Journal articles on the topic 'Autosomico recessivo'
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1
Cirulli, Catia. "L'ARPKD in 4 sessioni e una fiaba illustrata." Giornale di Clinica Nefrologica e Dialisi 26, no. 3 (October 20, 2014): 306–9. http://dx.doi.org/10.33393/gcnd.2014.927.
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Catia Cirulli, una attiva volontaria di AIRP onlus, ha partecipato all'incontro “ARPKD chiama, AIRP risponde”, che si è tenuto lo scorso 27 settembre a Roma e ne ha tratto questo resoconto dettagliato, utile sia per chi non era presente, sia per chi, invece, c'era e può ritrovare qui tutti i contenuti principali del seminario. Ricordiamo che l'incontro di Roma è stato fortemente voluto da AIRP, che da anni si occupa della forma dominante di questa malattia, ma, da quest'anno, ha esteso il proprio impegno anche alla forma recessiva. Da qui, l'idea di organizzare un seminario per dare risposte alle famiglie, ma anche per aggiornare la comunità scientifica sulle più recenti evidenze in tema di rene policistico autosomico recessivo. Ecco il resoconto di Catia. (rev. scientifica: Dr.ssa Laura Massella)
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Cuneo, G., C. Cesarini, D. Cianfrini, and B. Gambi. "Osteopetrosi autosomica recessiva Diagnosi neonatale." Rivista di Neuroradiologia 15, no. 6 (December 2002): 757–62. http://dx.doi.org/10.1177/197140090201500615.
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Le osteopetrosi sono un raro gruppo eterogeneo di condizioni patologiche, caratterizzate da aumento della densità dell'osso dovuto ad un disordine del riassorbimento da parte degli osteoclasti. Esse sono più frequenti in gruppi etnici all'interno dei quali sono presenti consanguinei. Ne sono state descritte almeno cinque tipi, ma le forme più note sono la autosomica recessiva (AROP, detta anche maligna), la intermedia (IOP, anch'essa recessiva ma con insorgenza più tardiva), la forma con acidosi tubulare e la autosomica dominante (ADOP). Riportiamo un caso di AROP diagnosticato in epoca neonatale (3 settimane). Esso dimostra come alcune caratteristiche radiologiche (ma non tutte), siano già presenti alla nascita. Alla luce delle recenti acquisizioni terapeutiche (soprattutto trapianto di cellule staminali), una diagnosi precoce della malattia potrebbe, pertanto, prevenire importanti modificazioni patologiche alcune delle quali gravemente invalidanti.
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Basekim, C. C., E. Kizilkaya, A. M. Kutlay, and A. F. Karsli. "Proteinosi lipidica con calcificazioni ippocampali." Rivista di Neuroradiologia 8, no. 4 (August 1995): 589–91. http://dx.doi.org/10.1177/197140099500800415.
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La proteinosi lipidica è una rara malattia autosomica recessiva che affligge principalmente la pelle e le mucose e che viene considerata sistemica. È caratterizzata dal deposito di materiale ialino nelle pareti arteriolo-capillari e nelle membrane epiteliali. Viene presentato un caso di proteinosi lipidica con calcificazioni ippocampali bilaterali.
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Tarasyuk, B. A., I. V. Andruschenko, and I. S. Lukyanova. "The ultrasound signs of autosomic recessive policystic kidney disease in children." PERINATOLOGIYA I PEDIATRIYA, no. 2(62) (July 15, 2015): 77–80. http://dx.doi.org/10.15574/pp.2015.62.77.
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Battistella, P. A., P. Bertoli, F. Rossetti, L. Zanesco, G. Audino, and A. Peserico. "Rilievo RM di dismielinizzazione in una rara sindrome neurocutanea PIBI(D)S." Rivista di Neuroradiologia 5, no. 1_suppl (April 1992): 71–74. http://dx.doi.org/10.1177/19714009920050s113.
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Nel capitolo delle tricotiodistrofie è inclusa la PIBI(D)S, rara sindrome ereditaria autosomico-recessiva caratterizzata da fotosensibilità (P), ittiosi non congenita (I), capelli fragili e con ridotto contenuto di aminoacidi solforati (B), deficit intellettivo (I), fertilità incostantemente ridotta (D) e bassa statura (S). Riportiamo il caso di una giovane paziente con diagnosi clinica di PIBI(D)S posta all'età di 12 anni e rilievo RM di dismielinizzazione del SNC. Nei pazienti con tricotiodistrofia vanno quindi ricercate possibili alterazioni a carico di organi che derivano dall'ectoderma ed in particolare nel SNC, attualmente bene analizzabile con le nuove tecniche di immagine quali la RM.
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Chebil, A., l. Largueche, F. Kort, A. Hassairi, I. Habibi, F. Munier, and l. El Matri. "Clinical aspects of Autosomic Recessive Retinitis Pigmentosa Caused by USH2A Mutations in Consanguineous Tunisian Families." Acta Ophthalmologica 93 (September 23, 2015): n/a. http://dx.doi.org/10.1111/j.1755-3768.2015.0465.
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Svahn, Johanna, and Carlo Dufour. "Fanconi anemia - learning from children." Pediatric Reports 3, no. 2s (June 17, 2011): 8. http://dx.doi.org/10.4081/pr.2011.s2.e8.
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Fanconi Anemia (FA) is a rare autosomic recessive and X-linked disease with chromosomal instability after exposure to crosslinking agents as the hallmark. Clinical features of FA are somatic malformations, progressive bone marrow failure and cancer proneness, however there is wide clinical heterogeneity. The symptom most frequently and early associated with morbidity and mortality is progressive pancytopenia in the first decade of life although acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) can appear before aplastic anemia. Squamous cell carcinoma (SCC) of the head-neck, intestinal or genital tract has a very high incidence in FA and can appear at young age. This paper will focus on treatment of bone marrow failure in FA.
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Martini, Mariano, Maria Francesca Vardeu, Filippo Paluan, Nicola Luigi Bragazzi, and Cristina Tornali. "La storia della beta talassemia in Sardegna." Acta medico-historica Adriatica 17, no. 1 (July 1, 2019): 65–90. http://dx.doi.org/10.31952/amha.17.1.4.
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La beta thalassemia rappresenta una delle più comuni patologie autosomiche recessive nel mondo. I Paesi mediterranei, del Medio Oriente e del Sud Est Asiatico sono regioni ad alta prevalenza di beta thalassemia. Le più alte incidenze sono riportate a Cipro, nel Sud Est Asiatico e in Sardegna, correlate molto probabilmente alla pressione selettiva esercitata dal Pl. falciparum, agente eziologico della malaria. In Sardegna, per la rilevanza sanitaria della patologia e in seguito alla pubblicazione dei primi studi scientifici sul morbo di Cooley, sono fiorite importanti scuole di pediatria e genetica medica, che contribuiranno alla definizione dei criteri diagnostici, della terapia e della prevenzione, anche neonatale, dell’anemia mediterranea e delle emoglobinopatie.
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Guimarães, Susana, José Manuel Lopes, José Bessa Oliveira, and Agostinho Santos. "Idiopathic Infantile Arterial Calcification: A Rare Cause of Sudden Unexpected Death in Childhood." Pathology Research International 2010 (July 27, 2010): 1–5. http://dx.doi.org/10.4061/2010/185314.
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Unexpected child death investigation is a difficult area of forensic practice in view of the wide range of possible genetic, congenital, and acquired natural and nonnatural causes. Idiopathic infantile arterial calcification (IIAC) is a rare autosomic recessive disease usually diagnosed postmortem. Inactivating mutations of the ENPP1 gene were described in 80% of the cases with IIAC. We report a case of a 5-year-old girl submitted to a forensic autopsy due to sudden death and possible medical negligence/parents child abuse. Major alterations found (intimal proliferation and deposition of calcium hydroxyapatite around the internal elastic lamina and media of arteries; acute myocardial infarct, stenotic and calcified coronary artery; perivascular and interstitial myocardial fibrosis; and subendocardial fibroelastosis) were diagnostic of IIAC. We reviewed IIAC cases published in the English literature and highlight the importance of adequate autopsy evaluation in cases of sudden child death.
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Ortega-Arellano, Hector Flavio, Marlene Jimenez-Del-Rio, and Carlos Velez-Pardo. "Minocycline protects, rescues and prevents knockdown transgenic parkin Drosophila against paraquat/iron toxicity: Implications for autosomic recessive juvenile parkinsonism." NeuroToxicology 60 (May 2017): 42–53. http://dx.doi.org/10.1016/j.neuro.2017.03.002.
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Ciccone, E., D. Pende, O. Viale, G. Tambussi, S. Ferrini, R. Biassoni, A. Longo, J. Guardiola, A. Moretta, and L. Moretta. "Specific recognition of human CD3-CD16+ natural killer cells requires the expression of an autosomic recessive gene on target cells." Journal of Experimental Medicine 172, no. 1 (July 1, 1990): 47–52. http://dx.doi.org/10.1084/jem.172.1.47.
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We analyzed the recently defined ability of CD3-CD16+ cells to specifically recognize and lyse normal allogeneic target cells (PHA-induced blasts). The susceptibility to lysis by a given alloreactive natural killer (NK) clone ("1 anti-A") was expressed by PHA blasts derived from 9 of 38 random donors analyzed. In all instances, the specific lysis of "susceptible" target cells was greater than 35% while that of "nonsusceptible" targets was less than 6% at an E/T cell ratio of 5:1. In addition to 1 anti-A, A anti-1 specific CD3-CD16+ clones could also be isolated from the reverse MLC combination. The relationship existing between lysis of normal allogeneic cells or tumor cells by the same CD3-CD16+ effector cell has been investigated: 1 anti-A specific CD3-CD16+ clones lysed PHA blasts of three of six cancer patients, while they lysed fresh tumor cells (ovarian carcinoma) from all six patients. The type of inheritance of the character "susceptibility to lysis" was analyzed in representative families. This analysis revealed that the character is inherited in an autosomic recessive fashion, and it is therefore different from MHC. We further investigated the type of segregation of the opposite character "resistance to lysis" (which is inherited in a dominant mode). The finding that this character segregated in all donors expressing given MHC haplotypes indicated that the gene regulating the expression of the NK-defined alloantigen is present on chromosome 6.
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Zito, M. P., S. Maldone, I. Capelli, F. Centofanti, and C. Raimondi. "Impiego della dialisi peritoneale nell'encefalopatia mitochondriale neurogastrointestinale (MNGIE): un Caso Clinico." Giornale di Clinica Nefrologica e Dialisi 23, no. 2 (January 24, 2018): 13–17. http://dx.doi.org/10.33393/gcnd.2011.1429.
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L'Encefalomiopatia Mitocondriale Neurogastrointestinale (MNGIE) è una rara malattia autosomica recessiva causata da mutazioni del gene ECGF1 che codifica per l'enzima Timidina-Fosforilasi, il quale regola il catabolismo della timidina e della desossiuridina. Tali mutazioni causano la perdita della funzione dell'enzima, conseguente aumento dei livelli plasmatici di timidina e de-ossiuridina e alterazione dei meccanismi di riparazione e replicazione del DNA mitocondriale. La MNGIE è caratterizzata da deficit neurologici (neuropatia periferica, leucoencefalomiopatia), oftalmoplegia bilaterale, ptosi palpebrale, dismotilità/atonia gastrointestinale con malassorbimento e malnutrizione. Riportiamo un caso di trattamento combinato con Dialisi Peritoneale (DP) e Nutrizione Parenterale (NP) in una paziente affetta da MNGIE e severa malnutrizione, con disturbi gastrointestinali e dolori addominali complicati da occlusioni intestinali recidivanti e severo quadro di malnutrizione. È stata quindi iniziata una NP e, un trattamento mediante DP La scelta del tipo di soluzioni da utilizzare e delle modalità di scambio si è basata sul concetto di miglioramento della rimozione dei soluti nelle soste lunghe e del riassorbimento di glucosio e acqua dal liquido peritoneale, che, in questo caso, era auspicabile. La scelta della soluzione Nutrineal PD4 è stata fatta su base empirica e sulle esperienze effettuate nei pazienti con insufficienza renale cronica e MIA sindrome.
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Montemagno, C., S. Castorina, S. Cavina, T. De Tommaso, F. Lanzoni, C. Tridici, and M. P. Fiorito. "Adolescente e straniero in un “mondo” di adulti." Giornale di Clinica Nefrologica e Dialisi 24, no. 3 (January 26, 2018): 28–30. http://dx.doi.org/10.33393/gcnd.2012.1155.
