneration of the dorsal root ganglia (DRG) and in later stages the cerebellum may be involved. The expanded GAA-TR sequence is unstable in somatic cells in vivo, and although the mechanism of instability remains unknown, we hypothesized that age-dependent and tissue-specific somatic instability may be a determinant of the progressive pathology involving DRG and cerebellum. We show that transgenic mice containing the expanded GAA-TR sequence (190 or 82 triplets) in the context of the human FXN locus show tissue-specific and age-dependent somatic instability that is compatible with this hypothesis. Small pool PCR analysis, which allows quantitative analysis of repeat instability by assaying individual transgenes in vivo, showed age-dependent expansions specifically in the cerebellum and DRG. The (GAA)(190) allele showed some instability by 2 months, progressed at about 0.3-0.4 triplets per week, resulting in a significant number of expansions by 12 months. Repeat length was found to determine the age of onset of somatic instability, and the rate and magnitude of mutation. Given the low level of cerebellar instability seen by others in multiple transgenic mice with expanded CAG/CTG repeats, our data indicate that somatic instability of the GAA-TR sequence is likely mediated by unique tissue-specific factors. This mouse model will serve as a useful tool to delineate the mechanism(s) of disease-specific somatic instability in FRDA.

Friedreich's ataxia (FA) represents a degenerative, genetically determined disease of the nervous system in combination with myocardial affection and in some cases endocrinological disturbances. Manifestation of myocardial involvement usually follows symptoms of nervous system degeneration later in the course, but seems not to be secondary. These cardiac disturbances are the main cause of death in FA-patients. Therapeutic management of heart disease is possible and interdisciplinary neurologic-cardiologic cooperation should start early in the course of FA.

The neuropathological findings in a Tunisian patient with Friedreich's ataxia with vitamin E deficiency are reported. The main histological changes are: (1) spinal sensory system demyelination with neuronal atrophy, axonal spheroids and corpora amylacea; (2) neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate body, twelfth and ambiguus nuclei, spinal horns and posterior root ganglia. Ultrastructurally, the lipopigments were of uniform granularity without lipid droplets.

Observations have been made on a patient with Friedreich's ataxia who died 52 years after the onset of symptoms. The pathology of the brain and spinal cord was typical of this disorder. Apart from loss of dorsal root ganglion cells, severe loss of secondary sensory neurons was observed, including the nucleus dorsalis in the spinal cord, the spinal and principal trigeminal nuclei and, in particular, the mesencephalic trigeminal nucleus in the brain stem. Morphometric studies on the first sacral nerve root and on the sural nerve at levels from midthigh to ankle revealed a distally accentuated axonal loss that predominantly affected larger myelinated nerve fibres. Regenerative activity was seen, mainly in the spinal root and proximally in the sural nerve. Relative myelin thickness, assessed by a g ratios, tended to be reduced. As teased fibre studies showed only limited evidence of demyelination/remyelination and of axonal regeneration, this therefore suggests the presence of a hypomyelination. The results confirm the presence of a distal axonopathy and provide no evidence that this is preceded by axonal atrophy.

We have demonstrated onion bulb-like structures in human dorsal root ganglia (DRG). These onion bulbs morphologically consist of non-continuous layers of supporting-cell cytoplasms that encase thinly myelinated axons and are immunocytochemically recognized by anti-S-100 protein and anti-glial fibrillary acidic protein antibodies. These structures are present in normal controls and preferentially involve the initial complex of the large, light, neurofilament-rich neurons. The number of onion bulbs and their average number of lamellae reach a peak in the third decade and then decline. In three cases of amyotrophic lateral sclerosis (ALS), the onion bulbs involve non-myelinated axons as well as the thinly myelinated portion of the initial complex and are increased both in frequency and in average number of lamellae. Our studies suggest that these onion bulbs represent a normal biological process of DRG neurons that may be accentuated in ALS.

The bioptical morphometric and ultrastructural study of sural nerve in a 17-year-old boy with ataxia-telangiectasia (AT) is reported. Our findings include a loss of fibers, particularly of large ones, axonal degenerative changes, Schwann cell inclusions of various type, and rare signs of primary demyelination. Teased-fiber study showed paranodal myelin enlargements, segmental demyelination, shortening, and/or variability of internodal length. This picture is similar to that in Friedreich's ataxia (FA), although they differ in degree and time of onset. A correct neuropathologic diagnosis of AT cannot be made on the basis of sural nerve biopsy alone.

Fibroblasts from forearm skin biopsy specimens from 3 patients with Friedreich's ataxia and controls without evidence of hypersensitivity to ionising radiation were exposed to a range of doses of gamma or x-rays up to 550 rad, and cell survival was measured by counting clones derived from single fibroblasts. Cells from two of the three Friedreich cases were found to have an abnormally low survival at the dose levels used, the difference from controls run in parallel being significant. These findings suggest the possibility of defective DNA repair processes in at least some patients with Friedreich's ataxia.

Sural or superficial peroneal nerve biopsies of patients with clinical diagnosis of Friedreich's ataxia were studied. Patients were divided in two groups, typical and abortive forms: loss of fibers accompanied by axonal atrophy and segmental demyelination are the basic changes in both groups, although the decrease in number of myelinated fibers was most severe in typical FA. In the cases with slower progression there is a tendency to form onion bulb complexes.

The severity of Friedreich's ataxia was graded in ten patients by clinical examination and in five by use of posturography. These data were compared with neuroradiology findings. CT-confirmed infratentorial atrophy occured only in advanced cases of Friedreich's ataxia; the correlation with the clinical score was poor. On mid-sagittal MRI planes the diameters of fourth ventricle, brain stem at the level of the inferior olive and spinal cord at the levels of the foramen magnum and C3 were measured. Patients with Friedreich's ataxia had significant MRI-confirmed atrophy of the cranial spinal cord as compared with a normal, age-matched control group. This was also observed in patients with Friedreich's ataxia in the early stages. A reliable correlation between atrophy of the cranial spinal cord and the clinical score, however, could again not be found. MRI exploration of the cranial spinal cord may be recommended as an additional diagnostic marker in Friedreich's ataxia.