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1.
Ann Neurol ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652821

RESUMO

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases PMM enzyme activity in a PMM2-CDG worm-model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical and clinical characteristics including the Nijmegen Progression CDG Rating Scale, urine polyol levels and fibroblast glycoproteomics in PMM2-CDG patients. METHODS: We performed PMM enzyme measurements, multiplexed proteomics and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared to controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation towards the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of PMM2-CDG patients and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first PMM2-CDG pediatric patient treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. This article is protected by copyright. All rights reserved.

2.
Environ Res ; 203: 111800, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34364863

RESUMO

Concentrations of total mercury were measured in blood and hair samples collected as part of a human biomonitoring project conducted in First Nations communities of the Mackenzie Valley, Northwest Territories, Canada. Hair (n = 443) and blood (n = 276) samples were obtained from six communities in the Dehcho region and three communities in the Sahtú region of the Mackenzie Valley. The aim of this paper was to calculate hair to blood mercury ratios (for matched samples) and determine if: 1) ratios differed significantly between the two regions; 2) ratios differed from the 250:1 ratio proposed by the WHO; and, 3) point estimates of hair to blood mercury ratios could be used to estimate blood mercury concentrations. In addition, this paper aims to determine if there were seasonal patterns in hair mercury concentrations in these regions and if so, if patterns were related to among-season variability in fish consumption. The majority of mercury levels in hair and blood were below relevant health-based guidance values. The geometric mean hair (most recent segment) to blood mercury ratio (stratified by region) was 619:1 for the Dehcho region and 1220:1 for the Sahtú region. Mean log-transformed hair to blood mercury ratios were statistically significantly different between the two regions. Hair to blood ratios calculated in this study were far higher (2-5 times higher) than those typically reported in the literature and there was a large amount of inter-individual variation in calculated ratios (range: 114:1 to 4290:1). Using the 250:1 ratio derived by the World Health Organisation to estimate blood mercury concentrations from hair mercury concentrations would substantially over-estimate blood mercury concentrations in the studied regions. However, geometric mean site-specific hair to blood mercury ratios can provide estimates of measures of central tendency for blood mercury concentrations from hair mercury concentrations at a population level. Mercury concentrations were determined in segments of long hair samples to examine exposure of participants to mercury over the past year. Hair segments were assigned to six time periods and the highest hair mercury concentrations were generally observed in hair segments that aligned with September/October and November/December, whereas the lowest hair mercury concentrations were aligned with March/April and May/June. Mean log-transformed hair mercury concentrations were statistically significantly different between time periods. Between time periods (e.g., September/October vs. March/April), the geometric mean mercury concentration in hair differed by up to 0.22 µg/g, and the upper margins of mercury exposure (e.g., 95th percentile of hair mercury) varied by up to 0.86 µg/g. Results from self-reported fish consumption frequency questionnaires (subset of participants; n = 170) showed total fish intake peaked in late summer, decreased during the winter, and then increased during the spring. Visual assessment of results indicated that mean hair mercury concentrations followed this same seasonal pattern. Results from mixed effects models, however, indicated that variability in hair mercury concentrations among time periods was not best explained by total fish consumption frequency. Instead, seasonal trends in hair mercury concentrations may be more related to the consumption of specific fish species (rather than total wild-harvested fish in general). Future work should examine whether seasonal changes in the consumption of specific fish species are associated with seasonal changes in hair mercury concentrations.

3.
Nurse Educ ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34366415

RESUMO

BACKGROUND: Studies of the clinical learning environment document the importance of the student's clinical learning process. PURPOSE: The aim of this study was to gather information on students' perceptions of their learning in the clinical environment. METHODS: A mixed-method strategy was used to explore nursing students' (N = 194) perceptions of their clinical learning experiences. Data were collected using the Clinical Learning Environment Inventory (CLEI) survey and open-ended questions. RESULTS: The results showed that significant CLEI factors were affordances and engagement, student-centeredness, valuing nurses' work, and fostering workplace learning and that these factors were important to prelicensure nursing students' learning in the clinical environment. In addition, the thematic concepts that enhanced their learning were clinical faculty who exhibited strong communication, encouraged and challenged learners, and were readily available. CONCLUSIONS: Clinical faculty in the clinical environment must be competent and able to support the prelicensure nursing student learner.

