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A 59-year-old man, ex-professional boxer, met clinical criteria for probable Alzheimer's disease. The patient agreed to be included in a clinico-pathological study with donation to the brain bank, and he died at 71. The brain was grossly atrophic, with a prominent atrophy of the entorhinal cortex and hippocampus, and with pallor of the substantia nigra. Immunohistochemistry with anti-τ A4 revealed abundant and diffuse deposits in the neo-cortex, whereas amyloid angiopathy was absent. Coupled anti-τ AT8 immunohistochemistry and Congo red staining showed no neuritic plaques. τ-AT8-positive glial tangles and neurofibrillary tangles involved preferentially the superficial cortical layers, and were irregularly concentrated in the depth of cortical sulci and near vessels. Neurofibrillary degeneration was marked in amygdala, hippocampus, substantia nigra, and locus ceruleus. Enlarged and/or distorted axons were numerous in hippocampus and mid-brain. TDP 43-positive neuronal inclusions were numerous in amygdala and hippocampus. There was no synucleinopathy. These observations are in accordance with the previously reported data on chronic traumatic encephalopathy. The discussion is focused on professional boxing as it becomes evident that repetitive trauma on the brain provokes the deposition of abnormal proteins involved in neurodegeneration.

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.

Simultaneous combined superficial peroneal nerve and peroneous brevis muscle biopsy, via the same cutaneous incision, allows examination of several tissue specimens and significantly improves the diagnosis of systemic diseases with peripheral nerve involvement. Vasculitides are certainly the most frequently diagnosed on neuro-muscular biopsies, but this procedure is also well advised to asses a diagnosis of sarcoidosis or amyloidosis. More occasionally, combined nerve and muscle biopsy may reveal an unpredicted diagnosis of cholesterol embolism, intra-vascular lymphoma, or enables complementary diagnosis investigations on mitochondrial cytopathy or storage disease.

There has been considerable progress during the past 24 years in the molecular genetics of mitochondrial DNA and related nuclear DNA mutations, and more than 100 nerve biopsies from hereditary neuropathies related to mitochondrial cytopathy have been accurately examined. Neuropathies were first reported in diseases related to point mutations of mitochondrial DNA, but they proved to be a prominent feature of the phenotype in mitochondrial disorders caused by defects in nuclear DNA, particularly in 3 genes: polymerase gamma 1 (POLG1), mitofusin 2 (MFN2), and ganglioside-induced differentiation-associated protein 1 (GDAP1). Most patients have sensory-motor neuropathy, sometimes associated with ophthalmoplegia, ataxia, seizures, parkinsonism, myopathy, or visceral disorders. Some cases are caused by consanguinity, but most are sporadic with various phenotypes mimicking a wide range of other etiologies. Histochemistry on muscle biopsy, as well as identification of crystalloid inclusions at electron microscopy, may provide a diagnostic clue to mitochondriopathy, but nerve biopsy is often less informative. Nevertheless, enlarged mitochondria containing distorted or amputated cristae are highly suggestive, particularly when located in the Schwann cell cytoplasm. Also noticeable are clusters of regenerating myelinated fibers surrounded by concentric Schwann cell processes, and such onion bulb-like formations are frequently observed in neuropathies caused by GDAP1 mutations.

Gerstmann-Straussler-Scheinker (GSS) disease is a rare inherited neurodegenerative disease due to a mutation in the prion protein (PRNP) gene, resulting in dementia and/or ataxia associated with mandatory amyloid plaques visible in the cerebral and/or cerebellar cortices on specimens stained with haematoxylin-eosin. Such amyloid plaques are dichroic in polarized light after Congo red staining and well marked by immunohistochemistry to prion protein (PrP). Almost every GSS family carries a PRNP missense mutation and almost half of them are due to a P102L mutation present in the original Austrian family [1], and also in a large family from central England [2–4]. GSS cases were also reported with a P105L mutation in Japan [5], with an A117V mutation in French-Alsacian [6], American [7] and English [8] families, and with a F198S mutation in the Indiana Kindred [9]. Other rare mutations have briefly been reported [3]. Three GSS cases due to an octapeptide repeat insertion (OPRI) in their PRNP between codons 51 and 91 [3] have also been investigated, eight in two unrelated French families [10– 13] and seven in a Dutch family [14]. We report here a French case with a novel six OPRI.

Background: Multiple mitochondrial DNA (mtDNA) deletions usually have a mendelian inheritance secondary to mutation in nuclear genes. One of these is the Twinkle gene whose mutation is responsible for autosomal dominant progressive external ophthalmoplegia (PEO). The number of reported cases with mainly myopathic symptoms and possible nervous system involvement related to Twinkle gene mutation is limited. We present a new French family of whom two members displayed myopathy and neuropathy associated with PEO, and we perform a clinical review in light of other observations reported in the literature. Methods: The proband, one son and the daughter have been investigated. Southern blot analysis and long-range PCR assay have been performed from muscle biopsy specimens. Coding exons and flanking intron regions of polymerase gamma (POLG) and DNA helicase (Twinkle) genes were sequenced. Results: Multiple mitochondrial DNA deletions have been found and sequencing of the Twinkle gene showed the change p.R374Q. Conclusion: Two other families from the literature also had the R374Q mutation. Symptoms reported in association with this mutation were myopathy, peripheral neuropathy, dysarthria and/or dysphagia, respiratory insufficiency and parkinsonism. Respiratory insufficiency caused by chest wall weakness was reported in other families with different Twinkle gene mutations, and one might provide exercise intolerance, dysarthria and/or dysphagia as symptoms in favor of the diagnosis. Occurrence of impressive emaciation was a peculiarity in our family.

