Pure sensory neuropathy in patients with primary Sjogren's syndrome: clinical, immunological and electromyographic findings

A pure sensory neuropathy caused by lymphocytic infiltration of the dorsal root ganglia has been reported in a few patients with Sjögren's syndrome. The clinical, immunological, and electromyographic findings of five patients with this type of neuropathy and primary Sjögren's syndrome were reviewed. Typical clinical indications were the presence of a chronic asymmetrical sensory deficit, initial disease in the hands with a predominant loss of the vibratory and joint position senses, and an association with Adie's pupil syndrome or trigeminal sensory neuropathy. The simultaneous impairment of the central and peripheral evoked cortical potentials suggested that there was a lesion of the neuronal cell body. The neuropathy preceded the diagnosis of Sjögren's syndrome in four patients. Four patients were positive for Ro antibodies, but systemic vasculitis or malignancy was not found after a mean follow up of six years. These findings indicate that in patients with a sensory neuropathy the diagnosis of Sjögren's syndrome has to be considered, even if the patient denies the presence of sicca symptoms, and that appropriate tests must be carried out.

Hereditary hepatic and systemic amyloidosis caused by a new deletion/insertion mutation in the apolipoprotein AI gene.

We report a Spanish family with autosomal-dominant non-neuropathic hereditary amyloidosis with a unique hepatic presentation and death from liver failure, usually by the sixth decade. The disease is caused by a previously unreported deletion/insertion mutation in exon 4 of the apolipoprotein AI (apoAI) gene encoding loss of residues 60-71 of normal mature apoAI and insertion at that position of two new residues, ValThr. Affected individuals are heterozygous for this mutation and have both normal apoAI and variant molecules bearing one extra positive charge, as predicted from the DNA sequence. The amyloid fibrils are composed exclusively of NH2-terminal fragments of the variant, ending mainly at positions corresponding to residues 83 and 92 in the mature wild-type sequence. Amyloid fibrils derived from the other three known amyloidogenic apoAI variants are also composed of similar NH2-terminal fragments. All known amyloidogenic apoAI variants carry one extra positive charge in this region, suggesting that it may be responsible for their enhanced amyloidogenicity. In addition to causing a new phenotype, this is the first deletion mutation to be described in association with hereditary amyloidosis and it significantly extends the value of the apoAI model for investigation of molecular mechanisms of amyloid fibrillogenesis.

Relationship between autonomic neuropathy and thermogenesis in non diabetic and diabetic obese patients.

Autonomic neuropathy is a well known complication of diabetes. Diabetes is often superimposed on obesity. A reduction in the variability of the heart rate in the resting state has been demonstrated in 16 obese diabetic subjects as well as in 34 obese non-diabetic subjects. The coefficient of variation (CV) of the heart rate during 30 minutes of resting was significantly decreased in both obese groups (3.9 +/- 0.2% for the diabetics; 5.2 +/- 0.2%, p less than 0.01 for the non diabetics) as compared to their own controls (4.5 +/- 0.6% and 6.5 +/- 0.4%, respectively). Age also contributes to decreased heart rate variability. Furthermore, this defect of autonomic function has been correlated with the blunted glucose-induced thermogenesis (GIT) seen in both obese groups (r = 0.52, p. less than 0.001): the increase in energy expenditure over basal values following a 100 g oral glucose load was only 4.8 +/- 0.8% for the diabetic obese group (p less than 0.001), and 8.5 +/- 0.7% for the non-diabetic obese group (p less than 0.001) as opposed to their own controls (12.4 +/- 1.3% and 13.3 +/- 0.6% respectively). Measurement of the variability of heart rate in obese individuals may be of predictive value in assessing blunted glucose-induced thermogenesis in non diabetic and diabetic obese patients.

Scapulalgie et neuropathie sus-scapulaire en pathologie sportive [Scapular pain and supra-scapular neuropathy in sports medicine]

Eight patients with shoulder pain are reported with a history of athletic activities. On examination, performed with a delay of several months, all patients had painful paresis and atrophy of spinati fossa. Electroneuromyography was carried out in all cases and showed a suprascapular nerve axonal loss from the spinati muscles or infraspinatus muscle, signs of denervation-reinnervation in spinati or infraspinatus muscles, normal examination of other scapular girdle muscles, and a coordinate spinati contraction with shoulder displacement excluding rotator cuff tears. All patients had conservative treatment and only two improved. Six patients underwent surgical decompression of the suprascapular nerve; in three, motor function clearly improved, and in three others pain improved. The factors leading to entrapment include stretch mechanisms associated with shoulder movements, leading to suprascapular nerve liability to mechanical lesions. In patients with shoulder pain, the authors recommend an early electrophysiological work-up to recognize an isolated suprascapular neuropathy. The surgical decompression of the nerve should be based on persistent shoulder pain after conservative treatment.