4.
Schizophr Bull ; 2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34420057

RESUMO

Amotivation is related to value representation. A comprehensive account of amotivation requires a mechanistic understanding of how the brain exploits external information to represent value. To achieve maximal value discriminability, brain valuation system will dynamically adapt its coding sensitivity to the range of values available in any given condition, so-called range adaptive coding. We administered an experimental task to 30 patients with chronic schizophrenia (C-SCZ), 30 first-episode schizophrenia (FE-SCZ), 34 individuals with high social anhedonia (HSoA), and their paired controls to assess range adaptation ability. C-SCZ patients exhibited over-adaptation and their performances were negatively correlated with avolition symptoms and positive symptoms and positively correlated with blunted-affect symptoms and self-reported consummatory interpersonal pleasure scores, though the results were non-significant. FE-SCZ patients exhibited reduced adaptation, which was significantly and negatively correlated with avolition symptoms and positively correlated with the overall proportion of choosing to exert more effort. Although HSoA participants exhibited comparable range adaptation to controls, their performances were significantly and negatively correlated with the proportion of choosing to exert more effort under the lowest value condition. Our results suggest that different stages of schizophrenia spectrum showed distinct range adaptation patterns. Range adaptation impairments may index a possible underlying mechanism for amotivation symptoms in FE-SCZ and more complicated and pervasive effects on clinical symptoms in C-SCZ.

5.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
6.
Mol Genet Metab ; 133(4): 397-399, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34140212

RESUMO

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 µg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

7.
Genet Med ; 23(9): 1604-1615, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34040193

RESUMO

PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature. METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival. RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old. CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.


Assuntos
Doença de Crohn , Úlcera da Perna , Deficiência de Prolidase , Criança , Pré-Escolar , Diagnóstico Tardio , Humanos , Fenótipo , Deficiência de Prolidase/diagnóstico , Deficiência de Prolidase/genética
8.
J Am Coll Health ; : 1-13, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830892

RESUMO

Objective: This study used a multi-faceted methodological approach to examine if peer perceptions of stereotyped student groups' mental health needs varied by target race and student-athlete status.Participants: In Study 1, 502 university students completed an online experiment. Study 2 data were drawn from the American College Health Association (ACHA)-National College Health Assessment (N = 65,167) and Healthy Minds Study (N = 43,487).Methods: Study 1 participants rated the severity of various mental health concerns for Black non-student-athletes, White non-student-athletes, Black student-athletes, or White student-athletes. Study 2 conceptualized peer perceptions vis-à-vis mental health patterns in national data.Results: Study 1 generally revealed lower perceived severity of mental health concerns for Black non-student-athletes. In contrast, Study 2 patterns revealed more variations across student status groups, including that Black non-student-athletes exhibited relatively high prevalence rates of numerous mental health concerns.Conclusions: Results may suggest mental health under-/over-pathologizing, with implications for training and peer-to-peer mental health interventions.

9.
Nurs Educ Perspect ; 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33859153

RESUMO

ABSTRACT: Structural competency describes the ability to recognize structural factors that affect health disparities, such as inequity and stigma. These structural factors can alter a patient's symptoms and risk for certain diseases. The purpose of this study was to describe baccalaureate nursing students' attributions of the effects of structural factors on health. Participants in this study attributed structural factors as being relevant to adverse health outcomes. Findings demonstrated differences in attribution of structural factors by academic level. Given the shifting demographics in the United States and gaps in health care access, further research is needed on the development of structural competence in nursing students.

