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Charcot–Marie–Tooth disease type 1A (CMT1A) is associated with increased gene dosage for PMP22 . Therapeutic approaches are currently aiming at correcting PMP22 over-expression. It is unknown whether PMP22 can be used as a biological marker of disease progression and therapy efficacy. We performed quantitative real-time polymerase chain reaction on skin biopsies of 45 patients with CMT1A, obtained at study entry and after 24-months of treatment either with ascorbic acid or placebo. Data of a subgroup of patients were also compared with matched healthy subjects. Finally, we analysed PMP22 messenger RNA levels in sural nerve biopsies. We did not find significant differences in the levels of any known PMP22 transcripts in treated or untreated patients with CMT1A, thus confirming that ascorbic acid does not impact on the molecular features of CMT1A. Most importantly, we did not observe any correlation between PMP22 messenger RNA levels and the different clinical and electrophysiological outcome measures, underscoring the weakness of PMP22 to mirror the phenotypic variability of patients with CMT1A. We did not find increased PMP22 messenger RNA levels in skin and sural nerve biopsies of patients with CMT1A compared with relative controls. In conclusion, this study shows that ascorbic acid does not impact on PMP22 transcriptional regulation and PMP22 is not a suitable biomarker for CMT1A. * Abbreviations : cAMP : cyclic adenosine monophosphate CMT1A : Charcot–Marie–Tooth disease type 1A

Objective : To investigate cortical excitability in patients with corticobasal degeneration (CBD) and to find a reliable diagnostic technique for differentiating CBD from Parkinson's disease (PD). Methods : Using a paired transcranial magnetic stimulation technique, we studied motor cortex excitability at rest in 6 patients with clinically probable CBD, 10 patients with PD, and 10 normal subjects. The recovery cycle of the motor evoked potentials was tested by delivering paired magnetic stimulation over the hand area of the motor cortex at interstimulus intervals (ISIs) from 1 to 17ms. Results : In patients with CBD, paired magnetic stimuli delivered at short ISIs invariably elicited enlarged test MEPs. At ISIs of 1–10ms, the conditioned test MEPs were significantly larger in patients with CBD than in control subjects; and at ISIs of 1, 2, 4, and 6ms ,they were also larger in patients with CBD than in patients with PD. At the other ISIs tested, patients and control subjects had similar amplitude conditioned test responses. Conclusions : Our findings suggest that the unusual clinical manifestations of CBD might arise partly from motor cortex disinhibition. Paired magnetic stimulation could be a useful diagnostic test particularly in the early stages of the disease.

Connexin 32 (Cx32), a protein involved in gap-junction formation, in the peripheral nervous system is mainly localized in non-compact myelin of paranodes and Schmidt-Lanterman incisures. Despite patients with Cx32 mutations have a polyneuropathic phenotype, the pathophysiological correlates of Cx32 defects on axonal function are unknown in humans. Non-invasive methods for assessing axonal excitability have been recently developed (Burke et al., Clin. Neurophysiol. 2001, Priori et al. Brain 2002) in humans. These methods allow the indirect estimate of specific ionic conductances of human axons. We assessed the strength-duration function descriptors, the axonal refractoriness and supernormality in a group of Cx32 defective patients with polyneuropathy. Twenty-three healthy control subjects (38 nerves) and 5 patients (10 nerves) with a polyneuropathy and a genetic defect of Cx32 were studied. The ulnar nerve was bipolarly stimulated at the wrist and the CMAP was recorded from the abductor digiti minimi muscle. The descriptors (time constant: tsd, rheobasic current: rh50%, threshold: thr100%) of the motor axonal strength-duration function were estimated according to Priori et al. (2002). Axonal refractoriness was tested by delivering pairs (S1 and S2) of stimuli at variable intervals (10–300 ms). S1 strength was supramaximum, S2 intensity was adjusted to evoke a CMAP 50% of the maximum. The rh50% and the thr100% were markedly increased (rh50% patients [n = 10, mean ± SD] 13 ± 5.7 mA, controls [n = 26] 4.8 ± 2.1 mA, p

Sera from 3 patients with breast or ovarian tumors and paraneoplastic cerebellar degeneration (PCD) contained anti-Purkinje cell antibodies (PCAbs) which also bind to other neurons on frozen sections of adult rodent brain. PCAbs tested on new-born rodent (rabbit, rat, mouse) brain tissue detected only oligodendrocyte-like cells (ODLC) in the white matter and allowed us to speculate on the nature of the antigenic structure in the neuronal cytoplasm. All these PCAbs appear histochemically identical and recognize antigens which belong to so-called "Yo" proteins.

To detect mitochondrial lesions in the spinal cord from an autoptic case of myoclonus epilepsy with ragged-red fibers (MERRF) that harbored the A8344G mutation and was deemed to be free of pathological abnormalities in the spinal cord after conventional post-mortem examination.Antibodies against subunits of complex III and IV of the respiratory chain were used to perform immunohistochemical analysis on cervical, thoracic and lumbar sections of the spinal cord from the case of MERRF and from controls. Immunostaining was carried out by the avidin-biotin peroxidase complex (ABC) method.A selective decreased expression of subunit II of cytochrome c oxidase (COX-II) was found in all spinal cord sections from the patient.The immunohistochemical demonstration of mitochondrial lesions in the spinal ventral horn cells from this case with MERRF seems to be consistent with the results of many genetic studies pointing to a high and homogeneous distribution of mutant mtDNA in different neuronal populations of patients with this disease. The use of these immunological probes in the study of mitochondrial encephalomyopathies can increase both the resolution and the specificity of morphological observations in the central nervous system (CNS).

Oligodendrocytes are a major target of the purported autoimmune response in multiple sclerosis (MS) lesions, but little is known about the mechanisms underlying their demise. Despite the expression of proapoptotic receptors, these cells are rarely seen to undergo apoptosis in situ. On the other hand, cytotoxic mediators present in MS lesions, such as tumor necrosis factor-alpha, are known to generate survival signals through the activation of the transcription factors NF-kappaB and c-jun. The aim of this study was to investigate in chronic active and silent MS lesions and control white matter the expression of c-jun, its activating molecule, JNK, as well as NF-kappaB complex and its inhibitor, IkappaB. By immunohistochemistry we found negligible reactivity for these molecules in control white matter and silent MS plaques. In active MS lesions, double-label immunohistochemistry with oligodendrocyte markers showed up-regulation of the nuclear staining for both NF-kappaB and JNK on a large proportion of oligodendrocytes located at the edge of active lesions and on microglia/macrophages throughout plaques. Oligodendrocytes showed no reactivity for IkappaB, which was predominantly confined to the cytoplasm of microglia/macrophages. We hypothesize that activation of these transcriptional pathways may be one mechanism accounting for the paucity of oligodendrocyte apoptosis reported in MS.

Clinical features and pathological findings of sural nerve biopsy are reported of a 3-year-old child affected with coeliac disease who developed a progressive polyneuropathy, unresponsive to a gluten-free diet, nor to vitamin E and folic acid supply. There was no evidence of malabsorption, nor of blood factor deficiency, nor of metabolic abnormalities which might account for the neuropathy. A sural nerve biopsy showed marked loss of myelinated fibres without evidence of regenerative phenomena. Distal involvement and features of nerve pathology are consistent with a "dying-back" mechanism to underlie the nerve damage. The lack of response to a gluten-free diet suggests that direct toxicity of gliadin is not implicated.

In the present study, the monoclonal antibody Alz-50 has been used to determine and compare the immunohistochemical localization of phosphorylated tau proteins in the developing and normal adult spinal cord. At all stages of fetal life Alz-50 fiber immunoreactivity was observed in the dorsal roots, in the dorsal and dorsolateral funiculi, and in restricted regions of the dorsal horn. Alz-50 immunoreactivity was also demonstrated in the dorsal root ganglion neurons. In the adult spinal cord a consistent pattern of Alz-50 fiber immunoreactivity was localized in the superficial layers of the dorsal horn (lamina I and II) but not in dorsal and dorsolateral funiculi and in the dorsal root ganglion. Comparable results in fetal specimens have been obtained employing PHF-1, a monoclonal antibody generated against paired helical filament proteins from Alzheimer brains, while no significant immunostaining for PHF-1 was observed in the adult spinal cord. In addition, the staining with monoclonal and polyclonal anti-tau antibodies overlapped with that of Alz-50. The transient, selective pattern of Alz-50 and PHF-1 immunoreactivity may disclose some relevant functions of tau proteins during somatosensory pathway development.

A genotype-phenotype study based on the primary clinical features of adult myotonic dystrophy (DM) included 116 patients from 62 Italian pedigrees. A significant correlation between clinical severity and the number of repeats at the 3′ untranslated region of the myotonin-protein kinase gene (MT-PK) was found. These results suggest that the CTG amplification is directly related to the myotonic dystrophy phenotype and provide important information on morbidity and prognosis in this disease.