International audience; Indications for nerve biopsy have decreased during the last 20 years. For the most part, this is a result of progress in the application of molecular biologic diagnostic testing for genetic peripheral neuropathies (PNs) and the increasing use of skin biopsy. The latter is primarily used to evaluate small-fiber PN, although it rarely discloses the specific etiology of a PN. Nerve biopsies are usually performed on either the sural or the superficial peroneal nerve, the latter in combination with removal of portions of the peroneus brevis muscle. The definite diagnosis of vasculitic lesions can be readily established on small paraffin-embedded nerve biopsy samples, although in some cases, the characteristic lesions are only apparent in muscle specimens. Other nerve specimens are routinely fixed in buffered glutaraldehyde and prepared for semithin sections and electron microscopy; frozen specimens are used for immunofluorescence studies. Electron microscopy is of great value in some cases of chronic inflammatory demyelinating polyneuropathies, monoclonal gammopathy, and storage diseases. Because more than 30 genes may be involved in genetic PNs, analysis of nerve lesions can direct the search for mutations in specific genes. Electron microscopy immunocytochemistry is mandatory in some cases of monoclonal dysglobulinemia. Thus, nerve biopsy is still of value in specific circumstances when it is performed by trained physicians and examined in a laboratory with expertise in nerve pathology.

Parkinsonism, chorea, and dystonia are well-known clinical manifestations of Creutzfeldt-Jakob disease (CJD), but lesions of the nigrostriatal pathway have never been thoroughly studied. We performed a detailed neuropathologic study of the nigrostriatal pathway in 15 sporadic CJD and 2 variant CJD cases that included clinical correlations and assessment of neuron subtype loss, distribution of prion protein, alpha-synuclein, ubiquitin, and 14-3-3 aggregation. We found evidence of nigrostriatal pathway damage in these CJD cases. Dopaminergic neurons and striatal outflow neurons were markedly affected in sporadic CJD, whereas cholinergic interneurons were spared. In cases of CJD with chorea or myoclonus, there was less presynaptic dopaminergic loss than in cases of CJD with parkinsonism. The 2 variant CJD cases with parkinsonism or chorea showed severe cholinergic interneuron loss in the caudate and putamen, a pattern that differed from that found in sporadic CJD. alpha-Synuclein, ubiquitin, and 14-3-3 aggregation coexisted with prion protein aggregation, thereby generating mixed pathological features. These findings suggest a possible pathophysiological overlap of abnormal protein aggregation in CJD and Parkinson disease.

Neurodegenerative disorders are characterized by the correlation of clinical symptoms and neuropathological changes in the brain. However, overlaps between distinct entities are becoming more and more evident. We report the coexistence of Alzheimer pathology and alpha-synuclein inclusions in a sporadic, methioninelvaline type 1, Creutzfeldt-Jakob disease (CJD) case. There were neurofibrillary changes in the neocortex and beta amyloid cerebral angiopathy was marked. Several Lewy bodies were present in the substantia nigra, locus ceruleus and the dorsal motor nucleus of the vagus, and alpha-synuclein cytoplasmic inclusions were also found in cortical neurons. These findings raise the debated relationship between Parkinson's disease with dementia, dementia with Lewy bodies and a Lewy body variant of Alzheimer disease. Among the factors that may have contributed to this considerable morphological overlap are the patient's age (79 years at autopsy) and the over 2-year duration of the disease. As the average disease duration in sporadic methionine/valine type 1 CJD is less than 6 months, it seems legitimate to speculate that the initial symptoms resulted from Alzheimer and alpha-synuclein related pathologies. This observation shows that CJD can be present in elderly patients who are suspected of having other neurodegenerative diseases, which could underline the importance of neuropathology-based surveillance systems.

Background: Peripheral neuropathy is known to be related to inflammatory bowel disease and it is one of the most frequently reported neurologic complications. Various studies have found peripheral nervous system complications, rather than central nervous system involvement, to be predominant. In the literature, there are a few cases of inflammatory polyneuropathy developed in the course of ulcerative colitis : 5 cases of Guillain-Barre syndrome, one case of chronic inflammatory demyelinating polyneuropathy, 10 cases of neuropathy and one case of perineuritis. Case presentation: We describe a case of chronic inflammatory polyneuropathy associated with ulcerative colitis. Conclusion: Peripheral neuropathy is not a common manifestation of IBD, highlighting the need for careful exclusion of other causes of neuropathy when both conditions are encountered in clinical practice.

