Leukodystrophies: clinical and therapeutic aspects

This chapter reviews that leukodystrophies is a genetic diseases that occur in early childhood. It is a possibility that leads to screening for leukodystrophy patients with early-onset dementia of unknown origin or atypical psychiatric symptoms. The chapter focuses on genetic cases of white matter involvement presenting with deficits in cognitive functions or dementia. Leukodystrophies are rare causes of dementia in the adult. They may cause a dementia of the frontal type or psychiatric symptoms than can mimic schizophrenia but are rapidly associated with long tract involvement. The presence of other cases in the family is a crucial step in the diagnosis but apparently isolated cases are frequent. Homochrony and homotypy are the rule but with many exceptions they have to be considered for genetic counseling. MRI is also critical, showing abnormal increased signals of the white matter on T2-weighted and FLAIR sequences, with a frontal predominance. Normal MRI imaging, at least at the beginning of the disease, does not rule out the diagnosis. The study of the pathogenetic mechanisms of leukodystrophies has been improved by the development and the analysis of animal models. The chapter states that no curative treatment is yet available. New perspectives have opened with the development of cell and gene therapies, even in adult forms, where the demyelination can at least be stabilized

Neuropathie démyélinisante au cours d’un traitement par anti-TNF alpha et revue de la littérature

Introduction Tumor necrosis factor- (TNF) blockers are efficient in the treatment of autoimmune disorders such as inflammatory bowel disease and rheumatoid arthritis, but can induce CNS adverse effects including retrobulbar optic neuritis or aggravation of multiple sclerosis. Observation We report a case of progressive demyelinating polyneuropathy after initiation of Adalimumab (Humira®). Corticosteroid and intravenous immunoglobulins were ineffective but the neuropathy improved within six months after adalimunab discontinuation. Discussion This case, and other reports recently published suggest that anti-TNF alpha drugs can induce demyelinating neuropathy. Conclusion Clinicians should be on the lookout for signs evocating neuropathy in patients given anti TNF alpha

Stable tubule only polypeptides (STOP) proteins co-aggregate with spheroid neurofilaments in amyotrophic lateral sclerosis

A major cytopathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of axonal spheroids containing abnormally accumulated neurofilaments. The mechanism of their formation, their contribution to the disease, and the possibility of other co-aggregated components are still enigmatic. Here we analyze the composition of such lesions with special reference to stable tubule only polypeptide (STOP), a protein responsible for microtubule cold stabilization. In normal human brain and spinal cord, the distribution of STOP proteins is uniform between the cytoplasm and neurites of neurons. However, all the neurofilament-rich spheroids present in the tissues of affected patients are intensely labeled with 3 different anti-STOP antibodies. Moreover, when neurofilaments and microtubules are isolated from spinal cord and brain, STOP proteins are systematically co-purified with neurofilaments. By SDS-PAGE analysis, no alteration of the migration profile of STOP proteins is observed in pathological samples. Other microtubular proteins, like tubulin or kinesin, are inconstantly present in spheroids, suggesting that a microtubule destabilizing process may be involved in the pathogenesis of ALS. These results indicate that the selective co-aggregation of neurofilament and STOP proteins represent a new cytopathological marker for spheroids

Syndrome de Garcin révélant un lymphome malin non hodgkinien

INTRODUCTION: R Garcin described progressive unilateral cranial nerve palsy in 1926. Garcin syndrome is characterized by progressive involvement of the cranial nerves culminating in total unilateral paralysis of all cranial nerves. Carcinoma of the skull base or ENT regions is the most common etiology. CASE REPORT: A 74-year-old man developed signs involving the left Vth (V2 and V3) cranial nerve then the VIth, VIIth and VIIIth cranial nerves and finally the IXth and Xth. MRI showed involvement of these cranial nerves with gadolinium uptake and involvement of the pons at the terminal phase. Careful ENT explorations failed to reveal a cause. The lymphocyte count was elevated in the cerebrospinal fluid. The patient died one year after diagnosis and the general autopsy was normal. The neuropathological studies led to the post-mortem diagnosis of type B non-Hodgkin lymphoma. CONCLUSION: In patients with Garcin syndrome, lymphoma is a possible diagnosis when carcinoma of the ENT regions or of the skull bases are not present