An outline of the principal reports dealing with the definition, distribution, course and treatment of the inflammatory polyradiculoneuropathies, including the Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), is given. Current diagnostic criteria for GBS are reaffirmed while the diagnosis of CIDP lacks proper standardization. Then, the boundaries between the two disorders are ill-defined. While GBS is rare and homogeneously distributed across developed and developing countries, the prevalence rate of CIDP is unknown. Several antecedent events have been implicated in the pathogenesis of GBS; yet, except for the swine-flu vaccine, the relation between infectious or toxic agents and the occurrence of the disease is purely anecdotal. The only factors known to influence the outcome of GBS are age, severity of opening symptoms, abnormal electrophysiologic characteristics of peripheral nerve function, and plasmapheresis. However, responders and non-responders to current treatment are far from defined. Although similarities have been found between experimental allergic neuritis and experimental allergic encephalomyelitis, the degree of CNS impairment in patients with inflammatory polyradiculoneuropathies needs further refinement. To provide a tentative answer to some of the unsolved questions on inflammatory polyradiculoneuropathies, a multicenter cohort study on newly diagnosed patients submitted to standard clinical and laboratory evaluation, and given common therapeutic regimes, is awaited.

A case of opsoclonus and palatal myoclonus following blunt head injury is described. The syndrome appeared 1 month after the injury and lasted unchanged until death. Postmortem examination showed the

In rats treated for 14 days with 2,5-hexanedione, the efficiency of ganglionic transmission was markedly reduced whereas only faint ultrastructural changes occurred in a few preganglionic fibers; evident signs of axonal pathology were observed on the 30th day of treatment. Choline acetyltransferase activity and acetylcholine formation showed no alteration at any time. The autonomic system is affected early during 2,5-hexanedione neuropathy, functional changes being more marked than morphological lesions.

A case of opsoclonus and palatal myoclonus following blunt head injury is described. The syndrome appeared 1 month after the injury and lasted unchanged until death. Postmortem examination showed the presence of widespread lesions of the brain stem affecting the dentato-rubro-olivary system. The main clinical features of the syndrome and their anatomical correlates are discussed.

The epidemiological, clinical, electrophysiological and nerve biopsy findings of 3 cases of n-hexane neuropathy in shoe industry are reported. The disease affects more than 1 person working in the same environment, regardless of their specific role, and occurs in factories where standards of hygiene are low. In the most severe cases the picture of peripheral neuropathy is associated with symptoms suggesting a concurrent involvement of the central nervous system such as dysarthria, disproportionate ataxia of the gait, blurred vision, and sometimes, after the recovery of the peripheral neuropathy, appearance of leg spasticity. Light- and electron microscopic study of peripheral nerve biopsies shows that the toxic produces a primary axonopathy characterized by segmental swellings of the fibers, due to accumulation of filaments. Retraction of the myelin from the node and segmental demyelination are secondary to the axonal changes. Experimental models of hexacarbon neurotoxicity may offer an explanation for the anatomical substrate underlying the symptoms related to the involvement of the central nervous system.

The clinico-pathological features of 4 cases of Creutzfeldt-Jakob disease, a transmissible virus dementia, are reported. The onset of the disease varied between 54 and 81 years of age: the course is dramatic and the demise occurs 1-4 months after the onset of symptoms. The clinical picture includes mental deterioration with amnesia, aphasia, apraxia and neurologic symptoms, mainly consisting in progressive rigidity and myoclonus. All cases show the typical 1/sec pseudorithmic spikes on EEG. Histological changes include severe astrocytosis of the cerebral cortex, status spongiosus and mild neuronal loss. The changes are more marked in the parieto-occipital lobes. Criteria of clinical and pathological diagnosis are reviewed. The precautions to be taken in handling biological as well as bioptic and autoptic specimens are emphasized, in order to avoid accidental transmission of the disease. It seems essential to institute a register of cases of Creutzfeldt-Jakob disease in Italy to assess the incidence and diffusion of the disease in our country.

The study was directed at detecting changes occurring in the early stages of the neurotoxic process induced by an intensive treatment with 2,5-hexanedione. Rats were injected intraperitoneally each day with 450 mg/kg of body weight for the first 14 days and then with 300 mg/kg for an additional 20 days. After 34 days of treatment typical axonal lesions were observed in the sciatic branches, together with electrophysiological signs of denervation in several fibres of the leg muscles. Morphological changes were also found in axons of the spinal cord and optic tracts. At an earlier stage (days 13 to 18), when clinical signs appeared, in the absence of morphological changes in peripheral nerves and of denervated muscle fibres, significant alterations in the functioning of several neuromuscular junctions were observed: increase in frequency and amplitude of miniature end-plate potentials, reduction of the mean quantal content of the evoked end-plate potential (epp) and absence of epp's in some fibres. These changes indicate a progressive functional impairment of nerve terminals which could possibly represent: (a) a primary alteration of the membrane resting and action potentials; (b) a secondary effect of changes in axonal transport. Both these hypothetical events could result from the inhibition of glycolitic enzymes of nervous tissue by 2,5-hexanedione.

A 50-year-old white woman with an 8-month history of Parkinson's syndrome which did not respond to levodopa therapy was found on pathological examination to have the topographical lesions of striato-nigral degeneration. In addition to those characteristic lesions, an associated degeneration of the optic pathways, from the level of the optic nerve to the geniculo-collicular fibers, of the corticospinal tract and of the olivo-dentate axis, were found. While offering further evidence for the concept of "multiple system degeneration", no pathogenetic relationship either to previous cases of striato-nigral degeneration or to other multiple system degenerations is implied.

An autopsied case of arteriovenous aneurysm of the vein of Galen in a 31/2-month-old female is reported. Arteriovenous aneurysm of the vein of Galen is a rare vascular malformation of the central nervous system consisting of a saccular dilatation of the vein which receives blood shunted through enlarged arteries. These peculiar structural and hemodynamic characteristics differentiate this particular malformation from the other AVMs of the central nervous system. In infants the arteriovenous aneurysm of the vein of Galen is characterized clinically by hydrocephalus and cardiomegaly. In the present paper the clinical features and diagnostic indications are discussed and, in particular, the role of computerized cranial tomography (CT) is emphasized as a rapid and noninvasive procedure for detection of intracranial disorders.

The authors report clinical, electrophysiological and pathological findings in 7 patients affected by peroneal muscular atrophy and postural tremor. Tremor in all patients showed similar features to essential tremor. Changes in sural nerve biopsies were typical either for neuronal or hypertrophic type of PMA.

The peripheral nerve biopsy specimens of 4 cases of toxic polyneruopathies induced by exposure to leather cement in shoe industries were studied. Analysis of the cements used in the manufacturing process proved them to contain n-hexane as a volatile substance. Light- and electron-microscopic examination of nerve biopsies showed segmental swelling of axons due to the accumulation of packed filaments and thinning of the overlying myelin sheath. Neither active nerve fibre degeneration nor regeneration were frequently seen. It has been suggested that features of so-called giant axonal neuropathy are the most common pattern of peripheral nerve degeneration in chronic n-hexane intoxication.

Light-, electron microscopic and immunopathological findings in a nerve biopsy of a patient with peripheral neuropathy associated with monoclonal gammopathy are reported. Loss of fibers, Wallerian-like degeneration and segmental demyelination were the most important features observed in light microscopy. In E.M. widening of the peripheral lamellae of myelin sheaths and occasional aspects of hypermyelination were seen. Immunoperoxidase study showed binding of IgM (k light chain) on the myelin sheath. The possible pathogenetic implications of these findings are discussed.

Histologically Alzheimer's disease is chiefly characterized by senile plaques and neurofibrillary degenerations. Electron microscopy has clarified the basic morphological changes and has shed some light on the pathogenesis of the lesions. The senile plaque includes three components: neurites in various stages of degeneration, amyloid, and glial cells or processes. Degeneration of neurites is considered to represent the major change since it occurs before amyloid deposition, therefore playing a primary role in the development of the plaque: therefore the senile or neuritic plaque is the result of a neuronal disease, even though there is no evidence of perikarion injury. Neurofibrillary tangles are due to the accumulation in the neuronal cytoplasm of large clusters of abnormal neurotubules about 200 A diameter with periodic narrowings every 800 A (Twisted tubules). The nature and significance of the pathological material observed within the neurons are discussed.

A 17-year-old girl with negative familial and personal history developed a progressive neurologic disorder characterized by cortical amaurosis, metal deterioration and spastic tetraparesis. Death occurred one year after the onset of symptoms. Histopathologic examination of the C.N.S. showed the presence of extensive, discontinuous demyelination of the white matter of the centrum ovale, with preservation of perivascular myelin islets, associated with massive fat degradation, loss of axons and severe astroglial proliferation. This case belongs to the group of sudanophilic leucodystrophies, being an atypical case, a transition between pure sudanophilic leucodystrophy and the group of Pelizaeus-Merzbacher's disease.