One characteristic histological lesion on biopsy specimens is mandatory to establish the diagnosis of vasculitis. Combined nerve and muscle biopsies, by the same cutaneous incision, improve significantly the percentage of positive results. Nerve fragments should be taken in every patient presenting sensory manifestations. Such vasculitic lesions are present in medium-sized arterioles and/or small vessels, and correspond mainly to 4 necrotizing vasculitis: panarteritis nodosa (PAN), microscopic polyangiitis (MPA), Churg and Strauss syndrome and Wegener granulomatosis. Microvasculitis should be added to these classical entities, because it corresponds to small vessel wall infiltration by inflammatory cells, as observed in PAN and MPA, but without any necrosis. Microvasculitis has to be differentiated from the inflammatory cell infiltrates surrounding small vessels. However, such perivascular inflammatory cell infiltrates enable the diagnosis of probable vasculitis when associated with clusters of neo-vessels, hemosiderin deposits, or a focal damage of nerve fibers. Grossly, one third of vasculitis diagnosis is confirmed on muscle fragments, a second third on nerve fragments, and the last third on both nerve and muscle fragments. Moreover, in the search for vasculitis, an unpredicted diagnosis of lymphoma or amyloidosis is occasionally established on the neuro-muscular biopsy.

Churg-Strauss syndrome (CSS) is a distinctive clinical entity in which systemic vasculitis, associated with eosinophilia, occurs almost exclusively in individuals with adult-onset asthma. The major complications of the condition result from damage to the lungs, heart, and peripheral nerves. Necrotizing vasculitis with eosinophils in the cellular infiltrate, vascular or perivascular infiltration by eosinophils in absence of vessel wall necrosis, extra-vascular eosinophil infiltrates, and vascular or extra-vascular granuloma are histopathological features supportive of CSS. As the peripheral nerve disease often dominates the clinical picture, the peripheral nerve biopsy may be decisive in establishing the diagnosis. In this retrospective study of neuro-muscular biopsies in 24 CSS cases, the authors give an extensive description of neuropathological lesions associated with this disorder. Fifteen patients (62.5%) exhibited eosinophils either in extra-vascular infiltrates or in vessel walls, and 6 of them (25%) had an associated necrotizing vasculitis. Granulomas were found in only 3 cases (12.5%). The clinical diagnosis of CSS was supported in 15 out of the 24 patients (62.5%), in the nerve in 2 cases (8.3%), in the muscle in 8 cases (33.3%), and in both nerve and muscle in 5 others (20.8%).

A 35-year-old man had prolonged occupational exposure to lead carboxylate, triethylbenzene, xylene, and dichloromethane, when he developed a subacute predominantly sensory neuropathy. Ultrastructural examination of a peripheral nerve biopsy showed axonal degeneration and unusual lesions of the myelin, with Schwann cell sequestration of vesicular and lamellar debris. Biochemical analysis of lead in a frozen peripheral nerve specimen revealed no significant difference between the propositus and a control. The authors were unable to find any similar peripheral nerve lesions in the literature dealing with neurotoxic chemicals. Any of the several organic solvents could have equally caused the neuropathy and may have been potentialized by the other chemicals.

Some mutations of the lamin A/C gene may be responsible for a combination of distinct phenotypes, such as muscular dystrophy and peripheral neuropathy. We describe muscle and peripheral nerve lesions in a patient with a dominant lamin A/C missense mutation, E33D. Myopathic and neurogenic patterns coexisted on muscle biopsy specimens, whereas the peripheral nerve presented a mixture of axonopathy and Schwann cell hypertrophy. A few abnormal nuclei were found in muscle fibers and Schwann cells. Our morphological findings in this case attest to the predominant axonal damage, but suggest possible involvement of Schwann cells in neuropathies related to laminopathies.

Wilson's disease (WD) with extensive cortico-subcortical lesions represents a rare neuropathological subgroup, the pathogenesis of which is not clearly determined. We report two new cases with identical lesions. In the families of each of the patient, there were mutations in the ATPase7B gene, especially in the family of proband 1, and in the first cousin of proband 2. These cases included massive destruction of the white matter in superior gyri, mostly frontal, extending to the deep cortex with neuronal loss and capillary proliferation. Astrocytes were of Alzheimer type 1 and 2; and type 1 were labeled by anti-metallothionein. Opalski cells were abundant and their macrophagic lineage was confirmed by immunostaining. Among the possible mechanisms proposed, the role of vascular factors and penicillamine treatment could be excluded. Cerebral copper content in white matter and putamen of case 1 was at the same level as in common WD but accumulation of unbound copper in the white matter was a distinctive feature, which suggested a pathological neurotoxic effect.

We performed a retrospective study of 35 peripheral nerve biopsies (PNBs) with amyloid deposits in the endoneurium. In every case, nerve lesions were studied on paraffin-embedded fragments (PEFs) and by ultrastructural examination (USE). In addition, muscle fragments were taken and embedded in paraffin. Immunohistochemistry was performed with anti-transthyretin (TTR) serum on 19 nerve and 15 muscle PEFs. Direct immunofluorescence with anti-light-chain sera was performed on frozen nerve fragments in 19 cases. Endoneurial amyloid deposits were easily identified on routine PEF in 26 cases, after Congo red or thioflavine staining in three, and by USE in six. A dramatic myelinated fiber loss was evidenced in 34 cases (77-2970 per mm2), and features of axonal degeneration were present in every case. Segmental demyelination was observed in 10 cases. A mutation in the TTR gene was present in 14 cases, with Met30 mutation in 10 and Ala49 in four members of the same family. Amyloid deposits were strongly marked by the anti-TTR serum in 11 other cases, twice in the endoneurium, five around muscle fibers, and four in both locations. In eight patients, light-chain positivity was evidenced in endoneurial deposits, lambda in six and kappa in two. Two other patients with monoclonal gammopathy did not present any light-chain fixation. In 17 cases, amyloidosis was disclosed by PNB and 13 had a TTR pathology; eight of them, over 65 years old, correspond to a late-onset form of familial amyloid polyneuropathy which is an underdiagnosed condition.