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L'iperossaluria primaria di tipo 1 è causata da mutazioni nel gene codificante per l'enzima L-alanina-gliossilato amino transferasi (AGT), che è espresso nel fegato. La trasmissione avviene con modalità autosomica recessiva: i genitori sono portatori sani della mutazione (e spesso non sanno di averla, soprattutto se non ci sono familiari affetti), mentre ciascun figlio della coppia ha il 25% di probabilità di essere malato. Esiste anche un secondo tipo della malattia (iperossaluria primaria di tipo 2), causato dalla carenza di un altro enzima, la D-glicerato deidrogenasi, e un terzo tipo (iperossaluria di tipo 3), identificato piú di recente e causato dal difetto del gene DHDPSL. Sulla base dell'osservazione clinica ed eventualmente della storia familiare, la diagnosi di iperossaluria primaria può essere formulata grazie a test di laboratorio (misurazione dell'ossalato di calcio nelle urine e nel sangue) e analisi genetica, con ricerca delle mutazioni nel gene coinvolto. La diagnosi e il trattamento precoci sono in grado di ridurre il rischio di evoluzione verso l'IRC e verso complicanze gravi come l'ossalosi sistemica. L'articolo riguarda un caso clinico che ha coinvolto il gruppo infermieristico che ha modificato l'approccio e la presa in carico di un adolescente in un “mondo” di adulti. (sian) (nursing)
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De Riso, Giulia, Mariella Cuomo, Teodolinda Di Risi, Rosa Della Monica, Michela Buonaiuto, Davide Costabile, Antonio Pisani, Sergio Cocozza, and Lorenzo Chiariotti. "Ultra-Deep DNA Methylation Analysis of X-Linked Genes: GLA and AR as Model Genes." Genes 11, no. 6 (June 4, 2020): 620. http://dx.doi.org/10.3390/genes11060620.
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Recessive X-linked disorders may occasionally evolve in clinical manifestations of variable severity also in female carriers. For some of such diseases, the frequency of the symptoms’ appearance during women’s life may be particularly relevant. This phenomenon has been largely attributed to the potential skewness of the X-inactivation process leading to variable phenotypes. Nonetheless, in many cases, no correlation with X-inactivation unbalance was demonstrated. However, methods for analyzing skewness have been mainly limited to Human Androgen Receptor methylation analysis (HUMARA). Recently, the X-inactivation process has been largely revisited, highlighting the heterogeneity existing among loci in the epigenetic state within inactive and, possibly, active X-chromosomes. We reasoned that gene-specific and ultra-deep DNA methylation analyses could greatly help to unravel details of the X-inactivation process and the roles of specific X genes inactivation in disease manifestations. We recently provided evidence that studying DNA methylation at specific autosomic loci at a single-molecule resolution (epiallele distribution analysis) allows one to analyze cell-to-cell methylation differences in a given cell population. We here apply the epiallele analysis at two X-linked loci to investigate whether females show allele-specific epiallelic patterns. Due to the high potential of this approach, the method allows us to obtain clearly distinct allele-specific epiallele profiles.
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Gonçalves, A. C., R. Santos, A. O’Neill, P. Escada, G. Fialho, and H. Caria. "Caratterizzazione della mutazione SLC26A4 c.918+2T>C e report di una nuova variante potenzialmente a rischio." Acta Otorhinolaryngologica Italica 36, no. 3 (May 2016): 233–38. http://dx.doi.org/10.14639/0392-100x-889.
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La sindrome di Pendred è, in ordine di frequenza, la seconda causa di ipoacusia su base genetica autosomica recessiva. Si manifesta con un ipoacusia accompagnata dalla presenza di un gozzo tiroideo con eventuale ipotiroidismo. Tali caratteristiche si accompagnano a malformazioni dell’orecchio interno, quali l’acquedotto vestibolare largo. Nel 50% dei casi vi è una mutazione del gene SLC26A4. Riportiamo nel presente lavoro il caso di una paziente portoghese di 47 anni affetta da ipoacusia di grado severo/profondo e ipotiroidismo. La madre e la sorella della paziente, entrambe decedute, erano a loro volta affette da ipoacusia associata a gozzo tiroideo. La risonanza magnetica e la TC hanno entrambe evidenziato un allargamento dell’acquedotto vestibolare e del sacco endolinfatico. La paziente è stata sottoposta a uno studio di GJB2 e GJB6 seguiti da uno screening di tutti gli esoni di SLC26A4 e delle regioni introniche 8 e 14. È stata rilevata, per la prima volta in omozigosi, una mutazione c.918 + 2T>C nella regione intronica 7 del gene SLC26A4. Sequenziando i campioni di controllo è stata rilevata una nuova mutazione c.821C>G presente in eterozigosi nell’estone 7 del gene SLC26A4, per la quale si è ipotizzato un ruolo dannoso. Il presente studio ha condotto alla scoperta di due nuovi genotipi di SLC26A4, e alla miglior definizione degli aspetti fenotipici associati alla sindrome di Pendred.
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Santos, João D., Francisco R. Pinto, João F. Ferreira, Margarida D. Amaral, Manuela Zaccolo, and Carlos M. Farinha. "Cytoskeleton regulators CAPZA2 and INF2 associate with CFTR to control its plasma membrane levels under EPAC1 activation." Biochemical Journal 477, no. 13 (July 10, 2020): 2561–80. http://dx.doi.org/10.1042/bcj20200287.
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Cystic Fibrosis (CF), the most common lethal autosomic recessive disorder among Caucasians, is caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, a cAMP-regulated chloride channel expressed at the apical surface of epithelial cells. Cyclic AMP regulates both CFTR channel gating through a protein kinase A (PKA)-dependent process and plasma membane (PM) stability through activation of the exchange protein directly activated by cAMP1 (EPAC1). This cAMP effector, when activated promotes the NHERF1:CFTR interaction leading to an increase in CFTR at the PM by decreasing its endocytosis. Here, we used protein interaction profiling and bioinformatic analysis to identify proteins that interact with CFTR under EPAC1 activation as possible regulators of this CFTR PM anchoring. We identified an enrichment in cytoskeleton related proteins among which we characterized CAPZA2 and INF2 as regulators of CFTR trafficking to the PM. We found that CAPZA2 promotes wt-CFTR trafficking under EPAC1 activation at the PM whereas reduction of INF2 levels leads to a similar trafficking promotion effect. These results suggest that CAPZA2 is a positive regulator and INF2 a negative one for the increase of CFTR at the PM after an increase of cAMP and concomitant EPAC1 activation. Identifying the specific interactions involving CFTR and elicited by EPAC1 activation provides novel insights into late CFTR trafficking, insertion and/or stabilization at the PM and highlighs new potential therapeutic targets to tackle CF disease.
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Ciccone, E., D. Pende, O. Viale, C. Di Donato, G. Tripodi, A. M. Orengo, J. Guardiola, A. Moretta, and L. Moretta. "Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans." Journal of Experimental Medicine 175, no. 3 (March 1, 1992): 709–18. http://dx.doi.org/10.1084/jem.175.3.709.