Neuropathie optique lors d'un traitement par disulfirame [Optic neuropathy while taking disulfiram]

INTRODUCTION: Disulfiram has been used since the late 1940s to treat chronic alcoholism. This drug interferes with alcohol metabolism resulting in an acetaldehyde increase. This causes painful symptoms, encouraging abstinence. Side effects include rare cases of bilateral optic neuropathies. Visual recovery occurs frequently upon cessation of therapy. METHOD AND OBSERVATION: We retrospectively studied patients referred for visual loss while treated with disulfiram between 1987 and 2005. Fourteen patients (three females, 11 males; aged 35-62 years) complained of visual loss, but a toxic, disulfiram-related, optic neuropathy was diagnosed in only five patients. Following cessation of disulfiram therapy, visual acuity and field improved in all five patients. DISCUSSION: and conclusion: When disulfiram toxicity is suspected with optic neuropathy, cessation of treatment is mandatory. Visual prognosis is good in the majority of cases, as illustrated by our series. Disulfiram toxicity can be diagnosed only after excluding all other possible causes of visual loss.

Novel pathogenic pathways in diabetic neuropathy.

Diabetic peripheral neuropathy (DPN) is a common complication affecting more than one third of diabetes mellitus (DM) patients. Although all cellular components participating in peripheral nerve function are exposed to and affected by the metabolic consequences of DM, nodal regions, areas of intense interactions between Schwann cells and axons, may be particularly sensitive to DM-induced alterations. Nodes are enriched in insulin receptors, glucose transporters, Na(+) and K(+) channels, and mitochondria, all implicated in the development and progression of DPN. Latest results particularly reinforce the idea that changes in ion-channel function and energy metabolism, both of which depend on axon-glia crosstalk, are among the important contributors to DPN. These insights provide a basis for new therapeutic approaches aimed at delaying or reversing DPN.

A hypomorphic mutation in lpin1 induces progressively improving peripheral neuropathy in the rat

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat with a mutated Lpin1 gene (Lpin11Hubr ), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin11Hubr rats are characterized by hindlimb paralysis that is detectable from the second postnatal week. Sequencing of Lpin1 identified a missense mutation in the 5'-end splice site of exon 18 resulting in mis-splicing, a reading frame shift and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. As a consequence, Lpin11Hubr rats develop hypomyelination rather than the pronounced demyelination defect characteristic of Lpin1fld/fld mice, which carry a null allele for Lpin1. Furthermore, histological and molecular analyses revealed that this lesion improve in older Lpin11Hubr rats as compared to young Lpin11Hubr rats and Lpin1fld/fld mice. The observed differences between the murine Lpin1fld/fld mutant, with a complete loss of Lipin 1 function, and the Lpin1Hubr rat, with a truncated PAP1 activitydeficient form of Lipin 1, provide additional evidence for suggested non-enzymatic Lipin1 function residing outside of its PAP1 domain. While we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into pathogenicity of recently identified human Lpin1 mutations. *These authors contributed equally.

Bilateral anterior ischemic optic neuropathy following influenza vaccination.

Optic neuritis is an occasional complication of vaccination. Visual loss can be unilateral or bilateral, and most patients recover substantially without treatment. The presumptive mechanism is an immune-mediated demyelinating injury of the optic nerve. We report two patients who had permanent visual loss following influenza vaccination. Their pattern of visual loss, segmental optic disc changes, and failure of visual recovery were atypical for demyelinating optic neuritis and reminiscent of a primary ischemic injury to the optic nerve. We speculate that an immune complex-mediated vasculopathy following vaccination can cause anterior ischemic optic neuropathy. Clinicians should be aware of this entity because of the less favorable prognosis for visual recovery in these cases.

Franceschetti hereditary recurrent corneal erosion.

PURPOSE: To describe new affected individuals of Franceschetti's original pedigree of hereditary recurrent erosion and to classify a unique entity called Franceschetti corneal dystrophy. DESIGN: Observational case series. METHODS: Slit-lamp examination of 10 affected individuals was conducted. Biomicroscopic examinations were supplemented by peripheral corneal biopsy in 1 affected patient with corneal haze. Tissue was processed for light and electron microscopy and immunohistochemistry was performed. DNA analysis was carried out in 12 affected and 3 nonaffected family members. RESULTS: All affected individuals suffered from severe ocular pain in the first decade of life, attributable to recurrent corneal erosions. Six adult patients developed bilateral diffuse subepithelial opacifications in the central and paracentral cornea. The remaining 4 affected individuals had clear corneas in the pain-free stage of the disorder. Histologic and immunohistochemical examination of the peripheral cornea in a single patient showed a subepithelial, avascular pannus. There was negative staining with Congo red. DNA analysis excluded mutations in the transforming growth factor beta-induced (TGFBI) gene and in the tumor-associated calcium signal transducer 2 (TACSTD2) gene. CONCLUSION: We have extended the pedigree of Franceschetti corneal dystrophy and elaborated its natural history on the basis of clinical examinations. A distinctive feature is the appearance of subepithelial opacities in adult life, accompanied by a decreased frequency of recurrent erosion attacks. Its clinical features appear to distinguish it from most other forms of dominantly inherited recurrent corneal erosion reported in the literature.

Phenotypic and molecular characterization of the onset of neuropathy in rodent models of diabetes mellitus

Abstract : The principal focus of this work was to study the molecular changes leading to the development of diabetic peripheral neuropathy (DPN). DPN is the most common complication associated with both type I and II diabetes mellitus (DM). This pathology is the leading cause of non-traumatic amputations. Even though the pathological and morphological changes underlying DPN are relatively well described, the implicated molecular mechanisms remain poorly understood. The following two approaches were developed to study the development of DPN in a rodent model of DM type I. As a first approach, we studied the implication of lipid metabolism in DPN phenotype, concentrating on Sterol Response Element Binding Protein (SREBP)-lc which is the key regulator of storage lipid metabolism. We showed that SREBP-1c was expressed in peripheral nerves and that its expression profile followed the expression of genes involved in storage lipid metabolism. In addition, the expression of SREBP-1c in the endoneurium of peripheral nerves was dependant upon nutritional status and this expression was also perturbed in type I diabetes. In line with this, we showed that insulin elevated the expression of SREBP-1c in primary cultured Schwann cells by activating the SREBP-1c promoter. Taken together, these findings reveal that SREBP-1c expression in Schwann cells responds to metabolic stimuli including insulin and that this response is affected in type I diabetes mellitus. This suggests that disturbed SREBP-1c regulated lipid metabolism may contribute to the pathophysiology of DPN. As a second approach, we performed a comprehensive analysis of the molecular changes associated with DPN in the Akital~1~+ mouse which is a model of spontaneous early-onset type I diabetes mellitus. This mouse expresses a mutated non-functional isoform of insulin, leading to hypoinsulinemia and hyperglycaemia. To determine the onset of DPN, weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Akital+/+ mice during the first three months of life. A decrease in MNCV was evident akeady one week after the onset of hyperglycemia. To explore the molecular changes associated with the development of DPN in these mice, we performed gene expression profiling using sciatic nerve endoneurium and dorsal root ganglia (DRG) isolated from early diabetic male Akita+/+ mice and sex-matched littermate controls. No major transcriptional changes were detected either in the DRG or in the sciatic nerve endoneurium. This experiment indicates that the phenotypic changes observed during the development of DPN are not correlated with major transcriptional alterations, but mainly with alterations at the protein level. Résumé Lors ce travail, nous nous sommes intéressés aux changements moléculaires aboutissant aux neuropathies périphériques dues au diabète (NPD). Les NPD sont la complication la plus commune du diabète de type I et de type II. Cette pathologie est une cause majeure d'amputations. Même si les changements pathologiques et morphologiques associés aux NPD sont relativement bien décrits, les mécanismes moléculaires provoquant cette pathologie sont mal connus. Deux approches ont principalement été utilisées pour étudier le développement des NPD dans des modèles murins du diabète de type I. Nous avons d'abord étudié l'impact du métabolisme des lipides sur le développement des NPD en nous concentrant sur Sterol Response Element Binding Protein (SREBP)-1 c qui est un régulateur clé des lipides de stockage. Nous avons montré que SREBP-1 c est exprimé dans les nerfs périphériques et que son profil d'expression suit celui de gènes impliqués dans le métabolisme des lipides de stockage. De plus, l'expression de SREBP-1c dans l'endoneurium des nerfs périphériques est dépendante du statut nutritionnel et est dérégulée lors de diabète de type I. Nous avons également pu montrer que l'insuline augmente l'expression de SREBP-1c dans des cultures primaires de cellules de Schwann en activant le promoteur de SREBP-1c. Ses résultats démontrent que l'expression de SREBP-1c dans les cellules de Schwann est contrôlée par des stimuli métaboliques comme l'insuline et que cette réponse est affectée dans le cas d'un diabète de type I. Ces données suggèrent que la dérégulation de l'expression de SREBP-1c lors du diabète pourrait affecter le métabolisme des lipides et ainsi contribuer à la pathophysiologie des NPD. Comme seconde approche, nous avons réalisé une analyse globale des changements moléculaires associés au développement des NPD chez les souris Akita+/+, un modèle de diabète de type I. Cette souris exprime une forme mutée et non fonctionnelle de l'insuline provoquant une hypoinsulinémie et une hyperglycémie. Afin de déterminer le début du développement de la NPD, le poids, le niveau de glucose sanguin et la vitesse de conduction nerveuse (VCN) ont été mesurés durant les 3 premiers mois de vie. Une diminution de la VCN a été détectée une semaine seulement après le développement de l'hyperglycémie. Pour explorer les changements moléculaires associés avec le développement des NPD, nous avons réalisé un profil d'expression de l'endoneurium du nerf sciatique et des ganglions spinaux isolés à partir de souris Akital+/+ et de souris contrôles Akita+/+. Aucune altération transcriptionnelle majeure n'a été détectée dans nos échantillons. Cette expérience suggère que les changements phénotypiques observés durant le développement des NPD ne sont pas corrélés avec des changements importants au niveau transcriptionnel, mais plutôt avec des altérations au niveau protéique. Résumé : Lors ce travail, nous nous sommes intéressés aux changements moléculaires aboutissant aux neuropathies périphériques dues au diabète (NPD). Les NPD sont la complication la plus commune du diabète de type I et de type II. Cette pathologie est une cause majeure d'amputations. Même si les changements pathologiques et morphologiques associés aux NPD sont relativement bien décrits, les mécanismes moléculaires provoquant cette pathologie sont mal connus. Deux approches ont principalement été utilisées pour étudier le développement des NPD dans des modèles murins du diabète de type I. Nous avons d'abord étudié l'impact du métabolisme des lipides sur le développement des NPD en nous concentrant sur Sterol Response Element Binding Protein (SREBP)-1c qui est un régulateur clé des lipides de stockage. Nous avons montré que SREBP-1 c est exprimé dans les nerfs périphériques et que son profil d'expression suit celui de gènes impliqués dans le métabolisme des lipides de stockage. De plus, l'expression de SREBP-1c dans l'endoneurium des nerfs périphériques est dépendante du statut nutritionnel et est dérégulée lors de diabète de type I. Nous avons également pu montrer que l'insuline augmente l'expression de SREBP-1c dans des cultures primaires de cellules de Schwann en activant le promoteur de SREBP-1c. Ses résultats démontrent que l'expression de SREBP-1c dans les cellules de Schwann est contrôlée par des stimuli métaboliques comme l'insuline et que cette réponse est affectée dans le cas d'un diabète de type I. Ces données suggèrent que la dérégulation de l'expression de SREBP-1c lors du diabète pourrait affecter le métabolisme des lipides et ainsi contribuer à la pathophysiologie des NPD. Comme seconde approche, nous avons réalisé une analyse globale des changements moléculaires associés au développement des NPD chez les souris Akita~~Z~+, un modèle de diabète de type I. Cette souris exprime une forme mutée et non fonctionnelle de l'insuline provoquant une hypoinsulinémie et une hyperglycémie. Afin de déterminer le début du développement de la NPD, le poids, le niveau de glucose sanguin et la vitesse de conduction nerveuse (VCN) ont été mesurés durant les 3 premiers mois de vie. Une diminution de la VCN a été détectée une semaine seulement après le développement de l'hyperglycémie. Pour explorer les changements moléculaires associés avec le développement des NPD, nous avons réalisé un profil d'expression de l'endoneurium du nerf sciatique et des ganglions spinaux isolés à partir de souris Akital+/+ et de souris contrôles Akita+/+. Aucune altération transcriptionnelle majeure n'a été détectée dans nos échantillons. Cette expérience suggère que les changements phénotypiques observés durant le développement des NPD ne sont pas corrélés avec des changements importants au niveau transcriptionnel, mais plutôt avec des altérations au niveau protéique.