Universal Newborn Screening Program Research Articles

Newborn Screening for Congenital Cytomegalovirus in Canada

What Is the Issue Congenital cytomegalovirus (cCMV) infection is a leading cause of childhood hearing loss. It is estimated that 85% to 90% of newborns infected with cCMV will not show any symptoms at birth. Of those newborns with cCMV infection who are asymptomatic at birth, 10% to 15% will go on to develop long-term symptoms, including vision loss, hearing loss, and developmental delays. What Did We Do? This brief provides a summary about newborn screening for cCMV in Canada, including whether screening is available for cCMV in each province and territory, and if so, whether screening is universal or targeted using publicly available information. What Did We Find? Currently in Canada, 4 provinces (Alberta, Saskatchewan, Manitoba, Ontario) have or are implementing universal newborn screening for cCMV. Three provinces (British Columbia, New Brunswick, Nova Scotia) have province-wide targeted screening programs that offer cCMV testing to newborns who fail newborn hearing tests or who have suspected cCMV as identified by a clinician. Current clinical guidance and practice remain mixed on whether targeted or universal newborn screening is recommended, with each having a different distribution of benefits and harms. cCMV infections can be detected using blood, urine, or saliva tests. Most universal newborn screening programs use dried blood spot tests, which are likely to produce false-negative results; saliva tests have a lower number of false-negative results but can result in a higher number of false-positives. Some programs recommend additional testing using a different method (either saliva or urine) after an initial positive test as a validation. What Does This Mean? As both universal and targeted newborn screening programs have been adopted by several jurisdictions in Canada, there is wide recognition that cCMV infection is a serious health issue and that early detection is important. Moreover, there is an opportunity to generate data and evidence about test performance and program impact over time that could support future decision-making. As evidence and new test and treatment options become available, such data will help to inform the type of newborn screening approach used for cCMV.

Analysis of Dried Blood Spot and Saliva PCR Screening for Detection of Congenital Cytomegalovirus Infection Informs Implementation of a Novel Universal Newborn Screening Program

Analysis of Dried Blood Spot and Saliva PCR Screening for Detection of Congenital Cytomegalovirus Infection Informs Implementation of a Novel Universal Newborn Screening Program

Positive Impacts of the Universal Newborn Screening Program on the Outcome of Children with Sickle Cell Disease in the Province of Quebec: A Retrospective Cohort Study

Background Sickle cell disease (SCD) is the most common monogenic disease worldwide. Benefits of preventive measures such as early penicillin prophylaxis and ease of neonatal diagnosis led to the inclusion of SCD in newborn screening programs (NSP) in the US and later in several Canadian provinces. Universal NSP was implemented in the province of Québec (QcNSP) in November 2013, close in time to the recommendation of early hydroxyurea (HU) therapy. Our study objective was to evaluate how the QcNSP impacted the clinical outcomes of SCD infants and children followed at CHU Ste-Justine between the age of 0-5 years of age. We hypothesized that the introduction of QcNSP has shortened the time to referral to SCD comprehensive centres and the time to HU initiation, while also reducing the number of acute SCD complications. Methodology This is a retrospective cohort study of patients referred to the pediatric comprehensive SCD centre at CHU Sainte-Justine (Montreal), a leading tertiary pediatric center in Canada from Jan 1-2000, to Dec 31-2019. To be included, patients had to be followed for at least two years. Two cohorts were defined: Cohort Pre-QcNSP included patients who had their first visit between January 1 st 2000 and October 31 st2013, whereas cohort post-QcNSP included patients who had their first visit between November 1st 2013 and December 31 st 2019. SCD genotypes were stratified into two groups: HbSS/Sß 0 and SC/Sß +. Reasons for referral were extracted. A Kaplan-Meier curve for hospitalization-free survival (HFS), a poisson regression for the number of VOC emergency (ED) visits and a logistic regression for clinical outcomes, adjusting for age at first visit, gender, place of birth, follow-up period and QcNSP were computed. The software R version 4.2.1 was used for all statistical analyses. The study was approved by the local IRB. Results Of 600 files examined, 410 met the inclusion criteria. 253 were referred pre-QcNSP, 157 post-QcNSP. There were equal gender representations in both groups, and no statistical differences between genotype representation between cohorts. Median age at 1st visit decreased from 1.2 [IQR: 0.2-6.0] pre-QcNSP to 0.2 years [IQR:0.1-4.8] post-QcNSP (p<0.001). The percentage of children born in the province of Qc diagnosed through NS increased from 48.1% (79) pre-QcNSP to 100% (102) post-QcNSP (p<0.004). The percentage of undiagnosed children born in Qc and referred after a first SCD-related complication (DRC) dropped from 42% to 0% (p<0.0001). The median age of HU-introduction for SS patients decreased from 4.5 [IQR:2.6-5.5] pre-QcNSP to 0.75 years [IQR:0.8-1.08] post-QcNSP (p<0.001). Similarly, the percentage of SS patients receiving HU by the age of 2 years old significantly increased from 28.6% preQcNSP to 59.3% post-DN patients (p=0.003). The overall percentage of SS patients eventually receiving HU was nevertheless statistically not different between cohorts (89.7% (61/68) post-QcNSP vs 82.5% (80/97) pre-QcNSP). The number of hospitalizations in HbSS/Sß 0 decreased from 2 hospitalizations/pt-year pre-QcNSP [IQR 1.0-3.0] to 1.0 [IQR: 0.6-1.4] (p<0.001). Hospitalization-free survival (HFS) also improved (257 days post-QcNSP vs. 140 days pre-QcNSP, p<0.001) for HbSS/Sß 0 patients. Similarly, HFS for VOC was significantly longer post-QcNSP (1320 days vs. 573 days, p<0.002). Evaluating ED visits for VOC, HbSS/Sß 0 children referred pre-QcNSP had much greater risk of ED-VOC visits than post-QcNSP (1.44, CI 1.22-1.67); similarly, SS/Sb 0 children referred for DRC vs NS had a higher risk of ED-visit for VOC (0.25, CI 0.02-0.48). There was however no statistical difference in SC/Sß + patients. Conclusion. In Quebec, the universalization of the NSP has enabled early detection and referral of children with SCD to comprehensive care centre. Earlier access to this expertise ensures that children benefit from the essential preventive interventions that are vaccination, prophylactic penicillin, early HU-use as well as caregiver education. These combined interventions may explain in part the improvement in acute events. This cohort study highlights that universal NSP of SCD is an essential public health measure.

Prospects for Expansion of Universal Newborn Screening in Bulgaria: A Survey among Medical Professionals.

Determining the scope of a newborn screening program is a challenging health policy issue. Our study aimed to explore the attitudes of specialists in pediatrics, neonatology, medical genetics, and biochemistry regarding the prospects for expanding the panel of diseases for universal newborn screening in Bulgaria. We conducted an online survey in March-May 2022. The questionnaire listed 35 disorders that could potentially be included in the Bulgarian panel for universal newborn screening. If endorsing a specific condition, participants had to justify their position by judging its performance against the ten principles of Wilson and Jungner. We found a high degree of knowledge about the current universal newborn screening program in Bulgaria. An overwhelming majority (97.4%) supported the expansion of the panel to include more conditions. Four disorders obtained more than 50% approval for inclusion: cystic fibrosis (87.0%), thalassemia (72.7%), spinal muscular atrophy (65.6%), and classical galactosemia (59.1%). The perception of the condition as an important health problem was the most significant factor in this support. The costs of diagnosis and treatment appeared to be the main source of concern. We recommend country-specific economic evaluations and research on the views of other stakeholders, including the government, payers, and patient organizations, to better understand and manage the complex nature of newborn screening policymaking.