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Previous studies indicated that CD3-CD16+ natural killer (NK) cells are capable of specific alloantigen recognition. Thus, alloreactive NK clones lysed normal allogeneic target cells (phytohemagglutinin [PHA] blasts) bearing the stimulating alloantigen but did not lyse autologous cells or the majority of unrelated allogeneic cells. In this study we investigated whether NK cells isolated from single individuals could exhibit different allospecificities. To this end, we derived large numbers of CD3-CD16+ clones (in the presence of PHA) from fresh CD3- peripheral blood lymphocytes. Cloning efficiencies ranged between 5 and 10%. The resulting CD3-CD16+ clones were tested for their reactivity against a panel of allogeneic PHA blasts (derived from six donors). In a given individual (A), four distinct groups of clones could be identified according to their pattern of reactivity (over 400 clones have been analyzed). Clones that could be assigned to one or another group of specificity represented 36% of all clones derived from this donor. The remaining clones did not display cytolytic activity against any of the allogeneic target cells used in the panel. None of the clones lysed autologous (A) PHA blasts, yet, these cells were lysed by the representative clones G10 and H12 specific for donor A. Clones displaying a cytolytic pattern of reactivity identical to that defined for donor A were present in other individuals studied, however not all groups of allospecific clones were necessarily represented in different individuals. Allospecific clones belonging to the various groups were homogeneous in the expression of EB6/GL183-triggering surface molecules, and could thus be assigned to one or another of the previously defined subsets of NK cells. Genetic analysis of the new NK-defined alloantigens was performed in representative families. The corresponding characters were found to segregate independently and, at least for three of them, an autosomic recessive type of inheritance could be demonstrated. Moreover, the comparative analysis of the segregation of the major histocompatibility complex haplotypes and the recessive or dominant alleles of the genes governing the five specificities analyzed indicated that there is no independent sampling between the two genetic traits, thus suggesting that the genes regulating the NK-defined specificities are carried by chromosome 6. Finally, some donors expressed more than one specificity, thus providing evidence for an NK-defined complex haplotype.
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Garone, Caterina, Saba Tadesse, and Michio Hirano. "Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy." Brain 134, no. 11 (September 20, 2011): 3326–32. http://dx.doi.org/10.1093/brain/awr245.
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Abstract Mitochondrial neurogastrointestinal encephalomyopathy is a rare multisystemic autosomic recessive disorder characterized by: onset typically before the age of 30 years; ptosis; progressive external ophthalmoplegia; gastrointestinal dysmotility; cachexia; peripheral neuropathy; and leucoencephalopathy. The disease is caused by mutations in the TYMP gene encoding thymidine phosphorylasethymine phosphorylase. Anecdotal reports suggest that allogeneic haematopoetic stem cell transplantation may be beneficial for mitochondrial neurogastrointestinal encephalomyopathy, but is associated with a high mortality. After selecting patients who fulfilled the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy and had severe thymidine phosphorylase deficiency in the buffy coat (<10% of normal activity), we reviewed their medical records and laboratory studies. We identified 102 patients (50 females) with mitochondrial neurogastrointestinal encephalomyopathy and an average age of 32.4 years (range 11–59 years). We found 20 novel TYMP mutations. The average age-at-onset was 17.9 years (range 5 months to 35 years); however, the majority of patients reported the first symptoms before the age of 12 years. The patient distribution suggests a relatively high prevalence in Europeans, while the mutation distribution suggests founder effects for a few mutations, such as c.866A>G in Europe and c.518T>G in the Dominican Republic, that could guide genetic screening in each location. Although the sequence of clinical manifestations in the disease varied, half of the patients initially had gastrointestinal symptoms. We confirmed anecdotal reports of intra- and inter-familial clinical variability and absence of genotype–phenotype correlation in the disease, suggesting genetic modifiers, environmental factors or both contribute to disease manifestations. Acute medical events such as infections often provoked worsening of symptoms, suggesting that careful monitoring and early treatment of intercurrent illnesses may be beneficial. We observed endocrine/exocrine pancreatic insufficiency, which had not previously been reported. Kaplan–Meier analysis revealed significant mortality between the ages of 20 and 40 years due to infectious or metabolic complications. Despite increasing awareness of this illness, a high proportion of patients had been misdiagnosed. Early and accurate diagnosis of mitochondrial neurogastrointestinal encephalomyopathy, together with timely treatment of acute intercurrent illnesses, may retard disease progression and increase the number of patients eligible for allogeneic haematopoetic stem cell transplantation.
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Di Lullo, A. M., M. Scorza, F. Amato, M. Comegna, V. Raia, L. Maiuri, G. Ilardi, E. Cantone, G. Castaldo, and M. Iengo. "An ex vivo model contributing to the diagnosis and evaluation of new drugs in cystic fibrosis." Acta Otorhinolaryngologica Italica 37, no. 3 (June 2017): 207–13. http://dx.doi.org/10.14639/0392-100x-1328.
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La fibrosi cistica (FC) è una malattia autosomica recessiva causata da mutazioni nel gene CFTR (Cystic Fibrosis Transmembrane conductance Regulator). Finora sono state descritte circa 2000 mutazioni, ma per la maggior parte di esse è difficile definirne leffetto senza complesse procedure in vitro. Abbiamo effettuato il campionamento (mediante brushing), la cultura e lanalisi di cellule epiteliali nasali umane (HNEC) utilizzando una serie di tecniche che possono aiutare a testare leffetto delle mutazioni CFTR. Abbiamo eseguito 50 brushing da pazienti FC e controlli, e in 45 casi si è ottenuta una coltura positiva. Utilizzando cellule in coltura: i) abbiamo dimostrato lespressione ampiamente eterogenea del CFTR nei pazienti e nei controlli; ii) abbiamo definito leffetto di splicing di una mutazione sul gene CFTR; iii) abbiamo valutato lattività di gating di CFTR in pazienti portatori di differenti mutazioni; iv) abbiamo dimostrato che il butirrato migliora in modo significativo lespressione di CFTR. I dati provenienti dal nostro studio sperimentale dimostrano che luso del modello ex-vivo di cellule epiteliali nasali è un importante e valido strumento di ricerca e di diagnosi nella studio della FC e può anche essere mirato alla sperimentazione ed alla verifica di nuovi farmaci. In definitiva, in base ai nostri dati è possibile esprimere le seguenti conclusioni: 1) il prelievo delle cellule epiteliali nasali mediante brushing è applicabile senza alcuna anestesia ed è ben tollerato da tutti i pazienti affetti da FC (bambini e adulti), è scarsamente invasivo e facilmente ripetibile, è anche in grado di ottenere una sufficiente quantità di HNECs rappresentative, ben conservate, idonee allo studio della funzionalità di CFTR; 2) la conservazione delle cellule prelevate è possibile fino a 48 ore prima che si provveda allallestimento della coltura e ciò permette di avviare studi multicentrici con prelievi in ogni sede e quindi di ottenere una ampia numerosità campionaria; 3) la coltura di cellule epiteliali nasali può essere considerata un modello adatto a studiare leffetto molecolare di nuove mutazioni del gene CFTR e/o mutazioni specifiche di pazienti carriers dal significato incerto; 4) il modello ex-vivo delle HNECs consente inoltre di valutare, prima dellimpiego nelluomo, leffetto di farmaci (potenziatori e/o correttori) sulle cellule di pazienti portatori di mutazioni specifiche di CFTR; tali farmaci possono modulare lespressione genica del canale CFTR aprendo così nuove frontiere terapeutiche e migliori prospettive di vita per pazienti affetti da una patologia cronica come la Fibrosi Cistica; 5) la metodologia da noi istituita risulta essere idonea alla misura quantitativa, mediante fluorescenza, dellattività di gating del canale CFTR presente nelle membrane delle cellule epiteliali nasali prelevate da pazienti portatori di differenti genotipi; in tal modo è possibile individuare: a) pazienti FC portatori di 2 mutazioni gravi con unattività < 10% (in rapporto ai controlli -100%), b) soggetti FC portatori contemporaneamente di una mutazione grave e di una lieve con unattività tra 10-30%, c) i cosiddetti portatori carriers- eterozigoti - con unattività tra 40-70%. In conclusione la possibilità di misurare lattività del canale CFTR in HNECs fornisce un importante contributo alla diagnosi di FC, mediante individuazione di un cut-off diagnostico, ed anche alla previsione della gravità fenotipica della malattia; quindi quanto rilevabile dalla misura del suddetto canale permette di prospettare per il futuro la possibilità di valutare meglio i pazienti per i quali il test del sudore ha dato risultati ambigui (borderline o negativi). La metodica da noi sperimentata consente anche di monitorare i pazienti durante il trattamento farmacologico, valutando in tal modo i reali effetti delle nuove terapie.