The genetical forms of hypertrophic neuropathies, inherited either as recessive or autosomal dominant trait, are classified, according to Dyck (1975), as HMSN type I, III, and IV. Sporadic cases are also reported. We studied three patients, one with autosomal recessive inheritance, and two without family history, who had the following common features: --onset of symptoms before the age to two years; --slowly progressive course; --peroneal muscular atrophy with absent tendon reflexes; --reduction of MCV and SCV; --decreased number of myelinated fibers; --schwannian cell hyperplasia, with onion bulb complexes formation; --absence of aspects of hypomyelination; --increased number of collagen pockets and denervated Schwann-Remak cells or processes. On light microscopy, multilamellated onion bulbs of large size were found in a very high percentage in case 1, while there were either simple in type or in a lower percentage in case 2. In the third, case, onion bulbs were recognized only on electron microscopy. It is known that in the various kinships affected with type I of HMSN, the pathological changes of peripheral nerves differ greatly. Therefore, despite early onset of symptoms and varying degree of severity of nerve changes, all three cases have been classified within the group of HMSN type I. The different severity of nerve damage may suggest the possibility of a genetical heterogeneity in this disorder.

4 patients with prosopagnosia are described. They presented associated neuropsychological deficits (achromatopsia, topographical disorientation) and visual field defects. In 1 case, gross pathological examination revealed bilateral symmetrical infero-medial occipito-temporal infarcts. In 2 other cases, computer tomography (CT) demonstrated bilateral inferior temporo-occipital infarction. In 1 case CT showed only occipital infarctions in the occipital lobes. This brings to 16 the number of anatomically studied cases of prosopagnosia (8 by necropsy, 8 by CT). In contrast to clinical localization, which often indicates only a right cerebral lesion, all anatomically verified cases of prosopagnosia exhibit bilateral lesions in the posterior cerebral artery distribution.

The results of a light and electron microscopy study of seven amputation neuromas are presented. The neuromas were removed during surgery for traumatic lesions of limbs. The histological study showed a complete disappearance of the nerve architecture at the neuroma level, where the fibres are collected in small bundles, enveloped in an abnormal perineural sheath, surrounded by an overgrowing connective tissue. In two cases a partial and incomplete reinnervation of the distal stump was found. The ultrastructural study shows abnormalities of the nervous fibers, both of the axon and of the relationships between the axonal part and the Schwann cell. The results of our data in man are compared to nerve regeneration patterns recently investigated in experimental models.

A case of Seitelberger's infantile neuroaxonal dystrophy (a rare familial neurologic disease of childhood) is described. The clinical picture is characterized by a progressive deterioration of psychomotor functions leading to flaccid paraplegia with hypotonia of axial muscles, complete involution of language, and total loss of communication with the external world; death due to recurrent unassociated disease occurred at the age of 4 years. Histology showed numerous axonal spheroids mainly in the gray matter of the C.N.S. and plurisystemic degenerations of the motor and sensory systems, of the cerebellum, of the basal ganglia, and of specific sensory system such as the optic and (reported here for the first time) of the olfactory and acoustic systems. In particular, the main histopathological findings included: 1) a characteristic distribution of axonal swellings prevailing in the posterior horn of the spinal cord and in the dorsolateral portions of the medulla oblongata, mainly at the level of the sensory nuclei; 2) demyelinization of the pyramidal tracts and of the ascendings pathways of the sensory system with fibrillar gliosis and myelin breakdown products in some areas (internal capsule, pes pedunculi, VPL thalamic nuclei); 3) severe cerebellar atrophy with almost complete loss of granule and Purkinje cells and marked fibrillary gliosis; 4) presence of enormous amount of sudanophilic lipids in the striatum and pallidum; 5) optic, acoustic and olfactory system degeneration with demyelinization and gliosis at all levels examined and, in particular, sudanophilic lipid deposition in the optic radiations, trigone, and olfactory striae. The discussion emphasized the dying-back type of evolution of the degenerative process insofar as a) the spheroids represent a peculiar alteration of presynaptic endings (as demonstrated by electron microscopy) prevailing at the first sensory neuron, and b) in all systems involved, the degeneration is most marked at distal levels. The striato-pallidal lipophanerosis suggests that the sudanophilic lipids are, here as in other systems, parenchymal degeneration products. On the other hand, there are still many unresolved problems in this rare and complex disease, such as a) the predilection of the lesions for the sensory systems which in our case involved all three special senses; b) the extreme cerebellar atrophy; and c) the etiopathogenetic substrate of the process. All biochemical and histochemical studies have not yielded any results up to the present.