Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

Sickle cell disease

A Kwan, RS Abraham, R Currier. JAMA. 2014;312(7):729–738

To assess the results of a spectrum of state-based newborn screening programs using the T-cell receptor excision (TREC) testing approach to develop more accurate population-based incidence of severe combined immunodeficiency (SCID) and other conditions associated with T-cell lymphopenia and document the effectiveness of early intervention in those newborns found to have a significant immunologic abnormality.

Cumulative TREC newborn screening data were evaluated from 10 states plus the Navajo Nation involving ∼3 million newborns.

This was an epidemiologic and retrospective observational study based on states invited to submit SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. The data evaluated were collected from January 2008 through …

https://pediatrics.aappublications.org/content/pediatrics/136/Supplement_3/S275.full.pdf

Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States

The rise of technologies that simultaneously measure thousands of data points represents the heart of systems biology. These technologies have had a huge impact on the discovery of next-generation diagnostics, biomarkers, and drugs in the precision medicine era. Systems biology aims to achieve systemic exploration of complex interactions in biological systems. Driven by high-throughput omics technologies and the computational surge, it enables multi-scale and insightful overviews of cells, organisms, and populations. Precision medicine capitalizes on these conceptual and technological advancements and stands on two main pillars: data generation and data modeling. High-throughput omics technologies allow the retrieval of comprehensive and holistic biological information, whereas computational capabilities enable high-dimensional data modeling and, therefore, accessible and user-friendly visualization. Furthermore, bioinformatics has enabled comprehensive multi-omics and clinical data integration for insightful interpretation. Despite their promise, the translation of these technologies into clinically actionable tools has been slow. In this review, we present state-of-the-art multi-omics data analysis strategies in a clinical context. The challenges of omics-based biomarker translation are discussed. Perspectives regarding the use of multi-omics approaches for inborn errors of metabolism (IEM) are presented by introducing a new paradigm shift in addressing IEM investigations in the post-genomic era.

https://www.mdpi.com/1422-0067/17/9/1555/pdf

Omics-based strategies in precision medicine: Toward a paradigm shift in inborn errors of metabolism investigations

Until the mid-1980s studies of steroidogenesis largely depended on identifying steroid structures and measuring steroid concentrations in body fluids. The molecular biology revolution radically revolutionized studies of steroidogenesis with the cloning of known steroidogenic enzymes, by identifying novel factors, and delineating the genetic basis of known and newly discovered diseases. Unfortunately, this dramatic success has led many young research-oriented endocrinologists to regard steroidogenesis as a 'solved area'. However, many important and exciting questions remain, especially concerning the mechanisms of cholesterol delivery to the steroidogenic machinery, the biochemistry of androgen synthesis, the regulation and biological role of adrenarche, fetal adrenal development and involution, the roles of steroids made in 'extraglandular' cells, and the search for genetic disorders. This review outlines some of these questions, but this list is necessarily incomplete.

Steroidogenesis: Unanswered Questions.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients.

/pdf/maple-syrup-urine-disease-mechanisms-and-management-2a3t70o7cu.pdf

J. Gerard Loeber

Papers

Current status of newborn screening worldwide: 2015