Photo-responsive polymer with erasable and reconfigurable micro- and nano-patterns: An in vitro study for neuron guidance

The interaction of cells with nanoscale topography has proven to be an important modality in controlling cell responses. Topographic parameters on material surfaces play a role in cell growth. We have synthesized a new bio compatible polymer containing photoswitching molecules. Stripepatterned (groove/ridge pattern) were patterned and erased with ease on this bio azopolymer with two different set-ups: one with the projection of an optical interference pattern and the other one by molecular self-organization with one single laser beam. These two set-ups allow the re-writing of pattern after erasing and its inscription in vitro. PC12 cells were cultured on the bio-photoswitching patterned polymer and compared with PC12 cells growing on a well know substrate: poly-L-lysine. This result is of interest for facilitating contact guidance and designing reconfigurable scaffold for neural network formation in vitro. (C) 2011 Elsevier B.V. All rights reserve

Cytoskeleton abnormalities in axonopathies of unknown aetiology: correlations with morphometry

To determine if specific axonal cytoskeleton abnormalities could be demonstrated in axonopathies without aetiology, nerve biopsies from five controls and nine cases were analyzed by morphometry and immunocytochemistry with anti-neurofilament (NF, subunits L, M, H) and anti-beta tubulin (TUB) antibodies. Morphometry revealed either large fiber atrophy (decrease in large fiber density with increased density in small fibers), degeneration of large fibers (decrease in large fiber density and in total density of fibers) or of all diameter fibers. NF immunostaining density decreased (by 21-89%) only in cases with fiber loss, in parallel to myelinated fiber density as determined by morphometry. On the contrary, the density of fibers labelled for TUB increased significantly in all except two cases by 52-102% over controls. Nevertheless, in these two cases--with a severe loss of fibers--as well as in other cases, the ratio of the density of fibers labelled for TUB and NFL (TUB/NFL) increased by 48-404%. Thus, the total density of myelinated fibers was always inversely correlated with the TUB/NFL ratio. Similar abnormalities have been described only after axotomy; our cases could thus be compared to

Periodic hypokalemic paralysis disclosing thyrotoxicosis

BACKGROUND: Hypokaliemic periodic paralysis is an uncommon complication of hyperthyroidism occurring sporadically almost exclusively in young Asian men. The clinical presentation is the same as in familial hypokaliemic periodic paralysis. Treatment consists of conventional management for thyrotoxicosis. CASE REPORT: A Laotian man aged 42 years had suffered episodes of pain and fatigue in the lower limbs lasting 2 to 7 days over the last few months. The patient was hospitalized with severe limb pain. Clinical examination found severe motor deficit involving all four limbs. Laboratory findings induced hypokaliemia (1.8 mmol/l) and hyperthyroidism (free thyroxin 36 pmol/l, TSH < 0.005 mlU/l). Thyroid echography revealed multinodular goitre with two heterogeneous nodules. Strong uptake was seen on the scintigram. The motor deficit regressed within 8 hours and the kaliemia was restored with 1.50 g KCl. The patient was discharged with carbimazole (30 mg/d). Three months later he was euthyroid and symptom free. Total thyroidectomy was performed and L-thyroxin prescribed. The patient remains symptom-free at the last follow-up, 5 months after thyroidectomy. DISCUSSION: The pathogenesis of hypokaliemic periodic paralysis involves the ATPase-dependent sodium-potassium pump whose activity is stimulated by thyroid hormones. The reasons for the ethnic and male predominance are poorly elucidated

Neurofilament high molecular weight-green fluorescent protein fusion is normally expressed in neurons and transported in axons: a neuronal marker to investigate the biology of neurofilaments