10.
Policy Polit Nurs Pract ; 22(3): 201-211, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33906510

RESUMO

Rural Health Clinics (RHCs) were created in 1977 to address the high health care needs, limited provider access, and poor health outcomes of rural Americans. Although innovative at their inception, the provider-centric model of RHC cost-based reimbursement structures has not evolved, leaving limited opportunities for change; many have failed. Comprehensive, proactive change is needed. Registered nurses (RNs) working at the top of their practice scope are a neglected clinical resource that can improve access, quality, value, and satisfaction for rural patient communities. RHC reimbursement policy must evolve to sustain and support this significant RN role. RNs have demonstrated value in care continuity and disease management, but there is little research on the utilization of RNs using their enhanced skill set in RHCs. Using the Bardach and Patashnik's eight steps of policy analysis, the authors will describe the background and regulations of RHCs, identify current barriers to improving the health of America's rural residents, and then provide evidence to support a new policy option according to the Quadruple Aim framework. The result is a sustainable policy recommendation designed to best serve rural communities.

11.
Nurs Educ Perspect ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33840780

RESUMO

AIM: The aim of the study was to explore how nurse faculty prepare students to teach chronic disease self-management. BACKGROUND: Self-management addresses patient activities in response to a change in baseline health. Evidence suggests nurses may not be educated on how to engage patients in chronic disease self-management. METHOD: This qualitative study used semistructured interviews to explore experiences of 13 nurse faculty across three universities in preparing nursing students to address self-management concepts for adults living with chronic disease. RESULTS: Three themes emerged from 104 identified significant statements: conceptualizing and valuing chronic disease self-management in nursing education, making chronic disease self-management fit, and sharing the impact of health care reform on chronic disease care. CONCLUSION: Self-management is regarded as highly complex and evolving. As such, nursing education curricula must also evolve to emphasize successful approaches to preventing chronic disease and incorporating chronic disease self-management and behavior modification in the curriculum.

12.
Lupus Sci Med ; 8(1)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658303

RESUMO

OBJECTIVE: Punch biopsy, a standard diagnostic procedure for patients with cutaneous lupus erythematosus (CLE) carries an infection risk, is invasive, uncomfortable and potentially scarring, and impedes patient recruitment in clinical trials. Non-invasive tape sampling is an alternative that could enable serial evaluation of specific lesions. This cross-sectional pilot research study evaluated the use of a non-invasive adhesive tape device to collect messenger RNA (mRNA) from the skin surface of participants with CLE and healthy volunteers (HVs) and investigated its feasibility to detect biologically meaningful differences between samples collected from participants with CLE and samples from HVs. METHODS: Affected and unaffected skin tape samples and simultaneous punch biopsies were collected from 10 participants with CLE. Unaffected skin tape and punch biopsies were collected from 10 HVs. Paired samples were tested using quantitative PCR for a candidate immune gene panel and semi-quantitative immunohistochemistry for hallmark CLE proteins. RESULTS: mRNA collected using the tape device was of sufficient quality for amplification of 94 candidate immune genes. Among these, we found an interferon (IFN)-dominant gene cluster that differentiated CLE-affected from HV (23-fold change; p<0.001) and CLE-unaffected skin (sevenfold change; p=0.002), respectively. We found a CLE-associated gene cluster that differentiated CLE-affected from HV (fourfold change; p=0.005) and CLE-unaffected skin (fourfold change; p=0.012), respectively. Spearman's correlation between per cent area myxovirus 1 protein immunoreactivity and IFN-dominant mRNA gene cluster expression was highly significant (dermis, rho=0.86, p<0.001). In total, skin tape-derived RNA expression comprising both IFN-dominant and CLE-associated gene clusters correlated with per cent area immunoreactivity of some hallmark CLE-associated proteins in punch biopsies from the same lesions. CONCLUSIONS: A non-invasive tape RNA collection technique is a potential tool for repeated skin biomarker measures throughout a clinical trial.


Assuntos
Lúpus Eritematoso Cutâneo , Estudos Transversais , Feminino , Voluntários Saudáveis , Humanos , Masculino , RNA , Pele
13.
Orphanet J Rare Dis ; 16(1): 102, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632285

RESUMO

A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study's conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients' lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.


Assuntos
Defeitos Congênitos da Glicosilação , Fosfotransferases (Fosfomutases) , Defeitos Congênitos da Glicosilação/tratamento farmacológico , Defeitos Congênitos da Glicosilação/genética , Humanos , Manose , Fosfotransferases (Fosfomutases)/deficiência , Fosfotransferases (Fosfomutases)/genética , Estudos Prospectivos , Reprodutibilidade dos Testes , Transferrina/análogos & derivados
14.
J Inherit Metab Dis ; 44(4): 987-1000, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33583022

RESUMO

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

15.
Hum Mol Genet ; 29(23): 3818-3829, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33432325

RESUMO

Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene, which results in transcriptional deficiency via epigenetic silencing. Most patients are homozygous for alleles containing > 500 triplets, but a subset (~20%) have at least one expanded allele with < 500 triplets and a distinctly milder phenotype. We show that in FRDA DNA methylation spreads upstream from the expanded repeat, further than previously recognized, and establishes an FRDA-specific region of hypermethylation in intron 1 (~90% in FRDA versus < 10% in non-FRDA) as a novel epigenetic signature. The hypermethylation of this differentially methylated region (FRDA-DMR) was observed in a variety of patient-derived cells; it significantly correlated with FXN transcriptional deficiency and age of onset, and it reverted to the non-disease state in isogenically corrected induced pluripotent stem cell (iPSC)-derived neurons. Bisulfite deep sequencing of the FRDA-DMR in peripheral blood mononuclear cells from 73 FRDA patients revealed considerable intra-individual epiallelic variability, including fully methylated, partially methylated, and unmethylated epialleles. Although unmethylated epialleles were rare (median = 0.33%) in typical patients homozygous for long GAA alleles with > 500 triplets, a significantly higher prevalence of unmethylated epialleles (median = 9.8%) was observed in patients with at least one allele containing < 500 triplets, less severe FXN deficiency (>20%) and later onset (>15 years). The higher prevalence in mild FRDA of somatic FXN epialleles devoid of DNA methylation is consistent with variegated epigenetic silencing mediated by expanded triplet-repeats. The proportion of unsilenced somatic FXN genes is an unrecognized phenotypic determinant in FRDA and has implications for the deployment of effective therapies.


Assuntos
Metilação de DNA , Epigênese Genética , Ataxia de Friedreich/patologia , Inativação Gênica , Leucócitos Mononucleares/patologia , Fenótipo , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Ataxia de Friedreich/genética , Humanos , Lactente , Leucócitos Mononucleares/metabolismo , Masculino , Adulto Jovem
16.
Transfusion ; 61(3): 979-985, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33475168

RESUMO

BACKGROUND: We report a case of apparent mother-child ABO group noninheritance. A Caucasian mother initially typed as group O and her infant group AB. Investigation ruled out preanalytical causes such as mislabeled samples and in vitro fertilization. MATERIALS AND METHODS: Red blood cells were characterized by routine serologic testing. Genomic data were analyzed by targeted polymerase chain reaction-restriction fragment length polymorphism and Sanger sequencing. Transferase structures were modeled using PyMOL molecular visualization software. RESULTS: Serologic testing initially demonstrated the mother was group O, father group AB, and infant group AB. Further testing of the maternal sample with anti-A,B demonstrated weak A expression. Molecular testing revealed the maternal sample had an ABO*O.01.01 allele in trans to an A allele, ABO*AW.29 (c.311T>A, p.Ile104Asn), determined by gene sequencing. The sample from the infant carried the same ABO*AW.29 allele in trans to a B allele, ABO*B.01. CONCLUSION: ABO genotyping revealed an A transferase encoded by ABO*AW.29, with apparent variable activity. Although A antigen expression is well known to be weak in newborns, it was robust on the red blood cells (RBCs) of the AB infant and undetectable with anti-A on the mother. Variable expression of weak subgroups may reflect competition or enhancement by a codominant allele, as well as glycan chain maturation on red cells. Previous examples in group AB mothers with Aweak infants suggested that the decreased expression is primarily due to glycan immaturity. To our knowledge, this is the first reported case of the ABO*AW.29 allele presenting with weak A expression in a group Aweak mother and robust A expression in a group AB infant, suggesting the in trans allele is an important factor in determining transferase activity and may override age-related effects.


Assuntos
Sistema ABO de Grupos Sanguíneos/sangue , Sistema ABO de Grupos Sanguíneos/genética , Eritrócitos/metabolismo , Glicosiltransferases/sangue , Glicosiltransferases/genética , Adulto , Alelos , Tipagem e Reações Cruzadas Sanguíneas , Eritrócitos/imunologia , Feminino , Genótipo , Glicosiltransferases/química , Hereditariedade , Humanos , Recém-Nascido , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA , Testes Sorológicos , Software
17.
Orphanet J Rare Dis ; 16(1): 20, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413482

RESUMO

BACKGROUND: The congenital disorders of glycosylation (CDG) are a heterogeneous group of rare metabolic diseases with multi-system involvement. The liver phenotype of CDG varies not only according to the specific disorder, but also from patient to patient. In this study, we sought to identify common patterns of liver injury among patients with a broad spectrum of CDG, and to provide recommendations for follow-up in clinical practice. METHODS: Patients were enrolled in the Frontiers in Congenital Disorders of Glycosylation natural history study. We analyzed clinical history, molecular genetics, serum markers of liver injury, liver ultrasonography and transient elastography, liver histopathology (when available), and clinical scores of 39 patients with 16 different CDG types (PMM2-CDG, n = 19), with a median age of 7 years (range: 10 months to 65 years). For patients with disorders which are treatable by specific interventions, we have added a description of liver parameters on treatment. RESULTS: Our principal findings are (1) there is a clear pattern in the evolution of the hepatocellular injury markers alanine aminotransferase and aspartate aminotransferase according to age, especially in PMM2-CDG patients but also in other CDG-I, and that the cholangiocellular injury marker gamma-glutamyltransferase is not elevated in most patients, pointing to an exclusive hepatocellular origin of injury; (2) there is a dissociation between liver ultrasound and transient elastography regarding signs of liver fibrosis; (3) histopathological findings in liver tissue of PMM2-CDG patients include cytoplasmic glycogen deposits; and (4) most CDG types show more than one type of liver injury. CONCLUSIONS: Based on these findings, we recommend that all CDG patients have regular systematic, comprehensive screening for liver disease, including physical examination (for hepatomegaly and signs of liver failure), laboratory tests (serum alanine aminotransferase and aspartate aminotransferase), liver ultrasound (for steatosis and liver tumors), and liver elastography (for fibrosis).


Assuntos
Defeitos Congênitos da Glicosilação , Fosfotransferases (Fosfomutases) , Defeitos Congênitos da Glicosilação/genética , Seguimentos , Glicosilação , Humanos , Lactente , Fígado/diagnóstico por imagem , Fígado/metabolismo
18.
J Inherit Metab Dis ; 44(1): 148-163, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32681750

RESUMO

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.

19.
J Clin Endocrinol Metab ; 106(2): e1002-e1013, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33141175

RESUMO

CONTEXT: Although stages of reproductive aging for women in the general population are well described by STRAW+10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors). OBJECTIVE: This work aimed to evaluate applying STRAW + 10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and to assess how cancer treatment gonadotoxicity is related to reproductive aging stage. DESIGN: The sample (n = 338) included AYA survivors from the Reproductive Window Study cohort. Menstrual bleeding data and dried-blood spots for antimüllerian hormone (AMH) and follicle-stimulating hormone (FSH) measurements (Ansh DBS enzyme-linked immunosorbent assays) were used for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records. RESULTS: Among participants, mean age 34.0 ±â€…4.5 years and at a mean of 6.9 ±â€…4.6 years since cancer treatment, the most common cancers were lymphomas (31%), breast (23%), and thyroid (17%). Twenty-nine percent were unclassifiable by STRAW + 10 criteria, occurring more frequently in the first 2 years from treatment. Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase AMH and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, and 7% postmenopause), endocrine biomarkers distinguished among peak, early, and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages. CONCLUSIONS: We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit the STRAW + 10 criteria, suggesting the need for modified staging for this population.

20.
Am J Med Genet A ; 185(1): 213-218, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33044030

RESUMO

Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.

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