In most cases of hereditary neuropathy with liability to pressure palsy (HNPP) the diagnosis is now assessed by molecular detection of 17p11.2 deletion. However, the family history may be missing and the clinical presentation is not always informative. In such cases, a peripheral nerve biopsy showing the characteristic focal myelin sheath thickening ("tomaculae") may be helpful. We present a retrospective study of peripheral nerve biopsies performed in 19 patients suffering from either a mononeuropathy or a generalized sensory-motor polyneuropathy, and for whom the finding of tomaculae led to a search for 17p11.2 deletion, which was confirmed secondarily. Tomaculae and other coexisting neuropathological lesions such as uncompacted myelin, "onion bulb" formations, and axonal degeneration are described and discussed in the view of previously reported data. It appears that demyelinating lesions with tomaculae are strongly suggestive of HNPP but are not specific as they may be observed in other conditions. Moreover, these features may be overlooked if axonal degeneration is marked.

Resume POEMS est un acronyme pour polyneuropathie, organomegalie, endocrinopathie, proteine monoclonale et signes cutanes (« skin changes » en anglais). Il est egalement denomme syndrome de Crow-Fukase principalement au Japon. Le plus souvent, les cinq elements du syndrome ne sont pas tous presents au moment du diagnostic, et les criteres minimum pour etablir le diagnostic sont la presence d’une neuropathie demyelinisante et axonale, associee a une gammapathie monoclonale IgG ou IgA, avec une chaine legere qui est presque toujours lambda, et au moins 2 des 8 autres signes du syndrome : plasmocytome sclerosant, endocrinopathie, lesions cutanees, organomegalie, maladie de Castleman, anasarque, œdeme papillaire ou thrombocytose. Aucun de ces signes n’est specifique, a l’exception des angiomes cutanes glomeruloides. L’identification ultrastructurale de lamelles de myeline non compactes sur la biopsie de nerf peripherique est, dans le contexte clinique, un element important en faveur du diagnostic. Une lesion osseuse habituellement osteocondensante doit etre soigneusement recherchee car son traitement peut ameliorer les autres signes du syndrome et specialement la neuropathie. Les cytokines et le facteur de croissance vasculaire endothelial pourraient jouer un role dans la pathogenie incompletement elucidee de cette affection multisystemique rare.

We report a case of Charcot-Marie-Tooth disease (CMT), with identified PMP22 gene duplication (CMT type 1A), and with evidence of an inflammatory demyelinating process superimposed on the course of the chronic genetic disease. Macrophage-associated demyelination was observed on the peripheral nerve biopsy. This observation supports some experimental data from the literature and shows that there may be a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds.

In 1969, Fardeau and Engel described polygonal organelles containing crystalline-like structures located in the Schwann cell cytoplasm of unmyelinated fibers. Such inclusions were reported in various conditions, mainly with axonal lesions. They were also reported in a few cases of peripheral neuropathy associated with primary mitochondriopathy. Although they are surrounded by a double membrane, their mitochondrial origin is not definitely proven. Their significance remains obscure but they deserve to be better known as Fardeau-Engel bodies, so as not to be mistaken with mitochondrial crystalline inclusions, which are frequently observed in patients with ragged-red fibers in muscle.

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa-induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X-associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado-Joseph disease related to an abnormal CAG repeat expansion in ataxin-3 (ATXN3) gene, Kufor-Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β-glucocerebrosidase (GBA) gene and Chediak-Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.

A 73-year-old man was investigated for a peripheral neuropathy which occurred in the course of a Waldenstrom's macroglobulinemia. Serum immuno-fixation electrophoresis demonstrated two IgM monoclonal gammopathies of the kappa and lambda chain isotypes, and one had the physical characteristics of cryoglobulin. Immunoblot studies on the patient's serum revealed antibodies which reacted with peripheral nervous system proteins of different molecular weights including the myelin-associated glycoprotein (MAG). An immunofluorescence study of a superficial peroneal nerve biopsy revealed not only a binding of IgM and kappa light chain on several myelin sheaths but also the presence of IgM and kappa light chain deposits in the endoneurium. On electron microscopic examination, numerous fibres presented a widely spaced myelin and the endoneurial deposits had the ultrastructure of cryoglobulin. This is the first case presenting features of widely spaced myelin related to serum anti-MAG activity associated with monoclonal cryoglobulin deposits in the endoneurium.