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Scarabino, T., A. Bertolino, M. Burroni, T. Popolizio, J. Duyn, D. R. Weinberger, and U. Salvolini. "White Matter Lesions in Phenylketonuria: Evaluation with Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy." Rivista di Neuroradiologia 16, no. 2 (April 2003): 251–61. http://dx.doi.org/10.1177/197140090301600204.
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Phenylketonuria (PKU) is a congenital metabolic autosomic recessive disease, caused by a deficit in the liver of phenyl-alanine hydroxylase, the enzyme responsible for conversion of phenyl-alanine (PHE) into tyrosine. Reduction of this enzymatic activity is responsible for increased phenyl-alanine in blood and tissues and, above all, in brain. Accumulation of PHE causes neural damage which produces a typical clinical picture with mental retardation, psychiatric symptoms and epilepsy. It is now possible to diagnose this disease early (with neonatal screening), before irreversible clinical symptoms reflecting central nervous system injury appear. Early diagnosis allows timely onset of therapy (the only possible) consisting of a special diet with reduced intake of PHE (integrated with a mix of aminoacids) whose objective is to keep levels of PHE low in the blood (3–6 mg/dl). Magnetic Resonance Imaging (MRI) is the elective diagnostic tool to evaluate in vivo the involvement of the brain in PKU. Previous MRI morphological studies in patients with PKU have reported various focal symmetrical lesions in periventricular white matter (especially parieto-occipital) of patients with PKU with PHE blood values higher than 10 mg/dl. These lesions, whose importance is not yet clear, seem to represent a reversible structural alteration of myelin, since they regress if blood PHE decreases. Proton magnetic resonance spectroscopy (1H-MRS) can measure in vivo brain metabolites which could help determine the nature of white matter lesions. In particular, changes in NAA (a marker of neuronal integrity) or mI (a potential astrocytic marker) could point to possible neurochemical dysfunction, whereas Cho levels may parallel the degree of the tissue myelination. The purpose of the present study was to evaluate morphologically and biochemically the regional specificity of white matter lesions with structural MRI and with 1H-MRSI. The study included 12 patients with PKU ten to 42 years of age. All patients underwent structural MRI scans while eight of them were also studied with 1H-MRSI. Structural MRI lesions in white matter were analyzed both qualitatively (signal intensity) and quantitatively (location and extension). 1H-MRSI metabolites were measured as the ratio of the area under each peak: NAA/Cr, NAA/Cho, Cho/Cr. Analysis of location and extension of the lesion on structural MRI data showed limited involvement of parieto-occipital white matter in three cases (with isointense or vaguely hypointense lesions in T1, and moderately hyperintense lesions in T2); medium involvement in six cases (with fairly hypointense or isointense lesions in T1, fairly or moderately hyperintense lesions in T2); serious involvement in three cases (with isointense or fairly hypointense lesions in T1, and fairly hyperintense lesions in T2). As for 1H-MRSI data, ANOVA showed a significant reduction of NAA/Cho and increase in Cho/Cr in white matter lesions, but no change in NAA/Cr. No correlation was found between clinical parameters and morphological or spectroscopic data. In conclusion, our morphological MRI data confirmed the presence of multiple signal alterations, focal and symmetrical, in deep periventricular white matter (especially posterior), with occasional involvement of subcortical white matter. However, these lesions do not seem to be strongly predictive of clinical outcome. 1H-MRSI data suggest increased Cho levels in white matter lesions. Since Cho is thought to reflect membrane turnover, these data may support the demyelinating nature of lesions, consistent with earlier post mortem studies.
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Karakas, Zeynep, Chiara Refaldi, Valentina Brancaleoni, Ismail Kurt, Elena Di Pierro, and Maria Domenica Cappellini. "Congenital Erythropoietic Porphyria Due to Co-Inheritance of GATA1 and UROS Gene Mutations." Blood 116, no. 21 (November 19, 2010): 3208. http://dx.doi.org/10.1182/blood.v116.21.3208.3208.
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Abstract Abstract 3208 The Congenital Erythropoietic Porphyria (CEP) is a rare form of Chronic Porphyria characterized by severe photosensivity. Secondary infections of cutaneous lesions may lead to scarring, deformities and disfigurement of the light-exposed parts of the body such as hands, ears, nose, and eyelids. Erythrodontia, osteodystrophia, combining osteolysis and osteoporosis, hypercellular bone marrow, hemolytic anemia, hypersplenism, splenomegaly and red-coloured urine are present in almost all patients. Generally, CEP is an autosomic recessive disease caused by mutations in homozygosis or compound heterozygosis in UROS gene coding for the fourth enzyme of the heme biosynthesis pathway. At present a new form of CEP with an X-linked inheritance associated with R216W mutation in the GATA 1 gene has been described only in one French-English family by Philips JD et al. GATA1 is a key zinc finger transcription factor that coordinates hematopoietic cell differentiation. We described a Turkish family where a severe CEP phenotype segregates with thalassemia and thrombocytopenia. The propositus is an 4 year old boy who presented photosensitive bullous dermatosis, splenomegaly, short stature and pallor. His mother was chronically anemic (Hb 10.9 g/dL) and thrombocytopenic (96×109/L) known as chronic immune thrombocytopenic purpura, whereas the father and the brother were asymptomatic. At birth, the boy had hypochromic, microcytic anemia, thrombocytopenia and thrombasthenia. Reticulocyte counts slightly increased. At 2 months he was transfused, splenomegaly and heart murmur were detected on physical examination. At this point his Hb level was 6,9 g/dl, WBC 7,400×109/L, platelets 64–106×109/L, MCV 70 flL, RDW 28%. The patient's peripheral-blood smear revealed microcytic, hypochromic red cells, target cells, basophilic stippling, and rare nucleated red cells, findings compatible with thalassemia but DNA analysis for beta and alpha thalassemia was normal. A bone marrow aspirate revealed a hypercellular marrow and erythroid hyperplasia. Dyserythropoiesis was noted with nuclear budding, nuclear bridging, and occasional multinucleation. Megakaryocytes were decreased in number, Hb electrophoresis revealed increased levels of fetal hemoglobin (HbA2 2%; Hb F 68%). At 3 years liver MRI detected iron overload. Ferritin level was 329ng/dL. Because of some skin lesions on his body he was then tested with urine and plasma analysis and the results were consistent with the diagnosis of congenital erythropoietic porphyria. Urine total porphyrins were 5414 nmol/mmol creatinin (N<35) with an excess of isomer I of both Uroporphyrins and Coproporhyrins. Total plasma porhyrins were 312 nmol/L (N<10). We analyzed the UROS gene and we identified a new mutation c.338A>T (D113V) in heterozygosis in the propositus, in his father and in his brother. On the basis of hematological status we decided to analyze also GATA1 gene and the mutation c.646C>T (R216W) has been detected in the child and on one allele of his mother who presents a balanced pattern of X-inactivation. The patient is similar to the case of association of CEP with an hematologic phenotype of beta-thalassemia intermedia. Markedly elevated Hb F levels, and thrombocytopenia result from mutations in the transacting factor GATA-1 presented by Philips JD et al. This patient additionally has a severe liver iron overload. A newborn sibling died at birth because of sepsis and neonatal hepatitis. Liver iron overload was also detected in the sibling's autopsy. All components of family were heterozygous for the H63D mutation in HFE gene but no other HAMP, HJV and SLC40A1 mutations were found. The patient started a regular transfusion program and Deferasirox was given for hemosiderosis after Desferroxamine uncompliance. This is the first report of the association of GATA1 and UROS gene mutations that could explain the very severe hematological phenotype. Disclosures: No relevant conflicts of interest to declare.
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Lima, Gabriela Elenor dos Santos, Carlos Henrique Lopes Martins, Carla Viana Dendasck, Ciane Martins de Oliveira, and Euzébio de Oliveira. "Profilo di pazienti visitati in un ambulatorio di genetica medica in un Centro Universitário De Belém, Pará, Amazzonia." Revista Científica Multidisciplinar Núcleo do Conhecimento, March 19, 2021, 48–62. http://dx.doi.org/10.32749/nucleodoconhecimento.com.br/salute/ambulatorio-di-genetica.
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La Genetica Medica (GM) è diventata una specialità medica riconosciuta, con concetti e approcci importanti nella diagnosi e nel trattamento di molte malattie comuni e rare. Le malattie genetiche seguono i modelli ereditari e possono essere autosomi recessive, autosomiche dominanti, legate al cromosoma X o al cromosoma Y, o multifattoriali. Lo scopo di questo studio era determinare il profilo dei pazienti trattati in una clinica ambulatoriale GM in un centro universitario di Belém, nello stato di Pará. I dati sono stati raccolti dalle cartelle cliniche dei pazienti, visti tra il 2014 e il 2019, utilizzando il questionario dei ricercatori, con dati analizzati e tabulati attraverso il programma Microsoft Excel. Sono state analizzate in totale 101 cartelle cliniche, con predominanza di femmine (51 pazienti). Inoltre, la maggior parte delle cure è stata per i bambini (41,5%). Per quanto riguarda l’etnia, sono state osservate solo le variabili “bianco” e “marrone”, con una maggiore prevalenza di pazienti marroni (78 del totale). Inoltre, Belém era la città più diffusa nella naturalezza dei pazienti (61 record). Le specialità con il maggior numero di rinvii alla clinica ambulatoriale GM erano endocrinologia e neurologia, con il ritardo dello sviluppo neuropsicomotorio come diagnosi più frequente. In 42 cartelle cliniche, l’età alla diagnosi non era presente. Dei 101 pazienti, solo 16 avevano consulenza genetica e nei restanti 85 non c’era traccia di queste informazioni. Infine, l’età materna alla nascita non è stata riscontrata nella maggior parte delle cartelle cliniche (assente nel 61,38%). Pertanto, è importante sviluppare un profilo del paziente visto in una clinica ambulatoriale GM, poiché diventa possibile identificare eventuali guasti nel servizio fornito, oltre ad adattare la relazione medico-paziente.
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"Classic Galactosemia Neurological Complications: An Overview." Advances in Neurology and Neuroscience 1, no. 1 (January 7, 2018). http://dx.doi.org/10.33140/an.01.01.01.
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Classic galactosemia is an autosomic recessive disorder that leads to increasegalactose 1 phosphate and galactitol intracellular levels; with clinical manifestations that arise from the ingestion of galactose from the diet but can be reverted when restricted. Yet about 90% of the patients develop neurological complications. Because of that we evaluate the impact of the diet on the generation of such complications, like the strict galactose restriction and the glycosilation impairment, galactosemia and social interactions as factors that influence neurodevelopment, oxidative stress secondary to galactosemia and its influence on neuroinflamation, epigenetics modifications secondary to the diet and the social interactions and other causes that can affect neurodevelopment on galactosemia.
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Castells-Sierra, Javier, Ana Guillem-Amat, Elena López-Errasquín, Lucas Sánchez, and Félix Ortego. "First detection of resistance to deltamethrin in Spanish populations of the Mediterranean fruit fly, Ceratitis capitata." Journal of Pest Science, November 14, 2022. http://dx.doi.org/10.1007/s10340-022-01578-1.
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AbstractThe control of the Mediterranean fruit fly (Medfly), Ceratitis capitata, in citrus orchards in Spain is mainly based in three insecticides (spinosad, lambda-cyhalothrin and deltamethrin) and the liberation of sterile males. However, Medfly control is compromised by the development of lambda-cyhalothrin resistance and the detection of spinosad-resistant alleles in field populations. We report here, for the first time, resistance to deltamethrin in populations collected in fields under different management strategies, including MagnetMed™ traps coated with this insecticide and/or spinosad and lambda-cyhalothrin used as bait sprays, and even in populations obtained from non-treated fields. Two deltamethrin-resistant strains (BP-delta and Rfg-delta) were generated from the descendants of some of the field populations that showed lower susceptibility to deltamethrin. Both strains showed low susceptibility to MagnetMed™ traps, moderate susceptibility to Ceratipack traps, and lacked cross-resistance to spinosad and lambda cyhalothrin. Our data suggest that deltamethrin resistance was mediated by P450 enzymes, since bioassays with synergists showed that PBO reverted resistance in a field population and the laboratory strains, whereas the effect of DEF and DEM was minor and no mutations were found in the VGSC gene. The inheritance of resistance for both strains was completely recessive, autosomic and did not fit the mortality expected for a recessive character under a monogenic or digenic model. We also found that deltamethrin resistance presented a fitness cost in terms of males’ weight, males’ and females’ longevity and lifetime fecundity, with a more pronounced effect in the BP-strain than in the Rfg-delta strain. Our results highlight the need to implement insecticide resistance management strategies to prevent control failures.
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Sirchia, Fabio, Ilaria Fantasia, Agnese Feresin, Elisa Giorgio, Flavio Faletra, Denise Mordeglia, Moira Barbieri, Valentina Guida, Alessandro De Luca, and Tamara Stampalija. "Prenatal findings of cataract and arthrogryposis: recurrence of cerebro-oculo-facio-skeletal syndrome and review of differential diagnosis." BMC Medical Genomics 14, no. 1 (March 25, 2021). http://dx.doi.org/10.1186/s12920-021-00939-6.
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Abstract Background Cerebro-oculo-facio-skeletal syndrome (COFS) is a severe and progressive neurologic condition characterized by prenatal onset of arthrogryposis, cataract, microcephaly and growth failure. The aim of this study was to present a case of recurrence of the COFS syndrome and to propose a differential diagnosis flow-chart in case of prenatal findings of arthrogryposis and cataract. Case presentation We report a case of recurrence of COFS3 syndrome within the same family, with similar diagnostic features. In the first case the COFS syndrome remained undiagnosed, while in the second case, due to prenatal findings of arthrogryposis and cataract, genetic investigation focusing on responsible genes of COFS (ERCC5, ERCC6 and FKTN genes) was carried out. The fetus was found to be compound heterozygous for two different ERCC5 mutations, confirming the clinical suspect of COFS syndrome. A review of the literature on possible causative genes of prenatal cataract and arthrogryposis was performed and we present a flow-chart to guide differential diagnosis and possible genetic testing in case of these findings. Conclusion COFS syndrome is a rare autosomic recessive condition. However, it can be suspected and diagnosed prenatally. The flow-chart illustrates a pathway to guide differential diagnosis according to the prenatal findings. Main syndromes, key testing and specific genes are included. Targeted molecular testing should be offered to the couple in order to reach a diagnosis and assess the recurrence risk for future pregnancies.
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Moreira, Danilo José Silva, Juliana Brito da Fonseca, Karoline Rossi, Suzana dos Santos Vasconcelos, Vinicius Faustino Lima de Oliveira, Claudio Alberto Gellis de Mattos Dias, Euzébio de Oliveira, et al. "Aspetti generali dello xeroderma pigmentoso: una revisione." Revista Científica Multidisciplinar Núcleo do Conhecimento, December 30, 2020, 114–26. http://dx.doi.org/10.32749/nucleodoconhecimento.com.br/salute/generali-dello-xeroderma.
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Xeroderma Pigmentoso (XP) è una malattia genetica rara, recessiva e autosomica che colpisce anche sia i sessi che tutte le etnie, essendo strettamente associata alle comunità con un alto tasso di consanguineità. Lo scopo di questa revisione era quello di dettagliare le principali vie di riparazione del DNA di XP, i diversi difetti funzionali che si traducono nello sviluppo degli 8 tipi di XP, le caratteristiche principali del quadro clinico di un paziente con XP, le principali comorbilità associate a XP e i trattamenti disponibili o che sono ancora in studi per individui affetti da XP. La ricerca bibliografica è stata condotta nelle banche dati: Redalyc, Institutional Repository dell’Università Federale di Juiz de Fora, Scielo, Biblioteca Digitale Brasiliana di Tesi e Tesi, Science Research.com, Lilacs e Pub Med, utilizzando parole chiave o le loro associazioni: Xeroderma – Xeroderma Pigmentoso. XP è una malattia genetica che non ha cura; l’individuo con XP ha una pelle fotosensibile e, se esposto alle radiazioni UV, può sviluppare diverse complicazioni dermatologiche; le manifestazioni di XP sono direttamente collegate al difetto genetico; NER è senza dubbio la via principale di riparazione del DNA quando si tratta di XP; in XP-V il by-pass del nastro con la lesione del DNA non è fatto dalla polimerasi pol eta ma da un’altra polimerasi della famiglia Y; difetti nelle vie di riparazione del DNA possono causare non solo XP, ma anche altre malattie; e il trattamento per XP è palliativo. Consiste nell’uso di specifici protettori UV, farmaci, enzimi di riparazione e vettori adenovirali, nonché criochirurgia, terapia fotodinamica (PDT), rimozione chirurgica di tumori e follow-up psicologico.
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Durand, Christelle M., Chloé Angelini, Vincent Michaud, Claire Delleci, Isabelle Coupry, Cyril Goizet, and Aurelien Trimouille. "Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia." BMC Neurology 22, no. 1 (February 12, 2022). http://dx.doi.org/10.1186/s12883-022-02553-0.
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Abstract Background VPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission. Recently, VPS13D biallelic pathogenic variants have been reported in patients displaying variable neurological phenotypes, with an autosomic recessive inheritance. The objectives of the study were to determine the genetic etiology of a patient with early onset sporadic progressive spastic ataxia, and to investigate the pathogenicity of VPS13D variants through functional studies on patient’s skin fibroblasts. Case presentation We report the case of a 51-year-old patient with spastic ataxia, with an acute onset of the disease at age 7. Walking difficulties slowly worsened over time, with the use of a wheelchair since age 26. We have used trio-based whole-exome sequencing (WES) to identify genes associated with spastic ataxia. The impact of the identified variants on mitochondrial function was assessed in patient’s fibroblasts by imaging mitochondrial network and measuring level of individual OXPHOS complex subunits. Compound heterozygous variants were identified in VPS13D: c.946C > T, p.Arg316* and c.12416C > T, p.(Ala4139Val). Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV. Conclusions Our findings confirmed implication of VPS13D in spastic ataxia and provided further support for mitochondrial defects in patient’s skin fibroblasts with VPS13D variants. This report of long-term follow up showed a slowly progressive course of the spastic paraplegia with cerebellar features. Furthermore, the performed functional studies could be used as biomarker helping diagnosis of VPS13D-related neurological disorders when molecular results are uneasy to interpret.
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Monfort, Beata, Kristian Want, Sylvain Gervason, and Benoit D’Autréaux. "Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia." Frontiers in Neuroscience 16 (March 2, 2022). http://dx.doi.org/10.3389/fnins.2022.838335.
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Friedreich’s ataxia (FRDA) is the most prevalent autosomic recessive ataxia and is associated with a severe cardiac hypertrophy and less frequently diabetes. It is caused by mutations in the gene encoding frataxin (FXN), a small mitochondrial protein. The primary consequence is a defective expression of FXN, with basal protein levels decreased by 70–98%, which foremost affects the cerebellum, dorsal root ganglia, heart and liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, iron accumulation and deposition in mitochondria, and sensitivity to oxidative stress. Based on these phenotypes and the proposed ability of FXN to bind iron, a role as an iron storage protein providing iron for Fe-S cluster and heme biosynthesis was initially proposed. However, this model was challenged by several other studies and it is now widely accepted that FXN functions primarily in Fe-S cluster biosynthesis, with iron accumulation, heme deficiency and oxidative stress sensitivity appearing later on as secondary defects. Nonetheless, the biochemical function of FXN in Fe-S cluster biosynthesis is still debated. Several roles have been proposed for FXN: iron chaperone, gate-keeper of detrimental Fe-S cluster biosynthesis, sulfide production stimulator and sulfur transfer accelerator. A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.
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Gougeon, Marie-Lise, Béatrice Poirier-Beaudouin, Jérome Ausseil, Michel Zérah, Cécile Artaud, Jean-Michel Heard, Kumaran Deiva, and Marc Tardieu. "Cell-Mediated Immunity to NAGLU Transgene Following Intracerebral Gene Therapy in Children With Mucopolysaccharidosis Type IIIB Syndrome." Frontiers in Immunology 12 (May 10, 2021). http://dx.doi.org/10.3389/fimmu.2021.655478.
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Mucopolysaccharidosis type IIIB syndrome (Sanfilippo disease) is a rare autosomic recessif disorder caused by mutations in the α-N-acetylglucosaminidase (NAGLU) gene coding for a lysosomal enzyme, leading to neurodegeneration and progressive deterioration of cognitive abilities in affected children. To supply the missing enzyme, several recent human gene therapy trials relied on the deposit of adeno-associated virus (AAV) vectors directly into the brain. We reported safety and efficacy of an intracerebral therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03300453), with a recombinant AAV serotype 2/5 (rAAV2/5) coding human NAGLU in four children with MPS IIIB syndrome receiving immunosuppression. It was reported that AAV-mediated gene therapies might elicit a strong host immune response resulting in decreased transgene expression. To address this issue, we performed a comprehensive analysis of cellular immunity and cytokine patterns generated against the therapeutic enzyme in the four treated children over 5.5 years of follow-up. We report the emergence of memory and polyfunctional CD4+ and CD8+ T lymphocytes sensitized to the transgene soon after the start of therapy, and appearing in peripheral blood in waves throughout the follow-up. However, this response had no apparent impact on CNS transgene expression, which remained stable 66 months after surgery, possibly a consequence of the long-term immunosuppressive treatment. We also report that gene therapy did not trigger neuroinflammation, evaluated through the expression of cytokines and chemokines in patients’ CSF. Milder disease progression in the youngest patient was found associated with low level and less differentiated circulating NAGLU-specific T cells, together with the lack of proinflammatory cytokines in the CSF. Findings in this study support a systematic and comprehensive immunomonitoring approach for understanding the impact immune reactions might have on treatment safety and efficacy of gene therapies.
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Landi, Estefania, Liliana Karabatas, Laura Ramirez, Mariana Gutierrez, Paula Alejandra Scaglia, Ana Claudia Keselman, Debora Braslavsky, et al. "MON-716 A Novel Human Heterozygous STAT5B Variant Leads to Impaired Growth and Developmental Defects in Zebrafish Embryos." Journal of the Endocrine Society 4, Supplement_1 (April 2020). http://dx.doi.org/10.1210/jendso/bvaa046.324.
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Abstract Signal transducer and activator of transcription 5b (STAT5b) has been identified as a key downstream mediator of GH signaling in somatic growth. Autosomic recessive human mutations in STAT5B lead to severe growth retardation associated to immune dysregulation. On the other hand, some heterozygous STAT5B mutations have been associated to a milder form of the disease. We have identified a heterozygous novel STAT5B mutation by Whole Exome Sequencing (WES) in a 2.2-year-old boy who presented proportionate short stature (height -2.77 SDS) with mild immune dysregulation. He also had normal GH response to provocative tests, low IGF-I levels, and a limited response to IGF generation test. This variant is located within the highly conserved SH2 domain responsible for recognizing and interacting with tyrosine-phosphorylated target peptides. The aim of our study was to evaluate the functional consequences of this novel heterozygous human STAT5B variant (K632N), using the zebrafish as a biosensor system, to determine its pathogenicity. To do this, we performed overexpression experiments microinjecting construct-derived mRNA for the wildtype (WT) and mutant variant into zebrafish embryos at the 1-cell stage and assessed the consequences at 72 hours post fertilization (hpf). The missense variant was introduced into the full length STAT5B cDNA clone (Origene) by site-directed mutagenesis. To generate mRNA, WT and mutant forms of STAT5B cDNAs were linearized by digestion with XhoI, purified and subsequently transcribed with Mmessage Mmachine T7 Transcription Kit. Zebrafish embryos microinjected with 100 and 200 pg of mutant mRNA show a dose dependent significant reduction of body length at 72 hpf compared to those microinjected with the same dose of WT mRNA (p<0.001). Body length reduction with 100 pg of mutant mRNA was 4%, while with 200 pg was 12.7% (p<0.001). In addition, a significant number of embryos injected with mutant mRNA show developmental defects including pericardial edema, bent spine, and cyclopia compared to those injected with WT mRNA (p<0.001). In the case of pericardial edema, the number of affected embryos increased significantly with the mutant mRNA dose (p<0.005). In conclusion, our study was able to evidence the pathogenic nature of the STAT5B K632N variant since it leads to growth and developmental defects in zebrafish embryos. The zebrafish, and its conserved GH-IGF-I axis, constitutes an ideal in vivo model for characterizing the functional effect of genetic variants in ortholog human genes.