Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non‐Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8± 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's diseas

Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies

Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity

A new autosomal recessive form of complete TLR3 deficiency reveals that human TLR3 is nonredundant in immunity against herpes simplex virus 1 in the central nervous system (CNS) but redundant in host defense against viruses outside the CNS

Fumonisins affect the intestinal microbial homeostasis in broiler chickens, predisposing to necrotic enteritis

Fumonisins (FBs) are mycotoxins produced by Fusarium fungi. This study aimed to investigate the effect of these feed contaminants on the intestinal morphology and microbiota composition, and to evaluate whether FBs predispose broilers to necrotic enteritis. One-day-old broiler chicks were divided into a group fed a control diet, and a group fed a FBs contaminated diet (18.6 mg FB1+ FB2/kg feed). A significant increase in the plasma sphinganine/sphingosine ratio in the FBs-treated group (0.21 +/- 0.016) compared to the control (0.14 +/- 0.014) indicated disturbance of the sphingolipid biosynthesis. Furthermore, villus height and crypt depth of the ileum was significantly reduced by FBs. Denaturing gradient gel electrophoresis showed a shift in the microbiota composition in the ileum in the FBs group compared to the control. A reduced presence of low-GC containing operational taxonomic units in ileal digesta of birds exposed to FBs was demonstrated, and identified as a reduced abundance of Candidatus Savagella and Lactobaccilus spp. Quantification of total Clostridium perfringens in these ileal samples, previous to experimental infection, using cpa gene (alpha toxin) quantification by qPCR showed an increase in C. perfringens in chickens fed a FBs contaminated diet compared to control (7.5 +/- 0.30 versus 6.3 +/- 0.24 log10 copies/g intestinal content). After C. perfringens challenge, a higher percentage of birds developed subclinical necrotic enteritis in the group fed a FBs contaminated diet as compared to the control (44.9 +/- 2.22% versus 29.8 +/- 5.46%)

Pompe disease diagnosis and management guideline

ACMG standards and guidelines are designed primarily as an educational resource for physicians and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. in determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these standards and guidelines.Duke Univ, Med Ctr, Durham, NC 27706 USAOregon Hlth Sci Univ, Portland, OR 97201 USANYU, Sch Med, New York, NY USAUniv Florida, Coll Med, Powell Gene Therapy Ctr, Gainesville, FL 32611 USAIndiana Univ, Bloomington, in 47405 USAUniv Miami, Miller Sch Med, Coral Gables, FL 33124 USAHarvard Univ, Childrens Hosp, Sch Med, Cambridge, MA 02138 USAUniversidade Federal de São Paulo, São Paulo, BrazilColumbia Univ, New York, NY 10027 USANYU, Bellevue Hosp, Sch Med, New York, NY USAColumbia Univ, Med Ctr, New York, NY 10027 USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Rôle des chimiokines et de leurs récepteurs au cours de la co-infection des cellules gliales humaines par le cytomegalovirus humain et le virus de l'immunodéficience humaine

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

L'ANGEITE PRIMITIVE DU SYSTEME NERVEUX CENTRAL CHEZ L'ENFANT

REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

L'ASTROCYTE DANS LA NEUROPATHOGENESE DE L'INFECTION PAR LE VIH-1 (EXPRESSION DES RECEPTEURS DE CHIMIOKINES, SUSCEPTIBILITE A L'INFECTION ET A LA TOXICITE INDUITE PAR LA GLYCOPROTEINE D'ENVELOPPE VIRALE, GP120/41)