Clinical, electrophysiological, and neuropathological features are reported associated with a novel heterozygote point mutation in the extracellular domain of the MPZ gene, where a transversion at codon 71 in exon 3 leads to a codon stop: Glu71stop (ie GAA→TAA). A 36 year old woman developed a mild recurrent neuropathy after intensive manual work. The motor nerve conduction velocities were slow without conduction blocks and the nerve biopsy showed signs of demyelination-remyelination, axonal loss, and regular uncompacted myelin lamellae. She inherited the mutation from her father who displayed the same mutation with a normal phenotype. This nonsense mutation may cause a dosage difference of normal P0, and is probably underrepresented in the current mutation data bases. This report further extends the phenotype of MPZ mutations and also emphasises that mild phenotype of CMT1B may be more frequent than has been appreciated.

The TrkAII tyrosine kinase receptor differs from the TrkAI isoform by an insertion of six amino acids in the extracellular domain. We used RT-PCR to determine their respective distribution in rat and human brain. Only trkAII transcripts were detected in 12 rat brain regions, while both trkAI and trkAII transcripts were detected in the cerebellum and pituitary gland. In human, both trkAI and trkAII transcripts were detected in the frontal, temporal, and occipital cortex and thalamus, while only trkAI transcripts were detected in the hippocampus and cerebellum. In the caudate and putamen, trkAII transcripts were exclusively detected. Thereafter, we studied the expression of TrkA isoforms in the striatum of five patients with Alzheimer's disease (AD), four patients with non-AD dementia, seven patients with Parkinson's disease, and six paired nondemented elderly control individuals. In controls and non-AD patients, a constant expression of trkAII transcripts was detected within all striatum parts. In AD patients, a heterogeneous decrease in trkAII expression was observed in the caudate, putamen, and ventral striatum, resulting either in a drop of trkAII transcript levels or in a weak coamplification of trkAII and trkAI transcripts. The alteration of TrkAII gene expression paralleled those of choline acetyltransferase. Together with previous data, this suggests that the alteration of trk gene expression could contribute to a decrease in NGF binding sites and its protective effects on cholinergic neurons of AD patients.

It is well known that patients with Charcot-Marie-Tooth (CMT) disease are liable to present with episodes of cortisone-responsive demyelination, and a superimposed inflammatory component has been suggested. We report a patient who presented with a chronic inflammatory demyelinating polyneuropathy due to a recent HIV infection, which revealed a previously asymptomatic CMT 1A disease documented by identification of the characteristic duplication on the p11.2 region of chromosome 17. The inflammatory process was characterized by pathologic findings on a superficial peroneal nerve biopsy, and the patient improved significantly after corticotherapy. This report gives support to the hypothesis of a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds.

We found a new C-terminal amyloidogenic variant of apolipoprotein AI (apoAI), Leu178His in a French kindred, associated with cardiac and larynx amyloidosis and skin lesions with onset during the fourth decade. This single-point mutation in exon 4 of the apoAI gene was detected by DNA sequencing of polymerase chain reaction amplified material and restriction fragment length polymorphism analysis in two siblings. Blood, larynx, and skin biopsies were available from one sibling. Anti-apoAI immunoblotting of isoelectric focusing of plasma showed a +1 alteration in the charge of the protein. Extraction of fibrils from the skin biopsy revealed both full-length and N-terminal fragments of apoAI and transthyretin (TTR). ApoAI and TTR co-localized in amyloid deposits as demonstrated by immunohistochemistry. The present report, together with the first recently described C-terminal amyloidogenic variant of apoAI, Arg173Pro, shows that amyloidogenicity of apoAI is not a feature exclusive to N-terminal variants. The most striking characteristic of amyloid fibrils in Leu178His is that wild-type TTR is co-localized with apoAI in the fibrils. We have previously determined that a fraction of plasma TTR circulates in plasma bound to high-density lipoprotein and that this interaction occurs through binding to apoAI. Therefore we hypothesize that nonmutated TTR might influence deposition of apoAI as amyloid.

A 45-year-old woman presented with a recent sensorimotor deficiency in all 4 limbs, and the next day she was totally paralyzed. A slight motor improvement began on day 27. The cerebrospinal fluid had normal cellularity, but the protein varied from 90 mg/dL on the first day to 800 mg/dL on day 15, and then 290 mg/dL on day 33. Electrophysiologic studies performed on days 15 and 23 revealed a universal peripheral nerve inexcitability. A superficial peroneal nerve biopsy was performed on day 23. Nine fascicles were examined on semi-thin sections and myelinated fiber damage varied greatly from one fascicle to another. At ultrastructural examination, certain axons were severely damaged, but the others were quite well preserved and were naked or wrapped in a myelin sheath presenting a multivesicular degeneration. A few fibers had a better-preserved myelin sheath that was sometimes dissociated by elongated processes from an invading histiocyte. Six cases of fulminant Guillain-Barré syndrome with inexcitability of nerves and ultrastructural examination of nerve fragments have been reported. Electrophysiologic study is often ambiguous and cannot determine the precise origin of such an axonal degeneration. Therefore, ultrastructural analysis of a nerve biopsy is mandatory in this setting.

The authors recently reexamined the peripheral nerve biopsies from 42 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). There were 27 males and 15 females, aged from 9 to 84 years, and 13 had relapses. No patient had vasculitis, monoclonal gammopathy, tumor, diabetes mellitus, Lyme disease, familial neuropathy, HIV, or any other immune deficiency. In the endoneurium, perivascular inflammatory cell infiltrates were present in only one case, but scattered histiocytes marked by KP1 on paraffin-embedded fragments were present in every case and there were no T-lymphocytes. At ultrastructural examination macrophage-associated demyelination was observed in 17 cases, of which 6 had relapses separated by intervals of several months or years. Axonal lesions without associated primary demyelination were observed in 4 cases and 3 of these had relapses. Thirty-two patients had mixed lesions of demyelination and axonal involvement. This study confirms other recent data indicating that in all cases of CIDP, macrophages are present in the endoneurium. Macrophage-associated demyelination is the characteristic feature of demyelinating forms. On the other hand, isolated primary axonal forms, which have been known since 1989, are relatively frequent and prone to relapses.

Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.

Revue Neurologique - In Press.Proof corrected by the author Available online since samedi 25 avril 2015

We thank J. P. Mazat for his helpful discussion, M. Perrot for the DNA quantification, and C. Mehaye for technical assistance. This work was supported by a grant from the Ministere des Affaires Sociales de la Sante et de la Ville, Projet Hospitalier de Recherche Clinique, in 1994.

We studied modifications of the molecular layer of the cerebellum in three patients with octapeptide repeat insertion (OPRI). Two brothers carrying a six-OPRI showed only spongiosis in haematoxylin & eosin preparations (H&E), whereas immunocytochemical examination (ICC) with an antiprion protein (PrP) antibody revealed numerous elongated PrP deposits. The third patient from a family with an eight-OPRI had numerous plaques visible in H&E preparations and had been diagnosed as Gerstmann-Straussler-Scheinker syndrome. So far, 15 other cases from seven families and three individual cases with OPRI have undergone neuropathological examination. Characteristic PrP deposits were seen in six other cases, two isolated cases with a four- and a seven-OPRI, whereas four cases with a six-OPRI came from three different families. Such deposits have never been reported in other cases of prion encephalopathy, without OPRI. Genuine plaques were observed in five out of the 15 other patients. Interestingly, four had an eight-OPRI and one a nine-OPRI. Cases with OPRI are prone to develop different PrP deposits: those only visible on ICC are not to be confused with genuine plaques visible in H&E preparations. Elongated PrP deposits are present in cases with a four- to seven-OPRI, whereas plaques are present when there is an eight- or a nine-OPRI. All these cases should be termed prion encephalopathy with OPRI.

Inflammatory polyneuropathies are mainly known by their acute form, Guillain-Barré syndrome, but there are also chronic cases and all are considered as having an autoimmune mechanism. In each form, peripheral nerve biopsies show scattered macrophages in the endoneurium and in certain cases macrophages invade the Schwann cell cytoplasm and destroy the myelin sheath. In rarer cases there is a primary axonal degeneration. The authors studied two chronic cases, which both exhibited mixed primitive axonal and demyelinating lesions, with peculiar histiocytes in the endoneurium. These rounded cells were characteristically well marked by KP1 but showed well-developed rough endoplasmic reticulum cysternae at ultrastructural examination. Such plasmacytoid histiocytes have mainly been studied in subacute lymphadenopathies and have been only briefly illustrated in a few cases of peripheral neuropathies due to Lyme disease or HIV infection. The two cases reported here had no associated diseases and probably correspond to a peculiar subacute autoimmune reaction.

Characteristic myelin modifications in patients with IgM monoclonal gammopathy and anti-MAG activity have mainly been studied in cases of undetermined significance, but also exist in cases with indolent Waldenström's macroglobulinemia, i.e., when lymphoplasmocytic infiltration in bone marrow is 15% or more, without any visceral involvement. Since 1983, the authors have examined nerve biopsies from 8 cases with Waldenström's macroglobulinelia by direct immunofluorescence examination on frozen sections and ultrastructural examination. At direct immunofluorescence, fixation of anti-IgM serum on myelinated fibers was present in 7 cases. At ultrastructural examination, a widening of some myelin lamellae at the periphery of a few fibers was visible in 8 cases. A few fibers with hypermyelination were present in 5 cases. In 2 of these 5 cases widening of some myelin lamellae was present in numerous fibers, 88% in one of them. Frequently, there was a major widening of some myelin lamellae with dilated lamellae present in the inner part of the myelin sheath. Certain lamellae were more dilated, up to 50 nm. Occasionally, enlarged lamellae were not compacted with each other. The authors also examined nerve biopsies from 36 patients with IgM monoclonal gammopathy of undetermined significance and anti-MAG activity, but found only one case with major widening of some myelin lamellae. Five other cases with major widening of some myelin lamellae, 4 Waldenström's macroglobulinemia and 1 IgM monoclonal gammopathy of undetermined significance, have been reported. Given that demyelinating neuropathies are far more numerous in cases with IgM monoclonal gammopathy of undetermined significance, it is likely that cases of indolent Waldenström's macroglobulinemia are prone to develop major myelin modifications, possibly due to another mechanism, added to the classic anti-MAG activity.

