Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
Am J Med Genet A ; : e63778, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829177

RESUMO

TANGO2 deficiency disorder (TDD) is a rare, autosomal recessive condition caused by pathogenic variants in TANGO2, a gene residing within the region commonly deleted in 22q11.2 deletion syndrome (22q11.2DS). Although patients with 22q11.2DS are at substantially higher risk for comorbid TDD, it remains underdiagnosed within 22q11.2DS, likely due to overlapping symptomatology and a lack of knowledge about TDD. Initiation of B-vitamin supplementation may provide therapeutic benefit in TDD, highlighting the need for effective screening methods to improve diagnosis rates in this at-risk group. In this retrospective, multicenter study, we evaluated two cohorts of patients with 22q11.2DS (total N = 435) for possible comorbid TDD using two different symptom-based screening methods (free text-mining and manual chart review versus manual chart review alone). The methodology of the cohort 1 screening method successfully identified a known 22q11.2DS patient with TDD. Combined, these two cohorts identified 21 living patients meeting the consensus recommendation for TANGO2 testing for suspected comorbid TDD. Of the nine patients undergoing TANGO2 sequencing with del/dup analysis, none were ultimately diagnosed with TDD. Of the 12 deaths in the suspected comorbid TDD cohort, some of these patients exhibited symptoms (rhabdomyolysis, cardiac arrhythmia, or metabolic crisis) suspicious of comorbid TDD contributing to their death. Collectively, these findings highlight the need for robust prospective screening tools for diagnosing comorbid TDD in patients with 22q11.2DS.

2.
Children (Basel) ; 10(1)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36670656

RESUMO

The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan's Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project's impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95-214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.

4.
J Pediatr ; 246: 116-122.e1, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35358588

RESUMO

OBJECTIVE: To assess the outcomes of neonates in a contemporary multi-institutional cohort who receive renal replacement therapy (RRT) for hyperammonemia. STUDY DESIGN: We performed a retrospective analysis of 51 neonatal patients with confirmed inborn errors of metabolism that were treated at 9 different children's hospitals in the US between 2000 and 2015. RESULTS: Twenty-nine patients received hemodialysis (57%), 21 patients received continuous renal replacement therapy (41%), and 1 patient received peritoneal dialysis (2%). The median age at admission of both survivors (n = 33 [65%]) and nonsurvivors (n = 18) was 3 days. Peak ammonia and ammonia at admission were not significantly different between survivors and nonsurvivors. Hemodialysis, having more than 1 indication for RRT in addition to hyperammonemia, and complications during RRT were all risk factors for mortality. After accounting for multiple patient factors by multivariable analyses, hemodialysis was associated with a higher risk of death compared with continuous renal replacement therapy. When clinical factors including evidence of renal dysfunction, number of complications, concurrent extracorporeal membrane oxygenation, vasopressor requirement, and degree of hyperammonemia were held constant in a single Cox regression model, the hazard ratio for death with hemodialysis was 4.07 (95% CI 0.908-18.2, P value = .067). To help providers caring for neonates with hyperammonemia understand their patient's likelihood of survival, we created a predictive model with input variables known at the start of RRT. CONCLUSIONS: Our large, multicenter retrospective review supports the use of continuous renal replacement therapy for neonatal hyperammonemia.


Assuntos
Hiperamonemia , Erros Inatos do Metabolismo , Amônia , Criança , Humanos , Hiperamonemia/etiologia , Hiperamonemia/terapia , Recém-Nascido , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/terapia , Terapia de Substituição Renal/efeitos adversos , Estudos Retrospectivos
5.
Cells ; 11(4)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35203319

RESUMO

Cystinosis is a lethal autosomal recessive disease that has been known clinically for over 100 years. There are now specific treatments including dialysis, renal transplantation and the orphan drug, cysteamine, which greatly improve the duration and quality of patient life, however, the cellular mechanisms responsible for the phenotype are unknown. One cause, programmed cell death, is clearly involved. Study of extant literature via Pubmed on "programmed cell death" and "apoptosis" forms the basis of this review. Most of such studies involved apoptosis. Numerous model systems and affected tissues in cystinosis have shown an increased rate of apoptosis that can be partially reversed with cysteamine. Proposed mechanisms have included changes in protein signaling pathways, autophagy, gene expression programs, and oxidative stress.


Assuntos
Cistinose , Transplante de Rim , Apoptose , Autofagia , Cisteamina/farmacologia , Cisteamina/uso terapêutico , Humanos
6.
Pediatr Neurol ; 119: 34-39, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33845444

RESUMO

BACKGROUND: TANGO2-related metabolic encephalopathy and arrhythmias (TRMEA) is a rare, phenotypically heterogeneous, neurological disease affecting children. METHODS: We conducted a chart review of five children with molecularly confirmed TRMEA diagnosed at our institution and compiled pathogenic variant frequency and symptom prevalence from cases previously reported in the literature. RESULTS: Including those patients in our case series, 76 patients with TRMEA have been described. Developmental delay (93%) and/or regression (71%), spasticity (78%), and seizures (57%) are common in TRMEA and frequently precede life-threatening symptoms such as metabolic decompensation with lactic acidosis (83%), cardiomyopathy (38%), and cardiac arrhythmias (68%). Deletion of exons 3 to 9 is the most common pathogenic variant (39% of alleles). The majority of reported intragenic variants (17 of 27) result in disruption of the reading frame, and no clear genotype-phenotype correlations could be identified for those variants wherein the reading frame is maintained, highlighting instead the variable expressivity of the disease. CONCLUSIONS: Patients with TRMEA frequently experience life-threatening complications that are preceded by common neurological symptoms underscoring the need for pediatric neurologists to be familiar with this condition. Additional work pertaining to disease pathophysiology and potential therapeutics is needed.


Assuntos
Arritmias Cardíacas , Encefalopatias Metabólicas , Estudos de Associação Genética , Adolescente , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Ataxia/epidemiologia , Encefalopatias Metabólicas/epidemiologia , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/epidemiologia , Feminino , Humanos , Lactente , Masculino , Prevalência , Rabdomiólise/epidemiologia , Síndrome
7.
Int J Neonatal Screen ; 6(3)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-33239598

RESUMO

Two lysosomal storage disorders (LSDs), Pompe disease and Mucopolysaccharidosis type I (MPSI) were added to the Recommended Uniform Screening Panel (RUSP) for newborn screening (NBS) in 2015 and 2016, respectively. These conditions are being screened with variable practice in terms of primary and reflex analytes (either biochemical or molecular testing) as well as collection of short- and long-term follow-up elements. The goal of this study is to evaluate practices of state health departments in regards to screening methods and follow-up data collected. We conducted online surveys and phone questionnaires to determine each U.S. state's practices for screening and follow-up of positive newborn screens. We report the first snapshot of practices for NBS for the LSDs included on the RUSP. All 50 U.S. states responded to our survey. The majority of U.S. states are not currently screening for Pompe disease and MPSI as of March 2020, but this number will increase to 38 states in the coming 1-3 years based on survey results. Our survey identifies data elements used by state health departments for short-and long-term follow-up that could serve as the basis of common elements for larger, public health-based analyses of the benefits and efficacy of screening for Pompe disease and MPSI.

8.
Am J Med Genet A ; 182(11): 2704-2708, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32820583

RESUMO

Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.


Assuntos
Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/genética , Homocistinúria/tratamento farmacológico , Triagem Neonatal/métodos , Piridoxina/efeitos adversos , Insuficiência Respiratória/patologia , Rabdomiólise/patologia , Relação Dose-Resposta a Droga , Feminino , Homocistinúria/genética , Homocistinúria/patologia , Humanos , Recém-Nascido , Prognóstico , Piridoxina/administração & dosagem , Insuficiência Respiratória/induzido quimicamente , Rabdomiólise/induzido quimicamente , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/efeitos adversos
11.
Pediatr Nephrol ; 35(9): 1761-1769, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32232638

RESUMO

BACKGROUND: Outcomes for severe hyperammonemia treated with renal replacement therapy (RRT) reported in the literature vary widely. This has created differing recommendations regarding when RRT is beneficial for hyperammonemic patients. METHODS: To evaluate our institution's experience with RRT in pediatric patients with inborn errors of metabolism (IEMs) and potential prognostic indicators of a better or worse outcome, we performed a retrospective chart review of patients who received RRT for hyperammonemia. Our cohort included 19 patients with confirmed IEMs who received RRT between 2000 and 2017. Descriptive statistics are presented as medians with interquartile ranges with appropriate statistical testing assuming unequal variance. RESULTS: There were 16 males (84%) and 3 females (16%) identified for inclusion in this study. There were 9 survivors (47%) and 10 non-survivors (53%). The average age of survivors was 67 months (age range from 3 days to 15.6 years). The average age of non-survivors was 1.8 months (age range from 2 days to 18.7 months). Peak ammonia, ammonia on admission, and at RRT initiation were higher in non-survivors compared with survivors. Higher ammonia levels and no change in ammonia between admission and RRT initiation were associated with an increased risk of mortality. CONCLUSIONS: Hyperammonemia affects two distinct patient populations; neonates with markedly elevated ammonia levels on presentation and older children who often have established IEM diagnoses and require RRT after failing nitrogen-scavenging therapy. Our experience demonstrates no significant change in mortality associated with neonatal hyperammonemia, which remains high despite improvements in RRT and intensive care.


Assuntos
Hiperamonemia/terapia , Terapia de Substituição Renal/métodos , Criança , Pré-Escolar , Feminino , Humanos , Hiperamonemia/sangue , Hiperamonemia/etiologia , Hiperamonemia/mortalidade , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/complicações , Estudos Retrospectivos
12.
Breastfeed Med ; 14(8): 575-579, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31219317

RESUMO

Background: Returning to work and lack of support for expressing breast milk (pumping) at work is often cited as a reason that mothers discontinue breastfeeding, particularly among female physicians. It is unclear how these perceived difficulties affect resident mothers and how resident teams perceive coresidents who choose to pump at work. The goal of this study was to identify differences in perception of resident mothers and their coresidents about breastfeeding residents pumping. Materials and Methods: An online survey in 2017 was sent to 413 residents in Pediatrics, Internal Medicine, Family Medicine, and Anesthesia at the University of Michigan Health System. Results: A total of 82 residents completed the survey (20% response rate). Resident mothers (15% of respondents self-identified as a mother) were asked specific questions regarding their experiences with breastfeeding. Almost all mothers (92%) encountered difficulty in breastfeeding after returning to work. The majority of mothers reported that their mood was affected by these difficulties (85%). The most common challenge that breastfeeding residents encountered was not enough time to pump. The majority of all residents surveyed (74%) have worked with a breastfeeding resident. Forty percent of breastfeeding residents felt that their pumping adversely affected the team, whereas only 10% of coresidents felt the same. Conclusions: Breastfeeding residents encountered significant difficulties that affected their well-being when breastfeeding while returning to work. They also felt that their pumping can be detrimental to their job. However, their coresidents felt that pumping had no major setbacks to team efficiency or patient care and did not create additional work.


Assuntos
Aleitamento Materno/estatística & dados numéricos , Internato e Residência , Mães/estatística & dados numéricos , Local de Trabalho/psicologia , Aleitamento Materno/psicologia , Educação Médica , Feminino , Humanos , Masculino , Michigan , Mães/psicologia , Inquéritos e Questionários , Fatores de Tempo
13.
Arterioscler Thromb Vasc Biol ; 35(11): 2354-65, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26338297

RESUMO

OBJECTIVE: Collateral arteriogenesis, the growth of existing arterial vessels to a larger diameter, is a fundamental adaptive response that is often critical for the perfusion and survival of tissues downstream of chronic arterial occlusion(s). Shear stress regulates arteriogenesis; however, the arteriogenic significance of reversed flow direction, occurring in numerous collateral artery segments after femoral artery ligation, is unknown. Our objective was to determine if reversed flow direction in collateral artery segments differentially regulates endothelial cell signaling and arteriogenesis. APPROACH AND RESULTS: Collateral segments experiencing reversed flow direction after femoral artery ligation in C57BL/6 mice exhibit increased pericollateral macrophage recruitment, amplified arteriogenesis (30% diameter and 2.8-fold conductance increases), and remarkably permanent (12 weeks post femoral artery ligation) remodeling. Genome-wide transcriptional analyses on human umbilical vein endothelial cells exposed to reversed flow conditions mimicking those occurring in vivo yielded 10-fold more significantly regulated transcripts, as well as enhanced activation of upstream regulators (nuclear factor κB [NFκB], vascular endothelial growth factor, fibroblast growth factor-2, and transforming growth factor-ß) and arteriogenic canonical pathways (protein kinase A, phosphodiesterase, and mitogen-activated protein kinase). Augmented expression of key proarteriogenic molecules (Kruppel-like factor 2 [KLF2], intercellular adhesion molecule 1, and endothelial nitric oxide synthase) was also verified by quantitative real-time polymerase chain reaction, leading us to test whether intercellular adhesion molecule 1 or endothelial nitric oxide synthase regulate amplified arteriogenesis in flow-reversed collateral segments in vivo. Interestingly, enhanced pericollateral macrophage recruitment and amplified arteriogenesis was attenuated in flow-reversed collateral segments after femoral artery ligation in intercellular adhesion molecule 1(-/-) mice; however, endothelial nitric oxide synthase(-/-) mice showed no such differences. CONCLUSIONS: Reversed flow leads to a broad amplification of proarteriogenic endothelial signaling and a sustained intercellular adhesion molecule 1-dependent augmentation of arteriogenesis. Further investigation of the endothelial mechanotransduction pathways activated by reversed flow may lead to more effective and durable therapeutic options for arterial occlusive diseases.


Assuntos
Artérias/fisiopatologia , Circulação Colateral , Isquemia/fisiopatologia , Mecanotransdução Celular , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Animais , Artérias/metabolismo , Artérias/patologia , Velocidade do Fluxo Sanguíneo , Células Cultivadas , Modelos Animais de Doenças , Artéria Femoral/fisiopatologia , Artéria Femoral/cirurgia , Regulação da Expressão Gênica , Membro Posterior , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Isquemia/genética , Isquemia/metabolismo , Isquemia/patologia , Ligadura , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fluxo Sanguíneo Regional , Estresse Mecânico , Fatores de Tempo , Remodelação Vascular
14.
Physiol Genomics ; 46(2): 57-65, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24302644

RESUMO

Multiple cues have been suggested as the mechanical stimulus for the heart's hypertrophic response. Our work has previously suggested that the amount of cyclic shortening in cardiomyocytes controls myocyte shape and the amount of stretch controls myocyte size. To identify gene expression changes that occur in response to these mechanical perturbations, we used microarray analysis of papillary muscles cultured for 12 h at physiological or reduced levels of cyclic shortening and physiological or reduced mean stretch. Overall, genes related to extracellular matrix (ECM) were surprisingly prominent in our analysis. Connective tissue growth factor was among a small group of genes regulated by the amount of cyclic shortening regardless of the level of mean stretch, and many more ECM genes were regulated by shortening with reduced amounts of stretch. When we compared our results to gene expression data from an in vivo model of pressure overload (PO), which also decreases myocyte shortening, we found the genes that were commonly regulated in PO and our decreased shortening groups were most significantly enriched for ontology terms related to the ECM, followed by genes associated with mechanosensing and the cytoskeleton. The list of genes regulated in PO and our decreased shortening groups also includes genes known to change early in hypertrophy, such as myosin heavy chain 7, brain natriuretic peptide, and myosin binding protein C. We conclude that in intact myocardium, the amount of cyclic shortening may be an important regulator not only of myocyte genes classically associated with hypertrophy but also of ECM genes.


Assuntos
Perfilação da Expressão Gênica/métodos , Contração Miocárdica/genética , Miócitos Cardíacos/metabolismo , Músculos Papilares/metabolismo , Animais , Análise por Conglomerados , Matriz Extracelular/genética , Ontologia Genética , Masculino , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Músculos Papilares/citologia , Músculos Papilares/fisiologia , Pressão , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Mecânico , Técnicas de Cultura de Tecidos
15.
J Biomech ; 44(16): 2795-801, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21945569

RESUMO

The goal of this work was to create a finite element micromechanical model of the myotendinous junction (MTJ) to examine how the structure and mechanics of the MTJ affect the local micro-scale strains experienced by muscle fibers. We validated the model through comparisons with histological longitudinal sections of muscles fixed in slack and stretched positions. The model predicted deformations of the A-bands within the fiber near the MTJ that were similar to those measured from the histological sections. We then used the model to predict the dependence of local fiber strains on activation and the mechanical properties of the endomysium. The model predicted that peak micro-scale strains increase with activation and as the compliance of the endomysium decreases. Analysis of the models revealed that, in passive stretch, local fiber strains are governed by the difference of the mechanical properties between the fibers and the endomysium. In active stretch, strain distributions are governed by the difference in cross-sectional area along the length of the tapered region of the fiber near the MTJ. The endomysium provides passive resistance that balances the active forces and prevents the tapered region of the fiber from undergoing excessive strain. These model predictions lead to the following hypotheses: (i) the increased likelihood of injury during active lengthening of muscle fibers may be due to the increase in peak strain with activation and (ii) endomysium may play a role in protecting fibers from injury by reducing the strains within the fiber at the MTJ.


Assuntos
Modelos Biológicos , Fibras Musculares Esqueléticas , Entorses e Distensões/fisiopatologia , Estresse Fisiológico , Traumatismos dos Tendões/fisiopatologia , Tendões/fisiopatologia , Animais , Análise de Elementos Finitos , Masculino , Camundongos , Entorses e Distensões/patologia , Traumatismos dos Tendões/patologia , Tendões/patologia
16.
Am J Vet Res ; 69(12): 1637-45, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19046012

RESUMO

OBJECTIVE: To develop a reliable method for converting cultured equine skin-derived fibroblasts into muscle cells. SAMPLE POPULATION: Equine skin-derived fibroblasts. PROCEDURES: The equine myogenic differentiation 1 (eqMyoD) genomic sequence was obtained by use of equine bacterial artificial chromosome screening and PCR sequencing. Total mRNA was extracted from foal skeletal muscle, and eqMyoD cDNA was cloned into a plasmid vector with an internal ribosomal entry site to express bicistronic eqMyoD or enhanced green fluorescent protein (EGFP). Transient expression was confirmed by immunocytochemical analysis and western immunoblots in equine fibroblasts and fibroblasts from National Institutes of Health Swiss mouse embryos, prior to generation of a lentiviral vector containing the same coding sequences. Transformation of equine skin-derived cells into skeletal myotubes was examined by use of immunohistochemical analysis, western immunoblotting, and periodic acid-Schiff staining. RESULTS: eqMyoD mRNA consists of 960 bp and shares high homology with myogenic differentiation 1 from other mammals. Transfection confirmed the expression of a 53-kd protein with mainly nuclear localization. Lentiviral transduction was efficient, with approximately 80% of EGFP-positive cells transformed into multinucleated myotubes during 15 days, as determined by expression of the muscle-specific proteins desmin, troponin-T, and sarcomeric myosin and by cytoplasmic storage of glycogen. CONCLUSIONS AND CLINICAL RELEVANCE: Equine primary fibroblasts were transformed by lentiviral transduction of eqMyoD into fusion-competent myoblasts. This may offer a preferable alternative to primary myoblast cultures for the investigation of cellular defects associated with muscle diseases of horses, such as recurrent exertional rhabdomyolysis and polysaccharide storage myopathy.


Assuntos
Fibroblastos/citologia , Cavalos , Lentivirus/fisiologia , Fibras Musculares Esqueléticas/citologia , Proteína MyoD/metabolismo , Pele/citologia , Células 3T3 , Sequência de Aminoácidos , Animais , Regulação da Expressão Gênica/fisiologia , Humanos , Camundongos , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/virologia , Proteína MyoD/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...