Current challenges and new approaches to implementing optimal management of sickle cell disease in sub-Saharan Africa

Sickle cell disease (SCD) is the most common life-threatening monogenic disorder in the world. The disease is highly prevalent in malaria endemic areas with over 75% of patients residing in Sub-Saharan Africa (SSA). It is estimated that, without proper care, up to 90% of children with SCD will not celebrate their fifth birthday. Early identification and enrolment into comprehensive care has been shown to reduce the morbidity and mortality related with SCD complications. However, due to resource constraints, the SSA is yet to implement universal newborn screening programs for SCD. Furthermore, care for patients with SCD in the region is hampered by the shortage of qualified healthcare workers, lack of guidelines for the clinical management of SCD, limited infrastructure for inpatient and outpatient care, and limited access to blood and disease modifying drugs such as Hydroxyurea which contribute to poor clinical outcomes. Curative options such as bone marrow transplant and gene therapy are expensive and not available in many SSA countries. In addressing these challenges, various initiatives are ongoing in SSA which aim to enhance awareness on SCD, improve patient identification and retention to care, harmonize the standards of care for SCD, improve the skills of healthcare workers and conduct research on pertinent areas in SCD in the SSA context. Fortifying these measures is paramount to improving the outcomes of SCD in SSA.

Diagnostic and Communication Challenges in Cystic Fibrosis Newborn Screening.

As of December 2009, cystic fibrosis (CF) newborn screening (NBS) is performed in all 50 US states and the District of Columbia. Widespread implementation of CF newborn screening (CFNBS) in the US and internationally has brought about new and varied challenges. Immunoreactive trypsinogen (IRT) remains the first, albeit imperfect, biomarker used universally in the screening process. Advances in genetic testing have provided an opportunity for newborn screening programs to add CFTR sequencing tiers to their algorithms. This in turn will enable earlier identification of babies with CF and improve longer-term outcomes through prompt treatment and intervention. CFTR sequencing has led to the ability to identify infants with CF from diverse ethnic and racial backgrounds more equitably while also identifying an increasing proportion of infants with inconclusive diagnoses. Using the evolution of the New York State CF newborn screening program as a guide, this review outlines the basic steps in a universal CF newborn screening program, considers how to reduce bias, highlights challenges, offers guidance to address these challenges and provides recommendations for future consideration.

A Roadmap for Potential Improvement of Newborn Screening for Inherited Metabolic Diseases Following Recent Developments and Successful Applications of Bivariate Normal Limits for Pre-Symptomatic Detection of MPS I, Pompe Disease, and Krabbe Disease.

The mucopolysaccharidoses (MPS), Pompe Disease (PD), and Krabbe disease (KD) are inherited conditions known as lysosomal storage disorders (LSDs) The resulting enzyme deficiencies give rise to progressive symptoms. The United States Department of Health and Human Services' Recommended Uniform Screening Panel (RUSP) suggests LSDs for inclusion in state universal newborn screening (NBS) programs and has identified screening deficiencies in MPS I, KD, and PD NBS programs. MPS I NBS programs utilize newborn dried blood spots and assay alpha L-iduronidase (IDUA) enzyme to screen for potential cases. Glycosaminoglycans (GAGs) offer potential as a confirmatory test. KD NBS programs utilize galactocerebrosidase (GaLC) as an initial test, with psychosine (PSY) activity increasingly used as a confirmatory test for predicting onset of Krabbe disease, though with an excessive false positive rate. PD is marked by a deficiency in acid α-glucosidase (GAA), causing increased glycogen, creatine (CRE), and other biomarkers. Bivariate normal limit (BVNL) methods have been applied to GaLC and PSY activity to produce a NBS tool for KD, and more recently, to IDUA and GAG activity to develop a NBS tool for MPS I. A BVNL tool based on GAA and CRE is in development for infantile PD diagnosis. Early infantile KD, MPS I, and PD cases were pre-symptomatically identified by BVNL-based NBS tools. This article reviews these developments, discusses how they address screening deficiencies identified by the RUSP and may improve NBS more generally.

Strategies to increase access to basic sickle cell disease care in low- and middle-income countries

Introduction Sickle cell disease (SCD) is the most common hemoglobinopathy in the world. Over 90% of those born with SCD live in low- and middle-income countries (LMICs), yet individuals in these settings have much poorer outcomes compared to those in high-income countries. Areas Covered This manuscript provides an in-depth review of the cornerstones of basic SCD care, the barriers to implementing these in LMICs, and strategies to increase access in these regions. Publications in English language, peer-reviewed, and edited from 2000-2021 were identified on PubMed. Google search was used for grey literature. Expert Opinion Outcomes for patients with SCD in high-income countries have improved over the last few decades due to the implementation of universal newborn screening programs and use of routine antimicrobial prophylaxis, increase in therapeutic and curative options, and the adoption of specific measures to decrease risk of stroke. This success has not translated to LMICs due to several reasons including resource constraints. A combination of several strategies is needed to increase access to basic SCD care for patients in these settings.

Benefits of a Disease Management Program for SCD in Germany 2011 - 2019: The Increased Use of Hydroxyurea Correlates with a Reduced Frequency of Acute Chest Syndrome

BackgroundWorldwide, Sickle Cell Disease (SCD) is the most common single gene disorder affecting >250,000 newborns annually. In Germany, SCD qualifies as a rare disease and almost exclusively affects immigrants from endemic countries and their descendants. The recent surge of immigration from high-prevalence countries increased the numbers of patients with SCD in Germany and raised awareness for the need of specialized care.In 2012, the German Society for Pediatric Oncology and Hematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. This consortium issued treatment guidelines for SCD that strongly favor the use of hydroxyurea, initiated patient and physician education events, prepared for a universal newborn screening program that will start 09/2021, moderated a consensus on the indication of allogeneic stem cell transplantation for patients with SCD, and established a national patient registry.MethodsIn order to quantify the effect of these activities, we made use of claims data that were collected by the research institute (WIdO) of the major German insurance company, the Allgemeine Ortskrankenkasse (AOK), and of publicly accessible data collected by the Federal Statistical Office (Statistisches Bundesamt, Destatis). ICD10 codes were used to identify patients with SCD and their comorbidities. Pharmacologic treatments were quantified using the German Anatomical Therapeutic Chemical (ATC)-Classification with defined daily doses.ResultsWe estimate that the number of patients with SCD in Germany increased from approximately 2,200 in 2011 to approximately 3,200 in 2019. Analyses of administered treatments illustrate that important components of recently issued national treatment guidelines have been largely implemented. Specifically, the use of hydroxyurea has more than doubled, resulting in a proportion of approximately 45% of all patients with SCD being treated with hydroxyurea in 2019 (Figure 1A). In strong negative correlation with the use of hydroxyurea, the frequency of acute chest syndromes decreased (Figure 1B). While before the widespread use of hydroxyurea (2011-2013) 8.1% of patients with SCD were admitted at least once per year for ACS, this proportion dropped to 6.6% in the period 2017 to 2019. Similarly, the proportion of patients who required analgesics, red blood cell transfusions and hospitals admissions declined from 2011 to 2019, indicating a reduced burden of SCD with the increased use of hydroxyurea.ConclusionIn sum, these data demonstrate an association between the dissemination of nationwide treatment guidelines and changes in clinical practice in particular relating to the use of hydroxyurea. These changes translate into a remarkable improvement of key measures of disease activity in a representative population based analysis. [Display omitted] DisclosuresLobitz: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulozik: BioMedX: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Lack of an Alberta Newborn Screening Program Is Associated with Delayed Diagnosis of Sickle Cell Disease

Background:Sickle cell anemia (SCA) is one of the major hemoglobin disorders worldwide. SCA has a high degree of disease-associated mortality and morbidity that can be prevented by early identification of affected individuals and implementation of comprehensive care measures. Newborn screening (NBS) has been shown to be an effective measure for early diagnosis and to help decrease disease related complications.Alberta has not implemented a routine newborn screening program for hemoglobin disorders. For this reason, we hypothesize that a significant portion of the SCA patients followed at Alberta Children's Hospital (ACH) are diagnosed at a later age (> 1 year of age) due to a presentation with sickle cell complications or from targeted screening at medical visits.The primary objective of the study is to identify the age of diagnosis of SCA patients followed at the Alberta Children's Hospital when a universal newborn screening program was not available.Methods:In this retrospective cohort study, we reviewed 100 charts for patients with hemoglobin (Hb) disorders who had attended Alberta Children's Hospital (ACH) hematology clinic during the period from January 2003 to January 2014. Only patients with SCA (HbSS, Hb SB0, Hb SB+, Hb SC, S-HPFH) were included in the study. Data collected included demographic variables, SCA diagnosis related information such as the age of diagnosis, the reason for screening, and characteristics of the first SCA presentation. Late diagnosis was defined as a diagnosis after 12 months of age. The clinical course of SCA as complications, the age of penicillin prophylaxis initiation and the age of first transcranial Doppler testing (TCD) were obtained as secondary measures.Results:A total of 77 patients with SCA (40.3% male, 59.7% Female) that attended sickle cell clinic at ACH met our inclusion criteria. Thirty-four percent (N=26) of patients were born in Alberta, 26.5% (N=19) in other Canadian provinces and the United States and 41% (N=32) in other parts of the world. The majority (94.8 %) were African, and 5.2% were of other ethnic backgrounds including Arab/Latin American and South Asian.More than half of the patients who were born in Alberta (58 %) were diagnosed after the age of 12 months. The mean (M) age of diagnosis for the patients born in Alberta was 21.4 ± 21 months (median 19, range 0-84). None of the patients were diagnosed because of newborn screening whereas 39% were identified due to family history, 50% due to disease related complication and 8% due to abnormal lab low Hb/abnormal smear. Fifteen percent of those patients never started on penicillin prophylaxis due to old age at the time of diagnosis, otherwise, the mean age of penicillin initiation was 15 ± 10.8 months (median 14, range 2-36). Only 65% of the patients had TCD testing with mean age of the first TCD was 44 ± 24 months (median 36, range 24-96).The mean age of diagnosis was 8 ± 18 months (median 0, range 0-72) for children who were born in other Canadian provinces/US where newborn screening is available. There was a significant difference in the mean age of diagnosis in children with SCA who were born in Alberta (M = 21.4, SD = 21) where newborn screening is not available and sickle cell patients who were born in the United States and elsewhere in Canada (M = 8, SD = 18); t (43) = 2.08, p = 0.043, 95% CI [0.4,25], using an independent samples t-test to compare the mean age.Conclusion:The number of SCA patients attending the ACH Hematology clinic has almost tripled since the time of data collection due to upward trends in immigration. Patients who were born in our province had a significant late diagnosis compared to other jurisdictions and frequently present initially with severe disease complications. Our findings provide strong evidence to support the implementation of a provincial universal screening program so prophylactic treatment, and comprehensive care is provided before the development of clinical complications. Also, positive screening results could provide an additional opportunity to provide timely genetic counseling to at-risk individuals and families in Alberta. DisclosuresNo relevant conflicts of interest to declare.

Extended-hearing targeted screening for congenital cytomegalovirus infection.