CE TRAVAIL A PORTE SUR L'ETUDE DE L'ASTROCYTE DANS LA NEUROPATHOGENESE DU VIH. NOTRE OBJECTIF ETAIT D'EXAMINER (1) LA SUSCEPTIBILITE DES ASTROCYTES A LA CYTOTOXICITE DE LA GLYCOPROTEINE D'ENVELOPPE VIRALE, GP120/41 (2) LE MECANISME D'ENTREE DU VIRUS DANS LES ASTROCYTES. EN COCULTURE AVEC DES MONOCYTES INFECTES PAR UNE SOUCHE DE VIH-1 M-TROPIQUE (VIH-1 9 5 3 3), LES ASTROCYTES PRESENTENT DES ALTERATIONS MORPHOLOGIQUES INITIEES AU POINT DE CONTACT ENTRE LES 2 TYPES CELLULAIRES. LE DOSAGE DE LDH DANS LE SURNAGEANT DES COCULTURES A PERMIS DE QUANTIFIER CET EFFET CYTOTOXIQUE. LES ASTROCYTES COCULTIVES AVEC DES MONOCYTES INFECTES PAR VIH-1 9 5 3 3 OU PAR UNE AUTRE SOUCHE (VIH-1 B X 0 8) PRESENTENT UNE AUGMENTATION DU RELARGAGE DE LDH ET CET EFFET EST INHIBE EN PRESENCE D'UN ANTICORPS ANTI-GP120 (NEA-9305). LA COCULTURE AVEC DES CELLULES MICROGLIALES TRANSFECTEES AVEC LE GENE ENV DE L'ISOLAT VIH-1 B X 0 8 ET EXPRIMANT GP120/41 A LA MEMBRANE INDUIT UN EFFET SIMILAIRE SUR LES ASTROCYTES. EN REVANCHE, LA FORME SOLUBLE DE GP120 DE L'ISOLAT VIH-1 B X 0 8 N'INDUIT PAS D'EFFET CYTOTOXIQUE ASTROCYTAIRE. POUR PENETRER DANS LES CELLULES IMMUNITAIRES, LE VIH-1 UTILISE LE CD4 ET UN RECEPTEUR DE CHIMIOKINE : CCR5 POUR LES SOUCHES M-TROPIQUES (R5) ET CXCR4 POUR LES ISOLATS T-TROPIQUES (X4). LES ASTROCYTES N'EXPRIMENT PAS LE CD4. UNE AUGMENTATION DU CALCIUM INTRACELLULAIRE EST OBSERVEE DANS LES ASTROCYTES EN PRESENCE D'AGONISTES DE CCR5 (RANTES ET MIP-1) ET DE CXCR4 (SDF-1). APRES INCUBATION DES ASTROCYTES AVEC UNE SOUCHE R5 DE VIH-1, IL N'EST PAS DETECTE D'ADN VIRAL PAR PCR QUANTITATIVE. EN REVANCHE, CET ISOLAT PENETRE DANS LES CELLULES EN CULTURE MIXTE (COMPOSEE DE NEURONES, D'ASTROCYTES ET DE CELLULES MICROGLIALES) OU LE CD4 A PU ETRE MIS EN EVIDENCE. L'ENTREE DU VIRUS EST INHIBEE EN PRESENCE D'ANTICORPS ANTI-CD4 ET ANTI-CCR5. ENFIN, NI LES ASTROCYTES NI LES CULTURES MIXTES NE SONT SUSCEPTIBLES A L'INFECTION PAR UNE SOUCHE X4 DE VIH-1. CES RESULTATS INDIQUENT QUE GP120/41 MEMBRANAIRE, CONTRAIREMENT A GP120 SOLUBLE, EST TOXIQUE POUR LES ASTROCYTES. LES ASTROCYTES EXPRIMENT DE FACON FONCTIONNELLE LES CORECEPTEURS DU VIH-1, CCR5 ET CXCR4. CEPENDANT, LE CCR5 SUR LES ASTROCYTES NE PEUT SERVIR DE RECEPTEUR PRIMAIRE POUR LES ISOLATS R5 DE VIH-1. COMME DANS LES CELLULES IMMUNITAIRES, LA PENETRATION DU VIH-1 DANS LES ASTROCYTES REQUIERT LA PRESENCE DU CD4.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF