Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 60
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
JCI Insight ; 5(5)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161190

RESUMO

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.

2.
J Pediatr Hematol Oncol ; 42(2): e117-e120, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30629004

RESUMO

Saccharomyces cerevisiae is an emerging pathogen within the immunocompromised. We present a 4-year-old boy with acute lymphoblastic leukemia presenting with polymerase chain reaction-confirmed hepatosplenic S. cerevisiae infection and significant immune reconstitution symptoms. We explore the challenges of monitoring treatment efficacy using C-Reactive protein, ß-D-glucan, and imaging and the administration of chemotherapy alongside antifungals and steroids for control of immune reconstitution syndrome.

3.
Front Pediatr ; 7: 433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709204

RESUMO

Hematopoietic stem cell transplantation (HSCT) has been established as an effective therapy for selected inborn errors of metabolism. The success of HSCT in metabolic disease is best exemplified through the treatment of Hurler's syndrome, a lysosomal storage disease. Through the collaborative effort of several international centers, factors that predict successful patient and transplant outcomes have been identified. In this review, we discuss the principles that underlie the use of HSCT in metabolic diseases. We consider the clinical indications, conditioning regimens, and disease-specific follow-up for HSCT in different metabolic diseases. We highlight persisting challenges in HSCT to delay progression of certain organ systems that remain refractory to HSCT and the relatively high rates of aplastic graft failure. Finally, we evaluate the variable applicability of these principles to other inherited metabolic disorders including peroxisomal, mitochondrial, and other lysosomal storage diseases.

5.
Blood Adv ; 3(7): 1118-1128, 2019 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-30952678

RESUMO

When hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; P = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; P = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.

6.
Blood Adv ; 3(4): 570-574, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30787020

RESUMO

Umbilical cord blood (UCB) is the preferred donor cell source for children with Hurler syndrome undergoing transplant, and its use has been associated with improved "engrafted survival" rates. However, as in other pediatric recipients of UCB transplants for nonmalignant disease, immune-mediated cytopenia (IMC) is a significant complication. This article describes 8 episodes of IMC in 36 patients with Hurler syndrome undergoing UCB transplant. The incidence of IMC was increased in those with a higher preconditioning absolute lymphocyte count and in those conditioned with fludarabine-containing regimens rather than cyclophosphamide, and it included red cell alloantibodies directed at cord blood group antigens that are novel to the recipient. In several cases, IMC was a precursor to immune-mediated complete graft rejection. We describe IMC as part of a spectrum of graft rejection by a residual competent host immune system and a forme fruste of complete graft rejection.

8.
Cytotherapy ; 20(6): 830-838, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29753677

RESUMO

BACKGROUND: Adenovirus (ADV) reactivation can cause significant morbidity and mortality in children after allogeneic stem cell transplantation. Antiviral drugs can control viremia, but viral clearance requires recovery of cell-mediated immunity. METHOD: This study was an open-label phase 1/2 study to investigate the feasibility of generating donor-derived ADV-specific T cells (Cytovir ADV, Cell Medica) and to assess the safety of pre-emptive administration of ADV-specific T cells in high-risk pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT) to treat adenoviremia. Primary safety endpoints included graft-versus-host disease (GvHD), and secondary endpoints determined antiviral responses and use of antiviral drugs. RESULTS: Between January 2013 and May 2016, 92 donors were enrolled for the production of ADV T cells at three centers in the United Kingdom (UK), and 83 products were generated from 72 mobilized peripheral blood harvests and 20 steady-state whole blood donations. Eight children received Cytovir ADV T cells after standard therapy and all resolved ADV viremia between 15 and 127 days later. ADV-specific T cells were detectable using enzyme-linked immunospot assay (ELISpot) in the peripheral blood of all patients analyzed. Serious adverse events included Grade II GvHD, Astrovirus encephalitis and pancreatitis. CONCLUSION: The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy.


Assuntos
Infecções por Adenoviridae/prevenção & controle , Adenoviridae/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Infecções por Adenoviridae/complicações , Infecções por Adenoviridae/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/virologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade Celular , Lactente , Masculino , Fatores de Risco , Linfócitos T/imunologia , Imunologia de Transplantes , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Ativação Viral/imunologia
9.
Blood Adv ; 1(24): 2236-2242, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29296871

RESUMO

Hurler syndrome (HS) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Hematopoietic stem cell transplantation (HSCT) results in long-term survival, although with significant residual disease burden. How this residual disease affects the health-related quality of life is unknown. Therefore, we conducted a multicenter cohort study on functional and psychosocial health and compared the outcomes to normative data using the Child Health Questionnaire and Pediatric Outcomes Data Collection Instrument. Perception of care was evaluated by the Measure of Processes of Care questionnaire. Sixty-three HS patients receiving HSCT with at least 3 years of follow-up after HSCT were included. The influence of potential predictors was analyzed using linear regression analysis, and correlation analysis was performed using Spearman rank correlation. Functional health of transplanted HS patients was significantly diminished compared with normative data (median physical summary z score, -2.4 [range, -3.5 to -1.6]; median global functioning z score, -3.2 [range, -4.8 to -1.8]). Psychosocial health was comparable or only slightly reduced compared with healthy peers (median psychosocial summary z score, 0.15 [range, -0.7 to 0.8]). A higher obtained lysosomal enzyme level post-HSCT predicted for superior functional health. Overall, parents were satisfied with the care received. Functional health of transplanted HS patients appeared significantly more affected than psychosocial health. To improve functional health, the use of only noncarrier donors and striving to achieve full-donor chimerism, both resulting in higher enzyme levels, is advised. Assessing the health-related quality of life could play an important role in evaluating outcomes of HS patients receiving novel (cell) therapies, including autologous gene-transduced HSCT.

10.
Lancet Haematol ; 3(11): e526-e536, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27746112

RESUMO

BACKGROUND: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. METHODS: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. FINDINGS: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37). INTERPRETATION: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications. FUNDING: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.


Assuntos
Área Sob a Curva , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Relação Dose-Resposta a Droga , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/mortalidade , Adolescente , Adulto , Bussulfano/uso terapêutico , Bussulfano/toxicidade , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Lactente , Masculino , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , Resultado do Tratamento
11.
Curr Opin Hematol ; 23(6): 530-535, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27662232

RESUMO

PURPOSE OF REVIEW: This review summarizes the main results of haematopoietic stem cell transplantation (HSCT) in selected inborn errors of metabolism (IEMs). RECENT FINDINGS: Early diagnosis and immediate referral to an IEM specialist is of paramount importance to improve clinical outcome: patients who are transplanted early or in their presymptomatic phase generally achieve better correction of their somatic symptoms and neurocognitive development. Long-term outcome in children with Hurler syndrome is influenced by age at HSCT, baseline clinical status and post-HSCT enzyme levels. Myeloablative Busulfan-based conditioning regimens with therapeutic drug monitoring are recommended to achieve full donor engraftment and more robust enzyme delivery after HSCT. Gene therapy can lead to production of supranormal enzyme levels, and preliminary clinical results are also promising in IEMs historically not responsive to allogeneic HSCT. SUMMARY: Allogeneic HSCT has largely contributed to the improved survival and quality of life of many children affected by IEMs. Neonatal screening could enable earlier HSCT, and this might significantly reduce residual disease burden and improve clinical outcome. Novel strategies, such as gene therapy, have shown encouraging clinical results in selected IEMs and might become more widely available in the future, with potentially better enzyme delivery and reduced transplant-related toxicity.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Erros Inatos do Metabolismo/terapia , Fatores Etários , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/mortalidade , Prognóstico , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
12.
Br J Haematol ; 173(3): 380-93, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27060988

RESUMO

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology, the British Society for Bone Marrow Transplantation and the UK Clinical Virology Network has reviewed the available literature and made recommendations for the diagnosis and management of respiratory viral infections in patients with haematological malignancies or those undergoing haematopoietic stem cell transplantation. This guideline includes recommendations for the diagnosis, prevention and treatment of respiratory viral infections in adults and children. The suggestions and recommendations are primarily intended for physicians practising in the United Kingdom.


Assuntos
Neoplasias Hematológicas/complicações , Infecções Respiratórias/virologia , Transplante de Células-Tronco/efeitos adversos , Viroses/diagnóstico , Viroses/terapia , Adolescente , Adulto , Criança , Feminino , Neoplasias Hematológicas/terapia , Hematologia/normas , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/terapia , Fatores de Risco , Reino Unido , Viroses/prevenção & controle , Adulto Jovem
14.
Mol Genet Metab ; 117(3): 373-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26832957

RESUMO

Haematopoietic stem cell transplantation is the treatment of choice for the severe form of Mucopolysaccharidosis Type I, or Hurler syndrome. In many centres standard practice is to deliver enzyme replacement therapy alongside haematopoietic stem cell transplantation to improve the condition of the patient prior to transplant. We report the combined 10 year experience of this approach in two paediatric metabolic and transplant centres. Of 81 patients who underwent a first transplant procedure for Hurler, 88% (71/81) survived and 81% (66/81) were alive and engrafted at a median follow-up of 46 months (range 3-124 months). The incidence of grade II-IV acute and any chronic graft versus host disease was 17% and 11% respectively. Urinary glycosaminoglycans were significantly reduced after a period of enzyme replacement therapy, and further reductions were seen at 13-24 months and 25+months after transplantation. In several individuals with decreased cardiac contractility, an improvement of their condition during enzyme replacement therapy enabled them to undergo transplantation, with one individual receiving full intensity conditioning.


Assuntos
Terapia de Reposição de Enzimas , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I/terapia , Pré-Escolar , Feminino , Seguimentos , Glicosaminoglicanos/urina , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Iduronidase/administração & dosagem , Lactente , Masculino , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
15.
Br J Radiol ; 88(1056): 20150088, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26369989

RESUMO

OBJECTIVE: Fanconi anaemia (FA) is an inherited disease associated with congenital and developmental abnormalities resulting from the disruption of a multigenic DNA damage response pathway. This study aimed to define the MRI appearances of the brain in patients with FA in correlation with their genetic and clinical features. METHODS: A review of the brain MRI in 20 patients with FA was performed. Pituitary size and frequencies of the radiological findings of individuals with FA and age-matched controls were determined. RESULTS: Abnormalities were identified in 18 (90%) patients with FA, the commonest being a small pituitary (68%, p < 0.01 females and p < 0.001 males). In five cases (25%, p = 0.02), the pituitary morphology was also abnormal. Posterior fossa abnormalities were seen in six cases (30%, p = 0.01) including Chiari I malformation (n = 3), Dandy-Walker variant (n = 2) and cerebellar atrophy (n = 2). Six patients (30%, p = 0.01) had morphological structural variation of the corpus callosum (CC). CONCLUSION: The incidence of central nervous system (CNS) abnormalities in FA is higher than previously reported, with a midline predominance that points to impact in the early stages of CNS development. MRI brain imaging is important for endocrine assessment and pre-transplant evaluation and can make an important contribution to clinical decision-making. ADVANCES IN KNOWLEDGE: The incidence of brain structural abnormalities in FA is higher than previously reported, with abnormalities of the posterior fossa, CC and pituitary being common. There is an association with gender and reduction in pituitary size which does not strongly correlate with biochemically evident endocrine abnormality.


Assuntos
Encéfalo/anormalidades , Anemia de Fanconi/complicações , Imagem por Ressonância Magnética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipófise/anormalidades , Adulto Jovem
16.
Orphanet J Rare Dis ; 10: 42, 2015 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-25887468

RESUMO

BACKGROUND: The lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB). The success of current therapies, including haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) may be influenced by a number of factors and monitored using biomarkers of metabolic correction. We describe the pattern of SDB seen in the largest MPS I cohort described to date and determine therapies and biomarkers influencing the severity of long-term airway disease. METHODS: Therapeutic, clinical and biomarker data, including longitudinal outcome parameters from 150 sleep oximetry studies were collected in 61 MPS I (44 Hurler, 17 attenuated) patients between 6 months pre to 16 years post-treatment (median follow-up 22 months). The presence and functional nature of an immune response to ERT was determined using ELISA and a cellular uptake inhibition assay. Multivariate analysis was performed to determine significant correlators of airway disease. RESULTS: The incidence of SDB in our cohort is 68%, while 16% require therapeutic intervention for airway obstruction. A greater rate of progression (73%) and requirement for intervention is seen amongst ERT patients in contrast to HSCT treated individuals (24%). Multivariate analysis identifies poorer metabolic clearance, as measured by a rise in the biomarker urinary dermatan sulphate: chondroitin sulphate (DS:CS) ratio, as a significant correlator of increased presence and severity of SDB in MPS I patients (p = 0.0017, 0.008). Amongst transplanted Hurler patients, delivered enzyme (leukocyte iduronidase) at one year is significantly raised in those without SDB (p = 0.004). Cellular uptake inhibitory antibodies in ERT treated patients correlate with reduced substrate clearance and occurrence of severe SDB (p = 0.001). CONCLUSION: We have identified biochemical and therapeutic factors modifying airway disease across the phenotypic spectrum in MPS I. Interventions maximising substrate reduction correlate with improved long-term SDB, while inhibitory antibodies impact on biochemical and clinical outcomes. Monitoring and tolerisation strategies should be re-evaluated to improve detection and minimise the inhibitory antibody response to ERT in MPS I and other lysosomal storage diseases. Future studies should consider the use of sleep disordered breathing as an objective parameter of clinical and metabolic improvement.