Mitochondrial defects within substantia nigra (SN) neurons are implicated in the pathogenesis of Parkinson's disease. SN neurons show increased mitochondrial defects, mitochondrial DNA deletion levels, and susceptibility to such dysfunction, although the role of mitochondria in neuronal degeneration remains uncertain. In this study, we addressed this important question by exploring changes within the mitochondria of SN neurons from patients with primary mitochondrial diseases to determine whether mitochondrial dysfunction leads directly to neuronal cell loss. We counted the pigmented neurons and quantified mitochondrial respiratory activity, deficiencies in mitochondrial proteins, and the percentage of pathogenic mutations in single neurons. We found evidence of defects of both complex I and complex IV of the respiratory chain in all patients. We found that marked neuronal cell loss was only observed in a few patients with mitochondrial disease and that all these patients had mutations in polymerase gamma (POLG), which leads to the formation of multiple mitochondrial DNA deletions over time, similar to aging and Parkinson's disease. Interestingly, we detected α-synuclein pathology in two mitochondrial patients with POLG mutations. Our observations highlight the complex relationship between mitochondrial dysfunction and the susceptibility of SN neurons to degeneration and α-synuclein pathology. Our finding that the loss of SN neurons was only severe in patients with POLG mutations suggests that acquired mitochondrial defects may be less well tolerated by SN neurons than by inherited ones.

We report a severe phenotype of Charcot-Marie-Tooth (CMT) disease type 1E caused by a novel p.Phe84Leufs*24 PMP22 point mutation. Ultrastructural examination of a nerve biopsy showed non- or partly myelinated axons which were surrounded by "onion bulb" formations mainly composed of concentric basement membranes and characterized by the presence of prominent concentric or longitudinal collagen fibrils interspersed with basement membranes. PMP22 point mutations are rare and responsible for polyneuropathies often demyelinating with onion bulb formations composed of concentric and redundant basement membranes. Entrapment of prominent collagen fibrils within onion bulb formations is unusual, even in the large spectrum of CMT disease with long duration and severe damage.

Summary A 36-year-old man had an oval, black, extradural tumor partly removed from the left C4 spinal root, with total removal 4 months later. In both specimens, most tumor cells were spindle-shaped. A few cells were large, epithelioid-like, with a prominent nucleolus. Mitoses were rarely seen. Many tumor cells contained coarse or fine granules of a brown pigment. Such cells were immunopositive for S-100 protein and HMB-45. Additionally, psammoma bodies were numerous in certain areas, indicating a diagnosis of psammomatous melanotic schwannoma (PMS). Periumbilical spotty pigmentation was found in the patient and in six of his siblings and their mother. The search for cardiac myxoma and endocrine overactivity was negative in the patient. Features of Carney's complex must be sought in a patient with PMS and in their primary relatives. So far, more than 150 patients and seven families with Carney’s complex have been reported.

✓ A rare case of lymphoplasmacyte-rich meningioma observed in a young girl is reported. The first clinical manifestations of the disease were seizures. Neuroradiological images favored the existence of a meningioma. Abnormalities in the patient's blood chemistry, principally including hypergammaglobulinemia and inflammatory syndrome, were associated with the disease. The tumor was histologically confirmed as meningioma with massive infiltrates of type B lymphocytes. The pathophysiology of the conspicuous lymphoplasmacyte infiltrates, responsible for peripheral blood abnormalities, has remained poorly understood. Alternative diagnostic hypotheses of masses that mimic this type of meningioma are discussed.

Either dominantly inherited mutations in MFN2 encoding mitofusin 2 or GDAP1 encoding ganglioside-induced differentiation associated protein 1 may be associated with mild neuropathy. The proband, a 41-year-old woman, and her daughter present a severe axonal form of Charcot–Marie–Tooth (CMT) disease. Both are heterozygous for the well-described mild variant p.R120W in GDAP1, which was transmitted by the pauci symptomatic proband’s mother. Given that they had an early onset in the first decade and delayed walking acquisition, the other genes implicated in axonal forms of CMT disease were analyzed. A second mutation truncating MFN2 (p.Val160fsX26) was found in the proband and her daughter. This mutation was transmitted by the proband’s father who has normal neurological examination. The proband underwent two nerve biopsies which showed an axonal degeneration, myelin modifications, and intra-axonal mitochondria with distorted cristae. Such abnormal mitochondria have been reported in cases with autosomal dominant MFN2 mutations and in one patient with an autosomal recessive GDAP1 mutation. Our two cases show that heterozygous truncation of MFN2, which is silent at least until the sixth decade, when combined with the mild p.R120W GDAP1 variant, leads to a severe neuropathy. This supports the emerging hypothesis of cumulative effects of MFN2 and GDAP1 mutation.

A patient with a mass lesion of Müllerian origin associated with a spinal dysraphism is reported. The mass lesion was a genuine uterine formation, and a hemorrhage arose from a functional endometrium. A spinal dysraphism was associated, including a low-lying conus medullaris, a subcutaneous lipoma, and a sinus between the cul-de-sac and the lipoma. This ectopic and mature tissue may be differentiated from teratoma and endometriosis.

Two patients suffering from acute myelomonoblastic leukaemia developed clinical evidence of peripheral nerve involvement. In both cases, a peripheral nerve biopsy revealed endoneurial cellular infiltrates which were identified as leukaemic cells by immunocytochemistry. Ultrastructural studies showed mainly axonal damage. Moreover, in one patient, a few features of active demyelination were also observed.

By using monoclonal antibodies directed against the conserved zinc binding site of zinc finger proteins, we detected 2 prominent zinc finger proteins in rat peripheral nervous system (PNS) during development, and in adult normal and Trembler mice sciatic nerves. The protein of 55 kDa is abundant in adult normal mice and rats, but is weakly expressed in adult Trembler mice. The 29 kDa protein is expressed in neonatal rats and in the Trembler mouse, but is absent in adult rats and mice. These results suggest that the Schwann cell proliferation stage may be associated with the 29 kDa protein expression, and the 55 kDa protein may be implicated in the PNS myelination process.

International audience; The age-related altered expression of neuron-related proteins as seen in other regions of the central nervous system is expected in the aging retina. Using immunohistochemical techniques, we characterized the distribution and aggregation of tau, βA4-amyloid, α-synuclein, and ubiquitin in human retina obtained from 19 enucleated eyes of patients aged 49 to 87 years and correlated the findings with the ages. Using a phosphorylation-independent antibody, tau aggregates were observed within the cytoplasm of several photoreceptor cells, and there was a positive correlation between age and the number of tau-positive ganglionic cells. Tau deposits were immunonegative with a phosphorylation-dependent antibody. We did not observe βA4-amyloid in subretinal pigment epithelium deposits or in neuroepithelial layers. α-Synuclein and ubiquitin inclusions were found in the inner nuclear layer, and there was colocalization of these proteins. The proportion of patients displaying such α-synuclein and/or ubiquitin intracytoplasmic inclusions was significantly higher with aging. The presence of ubiquitin deposits within drusen was remarkable, but diffuse ubiquitin aggregates between the retinal pigment epithelium and Bruch membrane were also noticed. These results indicate that protein aggregation in the retina increases with aging and that tau, α-synuclein, and ubiquitin should be the subjects of future investigations.

Objective Most cases of familial amyloid polyneuropathy are identified by molecular genetic analysis of the transthyretin (TTR) gene. However, it is not uncommon to find unexpected amyloid deposits marked by the anti-TTR serum in the endoneurium of aged patients. Light chain amyloid deposits may also be found in the endoneurium. During these past 5 years, we studied the muscle and nerve biopsies from 6 patients which revealed amyloid deposits. There were 2 patients with an idiopathic polyneuropathy and 4 with monoclonal gammopathy (MG). Methods In each case, specimens from the superficial peroneal nerve and peroneus brevis muscle were taken by the same cutaneous incision. Results Amyloid deposits were visible in the endoneurium of 2 cases and only on muscle specimens in 3 other cases, 1 with a MG and 2 with an idiopathic polyneuropathy. Amyloid deposits were strongly stained with the anti-TTR serum in the muscle specimens of the 2 idiopathic cases, mainly located in vessel walls. In one patient with polyneuropathy and MG, a small endoneurial amyloid deposit surprisingly revealed to be immunostained by the anti-TTR serum. In another case, a small amyloid deposit in close relationship with a macrophage was only visible in the endoneurium by electron microscopy. Comments Amyloid deposits were only visible on muscle fragments in 3 cases and were strongly marked by the anti-TTR serum in 2 of them, indicating their familial origin. Combining muscle and nerve biopsy raises the number of cases with visible amyloid deposits.

A peripheral nerve biopsy was performed in 15 patients with human immunodeficiency virus (HIV) infection and polyneuropathy. Two cases [1 asymptomatic, 1 AIDS-related complex (ARC)] presented with chronic inflammatory demyelinating polyneuropathy; there was 1 case (asymptomatic) of mononeuropathy multiplex and 12 cases (1 asymptomatic, 1 ARC, 10 AIDS) with distal symmetrical polyneuropathy. Epi- or endoneurial microvasculitis was observed in 6 cases. Electron microscopy showed that nerve fiber lesions were mainly axonal. Severe segmental demyelination was also present in both cases of chronic inflammatory demyelinating polyneuropathy, with characteristic features of active demyelination in one. Numerous plasmacytoid cells were found in the endoneurium in 4 patients. Tubuloreticular inclusions were present in endothelial cells in the 10 cases with AIDS but absent in the other patients. Direct immunopathological examination with anti-immunoglobulin sera was negative in all cases. HIV was evidenced by in situ hybridization in 2 AIDS patients; no Epstein-Barr virus or cytomegalovirus was detected.

A subacute ascending polyradiculoneuropathy was the main feature of a primary meningeal B lymphoma in two patients. Tumour cells appeared in the CSF eight and six months respectively after the onset of the disease. Treatment by intrathecal methotrexate resulted in transient improvement.

Two cases, a man and a woman, presented the initial signs of progressive dementia at about age 40 years. Aphasia, facial dyskinesias, and ataxia were associated with behavioral disturbances in the first patient. Aphasia, oculomotor distur bances, and ataxia coexisted with dementia in the second patient. In both cases, ultrastructural examination of a cerebral biopsy showed intraneuronal granular osmiophilic deposits mixed with lamellar structures and fingerprint profiles. Such deposits are characteristic of Kufs' disease. In the first patient, brain autopsy was performed 3 years after cerebral biopsy. Our two cases presenting dementia with motor disturbances correspond to type B Kufs' disease ( J Geriatr Psychiatry Neurol 1991; 4:110-115).