Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically ...diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic disorders, expanded the knowledge of known disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen–host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions.
Over 125 congenital disorders of glycosylation (CDG) are clinically diverse and cover all major glycosylation pathways.
Next-generation sequencing (NGS) enabled discovery of over 51 novel glycosylation disorders and identified de novo mutations in several disorders.
Complex genetic screening of human cells shows glycosylation is critical for many pathogens, especially viruses. Targeting glycosylation pathways could become a short-term treatment.
Simple monosaccharide therapies and novel chemical approaches offer treatments for several glycosylation disorders.
Abstract Background We aimed to define characteristics and needs of Facebook users in relation to congenital anomalies. Methods Cross-sectional analysis of Facebook related to four congenital ...anomalies: Anorectal Malformation(ARM), Congenital Diaphragmatic Hernia(CDH), Congenital Heart Disease(CHD) and Hypospadias/Epispadias(HS/ES). A keyword search was performed to identify relevant Groups/Pages. An anonymous survey was posted to obtain quantitative/qualitative data on users and their healthcare needs. Results 54 Groups and 24 Pages were identified (ARM:10 Groups; CDH:9 Groups, 7 Pages; CHD:32 Groups, 17 Pages; HS/ES: 3 Groups), with 16,191 Group members and 48,766 Page likes. 868/1103 (79%) of respondents were parents. Male:female ratio 1:10.9. 65% of users were 26-40 years old. Common reasons for joining these Groups/Pages included: seeking support, education, making friends, providing support to others. 932/1103 (84%) would like healthcare professionals (HCPs) actively participating in their Group. 31% of the respondents felt they did not receive enough support from their healthcare system. 97% of the respondents would like to join a Group linked to their primary hospital. Conclusions Facebook Groups/Pages related to congenital anomalies are highly populated and active. There is a need for HCPs and policy makers to better understand and participate in social media to support families and improve patient care.
Abstract Background Congenital hypothyroidism (CH) is the most common endocrine system disorder in newborns. Ectopic thyroid and agenesis are the most frequent thyroid structural malformations. ...Several reports have shown that CH is associated with birth defects (BD) ranging from congenital heart disease to ocular and gastrointestinal anomalies. Aims We investigated how many and what types of BD were associated with CH in Mexican children. Study design Cross-sectional study conducted in patients with confirmed CH. Setting Highly specialized government pediatric center in Mexico City. Subjects We included 212 patients with permanent CH identified by newborn screening. Results We found that 24% of patients with CH also had BD, and that there was a higher prevalence of thyroid agenesis in the group of patients with CH associated with BD (CH + BD) versus the isolated CH group ( p = 0.007). There were more females than males in both groups. The most common BD were congenital heart diseases, especially those of the atrial septum, followed by patent ductus arteriosus, found as a single malformation or as part of a complex congenital heart disease. In this study, we found Hirschsprung disease, Beckwith–Wiedemann syndrome, Pierre Robin sequence, Albright's osteodystrophy, VATER association, and frontonasal dysplasia associated with CH. Conclusions In this study population, there was a high prevalence of BD in patients with permanent CH. Thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH + BD underlines the need for a comprehensive clinical diagnostic approach of the patients with CH.
Summary
Congenital dyserythropoietic anaemia type I (CDA‐I) is one of a heterogeneous group of inherited anaemias characterised by ineffective erythropoiesis. CDA‐I is caused by bi‐allelic mutations ...in either CDAN1 or C15orf41 and, to date, 56 causative mutations have been documented. The diagnostic pathway is reviewed and the utility of genetic testing in reducing the time taken to reach an accurate molecular diagnosis and avoiding bone marrow aspiration, where possible, is described. The management of CDA‐I patients is discussed, highlighting both general and specific measures which impact on disease progression. The use of interferon alpha and careful management of iron overload are reviewed and suggest the most favourable outcomes are achieved when CDA‐I patients are managed with a holistic and multidisciplinary approach. Finally, the current understanding of the molecular and cellular pathogenesis of CDA‐I is presented, highlighting critical questions likely to lead to improved therapy for this disease.
Background
Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite ...undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes.
Objective
We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next‐generation sequencing.
Methods
Genetic diagnosis was performed by gene capture followed by next‐generation sequencing of 76 genes known to cause anemia syndromes.
Results
Genetic diagnosis was achieved in 13 out of 21 patients (62%). Six patients were diagnosed with pyruvate kinase deficiency, 4 with dehydrated hereditary stomatocytosis, 2 with sideroblastic anemia, and 1 with CDA type IV. Eight novel mutations were found. In 7 patients, the genetic diagnosis differed from the pretest presumed diagnosis. The mean lag time from presentation to diagnosis was over 13 years.
Conclusions
Targeted next‐generation sequencing led to an accurate diagnosis in over 60% of patients with rare anemias. These patients do not need further diagnostic workup. Earlier incorporation of this method into the workup of patients with congenital anemia may improve patients’ care and enable genetic counseling.
Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the
gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was ...mandatory to better quantify disease burden and determine best outcome measures.
We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored.
Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti-adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10.
Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population.
NCT02057705.
Pediatric intracranial infections Parmar, Hemant; Ibrahim, Mohannad
Neuroimaging clinics of North America,
11/2012, Letnik:
22, Številka:
4
Journal Article
Recenzirano
Infection of the central nervous system (CNS) in children is an important entity and early recognition is paramount to avoid long-term brain injury, especially in very young patients. The causal ...factors are different in children compared with adults and so are the clinical presentations. However, imaging features of CNS infection show similar features to those of adults. This article reviews some of the common types of pediatric infections, starting with the congenital (or in utero) infections followed by bacterial infections of the meninges and brain parenchyma.
In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and ...related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C
H
zinc finger transcription factors, including SALL4, a member of the
-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in
result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.
Background
Congenital anomalies are common, but the possibility that maternal cancer increases the chance of having a child with a birth defect is not fully understood.
Objectives
To examine the ...association between maternal cancer before or during pregnancy and the risk of birth defects in offspring.
Methods
We conducted a retrospective cohort study of live births in Quebec, Canada, between 1989 and 2022 using hospital data. The main exposure measure was maternal cancer before or during pregnancy. The outcome included birth defects detected in offspring during gestation or at birth. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association of maternal cancer with birth defects using log‐binomial regression models adjusted for potential confounders.
Results
In this study of 2,568,120 newborns, birth defects were present in 6.0% and 6.7% of infants whose mothers had cancer before or during pregnancy, respectively, compared with 5.7% of infants whose mothers never had cancer. Cancer during pregnancy was associated with heart (RR 1.58, 95% CI 1.03, 2.44), nervous system (RR 4.05, 95% CI 2.20, 7.46) and urinary defects (RR 1.72, 95% CI 1.01, 2.95). Among specific types of malignancies during pregnancy, breast cancer was the most prominent risk factor for birth defects (RR 1.55, 95% CI 1.02, 2.37). Cancer before pregnancy was not associated with any type of birth defect or with defects overall (RR 1.01, 95% CI 0.92, 1.11). Moreover, no specific type of cancer before pregnancy was associated with an increased risk of birth defects.
Conclusions
Maternal cancer during pregnancy is associated with the risk of congenital anomalies in offspring, however, cancer before pregnancy is not associated with this outcome.
Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal ...microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES).
In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly.
The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4–11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three 3·2% of 93 fetuses).
WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness.
UK Department of Health and Social Care and The Wellcome Trust.
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