The carboxy-terminal side arm of the neurofilament high subunit consists of a highly phosphorylated domain and a negatively charged region. Multiple evidences suggested that these domains are essential for the axonal phosphorylation and transport of neurofilaments and play a role in their abnormal accumulation following chemical intoxication or during neurodegenerative disorders such as amyotrophic lateral sclerosis. In order to investigate the consequences of altering this side arm of neurofilament high subunit we used a fusion protein (neurofilament high subunit-green fluorescent protein) between the mouse neurofilament high subunit missing a major part of the C-terminal domain and the reporter green fluorescent protein. In cell culture and in transgenic mice this fusion protein co-assembles and co-distributes with the endogenous intermediate filament network. Conditions known to disturb the cytoskeleton were also found to alter the distribution of the fusion protein in cell cultures. In transgenic mice the expression of the transgene evaluated by its fluorescent properties was found to be restricted to neurons, where the neurofilament high subunit-green fluorescent protein fusion protein is axonally transported. Biochemical approaches showed that the fusion protein is phosphorylated and co-purified with neurofilaments. Despite the presence of such an neurofilament high subunit-green fluorescent protein fusion protein, the axonal cytoskeletal density and the axonal caliber were not altered. Together these data show that removal of this portion of neurofilament high subunit does not affect the capacity of neurofilament high subunit to assemble and to be transported into axons, suggesting that this sequence is involved in another function. Moreover, the fluorescent properties of this fusion protein represent a useful marker

Neurofilaments form flexible bundles during neuritogenesis in culture and in mature axons in situ

Neurofilaments (NFs) undergo cation-dependent phospho-mediated associations with each other and other cytoskeletal elements that support axonal outgrowth. Progressive NF-NF associations generate a resident, bundled population that undergoes exchange with transporting NFs. We examined the properties of bundled NFs. Bundles did not always display a fully linear profile but curved and twisted at various points along the neurite length. Bundles retracted faster than neurites and retracted bundles did not expand following extraction with Triton, indicating that they coiled passively rather than due to pressure from the cell. Bundles consisted of helically wound NFs, which may provide flexibility necessary for turning of growing axons during pathfinding. Interactions between NFs and other cytoskeletal elements may be disrupted en masse during neurite retraction or regionally during remodeling. It is suggested that bundles within long axons that cannot be fully retracted into the soma could provide maintain proximal support yet still allow more distal flexibility for remodeling and changing direction during pathfinding

Optimizing Western Blots for the Detection of Endogenous α-Synuclein in the Enteric Nervous System

Background:Alpha-synuclein containing inclusions in neurons, the characteristic pathological lesions of Parkinson’s disease (PD), are not limited to the central nervous system, but also affect the enteric nervous system (ENS). This suggests that the ENS offer some potential as a surrogate of central nervous system pathology and that it may represent an original source of biomarkers for PD. However, the usefulness of α-synuclein detection in gastrointestinal biopsies as a biomarker for PD is still unclear, as the different immunohistochemical methods employed to date have led to conflicting results. Objective:Our aim is to propose an optimized immunoblotting method for the detection of endogenous α-synuclein in the healthy ENS that may be used to supplement the immunohistochemical analysis. Methods:Primary culture of rat ENS and homogenates of human small intestine were analyzed by Western Blot using seven different α-synuclein and phospho-α-synuclein antibodies along with two methods that increase α-synuclein retention on blot membranes, namely incubation of the membranes with paraformaldehyde (PFA) or treatment of samples with the crosslinker dithiobis[succinimidylpropionate] (DSP). Results:A moderate improvement in the detection of endogenous enteric α-synuclein was observed following membrane fixation with PFA for only two of the seven antibodies we tested. Immunodetection of total and phosphorylated α-synuclein in the ENS was markedly improved when samples were treated with DSP, regardless of the antibody used. Conclusions:Our results demonstrate that the detection of α-synuclein in the gut by Western Blot can be optimized by using methods for enhanced membrane retention of the protein along with the appropriate antibody. Such an optimized protocol opens the way to the development of novel biomarkers for PD that will enable a quantification of α-synuclein in gastrointestinal biopsies