Assuntos
Mucopolissacaridose I/metabolismo , Mucopolissacaridose I/terapia , Síndromes da Apneia do Sono/metabolismo , Síndromes da Apneia do Sono/terapia , Biomarcadores/urina , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Mucopolissacaridose I/urina , Análise Multivariada , Estudos Retrospectivos , Síndromes da Apneia do Sono/urina
17.
Biol Blood Marrow Transplant ; 21(6): 1106-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25708213

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment able to prevent progressive neurodegenerative disease in a selected group of mucopolysaccharidosis (MPS) disorders. However, its use was historically limited by the high risk of graft failure and transplantation-related morbidity and mortality. Therefore, since 2005 new international HCT guidelines for MPS disorders were proposed. The survival and graft outcomes of MPS patients receiving HCT according to these guidelines in 2 European centers of expertise were evaluated. Two consecutive conditioning regimens were used, busulfan/cyclophosphamide or fludarabine/busulfan-based, both with exposure-targeted i.v. busulfan. A noncarrier matched sibling donor (MSD), matched unrelated cord blood (UCB), or matched unrelated donor (MUD) were considered to be preferred donors. If not available, a mismatched UCB donor was used. Participants were 62 MPS patients (56 MPS type I-Hurler, 2 MPS type II, 2 MPS type III, and 2 MPS type VI) receiving HCT at median age 13.5 months (range, 3 to 44). Forty-one patients received a UCB donor, 17 MSD, and 4 MUD. High overall survival (95.2%) and event-free survival (90.3%) were achieved with only low toxicity: 13.3% acute graft-versus-host disease aGVHD) grades II to IV and 14.8% chronic GVHD (1.9% extensive). A mismatched donor predicted for lower event-free survival (P = .04). A higher age at HCT was a predictor for both aGVHD (P = .001) and chronic GVHD (P = .01). The use of a mismatched donor was a predictor for aGVHD (P = .01). Higher rates of full-donor chimerism were achieved in successfully transplanted UCB recipients compared with MSD/MUD (P = .002). If complying with the international HCT guidelines, HCT in MPS patients results in high safety and efficacy. This allows extension of HCT to more attenuated MPS types. Because a younger age at HCT is associated with reduction of HCT-related toxicity, newborn screening may further increase safety.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridoses/terapia , Agonistas Mieloablativos/uso terapêutico , Doenças Neurodegenerativas/prevenção & controle , Condicionamento Pré-Transplante/métodos , Doença Aguda , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Doença Crônica , Ciclofosfamida/uso terapêutico , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridoses/imunologia , Mucopolissacaridoses/mortalidade , Mucopolissacaridoses/patologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Guias de Prática Clínica como Assunto , Prognóstico , Recidiva , Irmãos , Análise de Sobrevida , Transplante Homólogo , Doadores não Relacionados , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
18.
Blood ; 125(13): 2164-72, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25624320

RESUMO

Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I/terapia , Adolescente , Adulto , Criança , Desenvolvimento Infantil , Pré-Escolar , Cognição , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/fisiopatologia , Mucopolissacaridose I/psicologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
J Biol Chem ; 289(52): 36194-203, 2014 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-25359774

RESUMO

Mucopolysaccharidosis I Hurler (MPSI-H) is a pediatric lysosomal storage disease caused by genetic deficiencies in IDUA, coding for α-l-iduronidase. Idua(-/-) mice share similar clinical pathology with patients, including the accumulation of the undegraded glycosaminoglycans (GAGs) heparan sulfate (HS), and dermatan sulfate (DS), progressive neurodegeneration, and dysostosis multiplex. Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for Hurler patients, but reduced intensity conditioning is a risk factor in transplantation, suggesting an underlying defect in hematopoietic cell engraftment. HS is a co-receptor in the CXCL12/CXCR4 axis of hematopoietic stem and progenitor cell (HSPC) migration to the bone marrow (BM), but the effect of HS alterations on HSPC migration, or the functional role of HS in MPSI-H are unknown. We demonstrate defective WT HSPC engraftment and migration in Idua(-/-) recipient BM, particularly under reduced intensity conditioning. Both intra- but especially extracellular Idua(-/-) BM HS was significantly increased and abnormally sulfated. Soluble heparinase-sensitive GAGs from Idua(-/-) BM and specifically 2-O-sulfated HS, elevated in Idua(-/-) BM, both inhibited CXCL12-mediated WT HSPC transwell migration, while DS had no effect. Thus we have shown that excess overly sulfated extracellular HS binds, and sequesters CXCL12, limiting hematopoietic migration and providing a potential mechanism for the limited scope of HSCT in Hurler disease.


Assuntos
Movimento Celular , Células-Tronco Hematopoéticas/fisiologia , Heparitina Sulfato/farmacologia , Mucopolissacaridose I/terapia , Animais , Medula Óssea/patologia , Quimiocina CXCL12/metabolismo , Sobrevivência de Enxerto , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicho de Células-Tronco
20.
Blood ; 124(18): 2867-71, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25193871

RESUMO

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.


Assuntos
Anemia Sideroblástica/congênito , Anemia Sideroblástica/genética , Deficiências do Desenvolvimento/complicações , Febre/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndromes de Imunodeficiência/complicações , Mutação/genética , RNA Nucleotidiltransferases/genética , Alelos , Anemia Sideroblástica/complicações , Anemia Sideroblástica/enzimologia , Deficiências do Desenvolvimento/genética , Febre/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA