Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Publication year range
1.
Sci Rep ; 14(1): 12463, 2024 05 30.
Article in English | MEDLINE | ID: mdl-38816452

ABSTRACT

The non-essential amino acid L-serine is involved in a number of metabolic pathways and in the brain its level is largely due to the biosynthesis from the glycolytic intermediate D-3-phosphoglycerate by the phosphorylated pathway (PP). This cytosolic pathway is made by three enzymes proposed to generate a reversible metabolon named the "serinosome". Phosphoserine phosphatase (PSP) catalyses the last and irreversible step, representing the driving force pushing L-serine synthesis. Genetic defects of the PP enzymes result in strong neurological phenotypes. Recently, we identified the homozygous missense variant [NM_004577.4: c.398A > G p.(Asn133Ser)] in the PSPH, the PSP encoding gene, in two siblings with a neurodevelopmental syndrome and a myelopathy. The recombinant Asn133Ser enzyme does not show significant alterations in protein conformation and dimeric oligomerization state, as well as in enzymatic activity and functionality of the reconstructed PP. However, the Asn133Ser variant is less stable than wild-type PSP, a feature also apparent at cellular level. Studies on patients' fibroblasts also highlight a strong decrease in the level of the enzymes of the PP, a partial nuclear and perinuclear localization of variant PSP and a stronger perinuclear aggregates formation. We propose that these alterations contribute to the formation of a dysfunctional serinosome and thus to the observed reduction of L-serine, glycine and D-serine levels (the latter playing a crucial role in modulating NMDA receptors). The characterization of patients harbouring the Asn133Ser PSP substitution allows to go deep into the molecular mechanisms related to L-serine deficit and to suggest treatments to cope with the observed amino acids alterations.


Subject(s)
Serine , Humans , Serine/metabolism , Mutation, Missense , Phosphoric Monoester Hydrolases/metabolism , Phosphoric Monoester Hydrolases/genetics , Fibroblasts/metabolism , Male , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/metabolism , Female
2.
Brain ; 145(1): 208-223, 2022 03 29.
Article in English | MEDLINE | ID: mdl-34382076

ABSTRACT

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy and movement disorder. We evaluated a large cohort of patients (n = 25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor and ataxia. Later in the disease course, they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibres and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.


Subject(s)
Alkyl and Aryl Transferases , Myoclonus , Neurodegenerative Diseases , Retinitis Pigmentosa , Child , Dolichols/metabolism , Humans , Neurodegenerative Diseases/genetics , Retinitis Pigmentosa/genetics
3.
Int J Stroke ; 14(9): 893-897, 2019 12.
Article in English | MEDLINE | ID: mdl-31092154

ABSTRACT

BACKGROUND: Intravenous thrombolysis is a well-established treatment of ischemic stroke within 4.5 h. However, its effectiveness in acute ischemic myelopathy is unknown. PURPOSE: We describe a series of four acute ischemic myelopathy patients treated with intravenous thrombolysis within 4.5 h and review the current literature to explore this treatment feasibility, potential safety, and efficacy. METHODS: We reviewed all routinely collected clinical, radiological, and follow-up data of patients with a final acute ischemic myelopathy diagnosis who received acute intravenous thrombolysis in our stroke network. We also reviewed thrombolyzed acute ischemic myelopathy patients in the literature. RESULTS: Four patients (three women) aged 57 to 83 years presented with acute uni- or bilateral extremity paresis, considered initially as cerebral strokes in two of them. After excluding contraindications by brain imaging in three, spinal computed tomography in one and confirmation of acute ischemic myelopathy on spinal magnetic resonance imaging in one patient, intravenous thrombolysis was administered at 135, 190, 240, and 245 min accordingly. Subacute diffusion-weighted imaging-magnetic resonance imaging confirmed acute ischemic myelopathy in all but one patient. Favorable outcome was achieved in two patients rapidly and in three patients at three-month follow-up. We identified seven other thrombolyzed acute ischemic myelopathy patients in the literature, who showed variable recovery and no hemorrhagic complications. CONCLUSIONS: With appropriate acute imaging, intravenous thrombolysis after acute ischemic myelopathy is feasible and potentially safe within 4.5 h. Given the potential of benefit of thrombolysis in acute ischemic myelopathy, this treatment warrants further efficacy and safety studies.


Subject(s)
Fibrinolytic Agents/therapeutic use , Spinal Cord Ischemia/drug therapy , Thrombolytic Therapy/methods , Tissue Plasminogen Activator/therapeutic use , Aged , Aged, 80 and over , Diffusion Magnetic Resonance Imaging , Female , Humans , Male , Middle Aged , Spinal Cord Ischemia/diagnostic imaging , Time-to-Treatment , Treatment Outcome
4.
Rev Med Suisse ; 15(648): 857-861, 2019 Apr 24.
Article in French | MEDLINE | ID: mdl-31021570

ABSTRACT

New antiepileptic drugs are regularly approved for treatment and offer large therapeutic opportunities. Efficacy of these drugs is relatively similar on-label with different mechanisms to be combined for a synergic effect. Treatments such as cannabidiol have benefitted from large media coverage despite limited clinical evidence so far. The objective of antiepileptic drugs is to stop the recurrence of epileptic seizures with as few adverse events as possible. When confronted to a difficult-to-treat epilepsy, referral to a specialised centre is strongly advised. The aim is to confirm that the diagnosis is correct, that the treatment is well adapted (indication, pharmacokinetic and compliance) and to evaluate the indication for non-pharmacological treatments such as epilepsy surgery.


De nouveaux traitements médicamenteux antiépileptiques arrivent régulièrement sur le marché, et permettent d'offrir une large palette thérapeutique. Les efficacités sont relativement similaires dans les indications approuvées, avec différents mécanismes à utiliser de façon synergique. Certains traitements, comme le cannabidiol, ont bénéficié d'un succès médiatique dépassant l'évidence clinique à ce jour. L'objectif du traitement est l'arrêt des crises d'épilepsie d'une part, et l'absence d'effet secondaire invalidant de l'autre. Devant une situation d'épilepsie difficile à traiter, une évaluation dans un centre spécialisé est indiquée. Le but est de confirmer le diagnostic d'épilepsie, vérifier l'adéquation du traitement (indication, pharmacocinétique, compliance) et évaluer l'indication aux traitements non pharmacologiques, comme une chirurgie de l'épilepsie.


Subject(s)
Anticonvulsants , Epilepsy , Anticonvulsants/therapeutic use , Epilepsy/complications , Epilepsy/drug therapy , Humans , Recurrence , Seizures/drug therapy , Seizures/etiology
5.
Rev Med Suisse ; 15(648): 870-873, 2019 Apr 24.
Article in French | MEDLINE | ID: mdl-31021573

ABSTRACT

The new antiepileptic drugs (AED) are not significantly more efficient than the older ones, but they are better tolerated and with a lower drug interactions. Despite the existing guidelines, the evidence-based medicine cannot answer unequivocally the question of the best AED for a given patient. The treatment must be individually tailored; in this article, we present some principles and important factors to guide that choice.


Les nouveaux médicaments antiépileptiques (MAE) ne sont pas significativement plus efficaces que les MAE plus anciens, mais leur tolérance est meilleure et leur potentiel d'interactions moindre. Malgré l'existence de guidelines, la médecine basée sur les preuves (EBM) ne permet pas de répondre sans équivoque à la question du meilleur MAE pour un patient donné. Le traitement doit donc être adapté individuellement ; dans cet article, nous présentons quelques principes et des facteurs pertinents pour guider ce choix.


Subject(s)
Anticonvulsants , Drug Interactions , Epilepsy , Anticonvulsants/therapeutic use , Comorbidity , Epilepsy/drug therapy , Evidence-Based Medicine , Humans
6.
Neurology ; 79(23): 2258-64, 2012 Dec 04.
Article in English | MEDLINE | ID: mdl-23175722

ABSTRACT

OBJECTIVE: To investigate the impact of corticosteroids (CS) on the viral-specific T-cell response, in particular the JC virus (JCV)-specific one, in an attempt to determine the optimal timing of CS in the management of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS). METHODS: A blood draw was performed before and 7 days after the administration of IV CS to 24 patients with relapsing multiple sclerosis (MS). The phenotypic pattern of T cells was determined by CCR7 and CD45RA. To assess the impact of CS treatment on proliferative response of JCV-, influenza-, and Epstein-Barr virus (EBV)-specific T cells, a thymidine incorporation proliferation assay was performed. An intracellular cytokine staining assay was performed to determine the effect of CS treatment on the production of cytokine by virus-specific T cells. JCV T-cell assays were performed only in JCV-infected patients with MS as detected by serologies (Stratify) or detection of JCV DNA in the urine by PCR. RESULTS: CS led T cells, CD4+ and CD8+, toward a less differentiated phenotype. There was a significant decrease of EBV-, influenza-, and JCV-specific T-cell proliferative response upon CS treatment. There was a significant decrease in the frequency of interferon (IFN) γ- and tumor necrosis factor (TNF) α-producing JCV-specific CD8+ T cells, but not EBV- or influenza-specific CD4+ or CD8+ T cells. CONCLUSIONS: CS have a profound impact on the virus-specific T-cell response, especially on JCV, suggesting that when CS are considered, they should not be given before the onset of clinical or radiologic signs of IRIS. Studies addressing directly patients with MS with natalizumab-caused PML are warranted. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that methylprednisolone treatment decreases the frequency of JCV-specific CD8+ T cells producing IFN-γ and TNFα, impairing control of JCV, suggesting this should be used to treat but not to prevent PML-IRIS. No clinical outcomes were measured.


Subject(s)
Adrenal Cortex Hormones/pharmacology , Immunity, Cellular/drug effects , JC Virus/immunology , Methylprednisolone/pharmacology , Multiple Sclerosis, Relapsing-Remitting/immunology , T-Lymphocytes/drug effects , Adrenal Cortex Hormones/therapeutic use , Adult , Female , Humans , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Methylprednisolone/therapeutic use , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , T-Lymphocytes/immunology
7.
J Exp Zool A Comp Exp Biol ; 301(2): 160-8, 2004 Feb 01.
Article in English | MEDLINE | ID: mdl-14743515

ABSTRACT

Cellular infiltrations forming lymphoid-like aggregates were previously observed in gonads of two turtle species exhibiting temperature-dependent sex determination (TSD): at hatching in Chelydra serpentina; at and after hatching in Emys orbicularis. We show here that such aggregates are also present in gonads of Testudo graeca by the end of embryonic development, suggesting that their occurrence is general in turtles. Since in C. serpentina, infiltrations were observed mainly in testes exhibiting remnants of the germinal epithelium, it was assumed that their occurrence was an expression of maleness leading to rejection of this epithelium. The generality of this hypothesis was tested in E. orbicularis by looking for lymphoid-like aggregates in three types of gonads (testes, ovotestes, and ovaries) and for the stages at which they occur. Gonads were from embryos, hatchlings, and young incubated at various temperatures. Ovotestes obtained by treatment with an aromatase inhibitor of eggs incubated at female-producing temperature were also examined. In these gonads, the differentiation of Sertoli cells in testicular cords/tubes was ascertained by expression of SOX9. Moreover, the cell composition of aggregates was determined on electron micrographs. Aggregates appear in ovaries and ovotestes by the end of embryonic development and are present in the majority of these gonads at hatching, and at least up to one year after hatching. They are composed mainly of lymphocytes and fibroblasts. Aggregates are not present in typical testes. Since they occur in most ovaries, they cannot be seen as an expression of maleness. Rather, lymphocytic infiltration and formation of lymphoid aggregates in turtle gonads can be seen as components of the immune system, and can be under the control of gonadal endogenous sex steroids.


Subject(s)
Gonads/cytology , Lymphocytes/physiology , Temperature , Turtles/physiology , Animals , Histological Techniques , Lymphocytes/ultrastructure , Microscopy, Electron , Sex Differentiation/physiology , Turtles/anatomy & histology , Turtles/embryology
8.
Rouxs Arch Dev Biol ; 197(6): 370-374, 1988 Oct.
Article in English | MEDLINE | ID: mdl-28305434

ABSTRACT

Drosophila melanogaster embryos were injected before the blastoderm stage with conditioned media from several male Burkitt's lymphoma human cell lines and the Daudi cell line. Such injections do not have any effect on the male genital apparatus or on the female tract. The Daudi conditioned medium modifies the ovarian morphogenesis of the flies and the rudimentary ovaries obtained look like nymphal gonads. Moreover, they have a drastically reduced number of germ cells. The ovaries that looked functional contain numerous necrotic germ cells and the mean number of ovarioles per fly is significantly smaller than that of the controls. The abnormalities observed resemble the results of experimental and genetic lack of germ cells. They disappear at very high dilution (1×10-6).

9.
Wilehm Roux Arch Dev Biol ; 183(2): 171-176, 1977 Jun.
Article in French | MEDLINE | ID: mdl-28304905

ABSTRACT

Cauterization of pole cells in embryos of the Colorado beetle does not prevent organogenesis of the gonads. So, pole cells do not govern to the differentiation of the gonadal mesoderm (this latter is limited to abdominal segments 6, 7 and 8). Moreover, this mesoderm develops into testis or ovary even without any innitial germ cells.

SELECTION OF CITATIONS
SEARCH DETAIL
...