The importance of neonatal screening for congenital cytomegalovirus infection (cCMV) is widely shared in the world scientific literature. However, currently, no programs for universal neonatal screening for cCMV have been reported in the literature, and only a few experiences of hearing targeted cCMV screening have been published. In the Tuscany Region, Italy, screening for cCMV has been mandatory since 2008 for each newborn that result "refer" at the Transient Evoked Otoacoustics Emissions (TEOAE) test, and in our university hospital since 2012, it has been extended to some categories at risk of cCMV. We present the results of the protocol for cCMV screening adopted at our Institution since 2012. From 2012 to 2017, 1615 newborns underwent cCMV screening. Twenty-five cases were positive for cCMV, (1.54% of all the newborn screened for cCMV and 0.19% of infants submitted to newborn hearing screening). Nineteen of these children (76%) had normal hearing, while 6 (24%) had a hearing deficit of variable degree. 2/25 (8%) cases presented a progression of the hearing deficit in the first months of life and no children had a late onset or fluctuating hearing loss. Our findings show how cCMV screening in newborns that result refer at TEOAE allows the detection of many cases; but many are still missed. It would be, therefore, important to adopt a universal newborn cCMV screening program or a program extended to newborns at higher risk.

Implementing newborn screening for sickle cell disease in Korle Bu Teaching Hospital, Accra: Results and lessons learned.

Early diagnosis of sickle cell disease (SCD) through newborn screening (NBS) is a cost-effective intervention, which reduces morbidity and mortality. In sub-Saharan Africa (SSA) where disease burden is greatest, there are no universal NBS programs and few institutions have the capacity to conduct NBS. We determined the feasibility and challenges of implementing NBS for SCD in Ghana's largest public hospital. The SCD NBS program at Korle Bu Teaching Hospital (KBTH) is a multiyear partnership between the hospital and the SickKids Center for Global Child Health, Toronto, being implemented in phases. The 13-month demonstration phase (June 2017-July 2018) and phase one (November 2018-December 2019) focused on staff training and the feasibility of universal screening of babies born in KBTH. During the demonstration phase, 115 public health nurses and midwives acquired competency in heel stick for dried blood spot sampling. Out of 9990 newborns, 4427 babies (44.3%) were screened, of which 79 (1.8%) were identified with presumptive SCD (P-SCD). Major challenges identified included inadequate nursing staff to perform screening, shortage of screening supplies, and delays in receiving screening results. Strategies to overcome some of the challenges were incorporated into phase one, resulting in increased screening coverage to 83.7%. Implementing NBS for SCD in KBTH presented challenges with implications on achieving and sustaining universal NBS in KBTH and other settings in SSA. Specific steps addressing these challenges comprehensively will help build on the modest initial gains, moving closer toward a sustainable national NBS program.

First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain).

Severe combined immunodeficiency (SCID), the most severe form of T-cell immunodeficiency, can be screened at birth by quantifying T-cell receptor excision circles (TRECs) in dried blood spot (DBS) samples. Early detection of this condition speeds up the establishment of appropriate treatment and increases the patient's life expectancy. Newborn screening for SCID started in January 2017 in Catalonia, the first Spanish and European region to universally include this testing. The results obtained in the first 2 years of experience are evaluated here. All babies born between January 2017 and December 2018 were screened. TREC quantification in DBS (1.5 mm diameter) was performed with the Enlite Neonatal TREC kit from PerkinElmer (Turku, Finland). In 2018, the retest cutoff in the detection algorithm was updated based on the experience gained in the first year, and changed from 34 to 24 copies/μL. This decreased the retest rate from 3.34 to 1.4% (global retest rate, 2.4%), with a requested second sample rate of 0.23% and a positive detection rate of 0.02%. Lymphocyte phenotype (T, B, NK populations), expression of CD45RA/RO isoforms, percentage and intensity of TCR αβ and TCR γδ, presence of HLA-DR+ T lymphocytes, and in vitro lymphocyte proliferation were studied in all patients by flow cytometry. Of 130,903 newborns screened, 30 tested positive, 15 of which were male. During the study period, one patient was diagnosed with SCID: incidence, 1 in 130,903 births in Catalonia. Thirteen patients had clinically significant T-cell lymphopenia (non-SCID) with an incidence of 1 in 10,069 newborns (43% of positive detections). Nine patients were considered false-positive cases because of an initially normal lymphocyte count with normalization of TRECs between 3 and 6 months of life, four infants had transient lymphopenia due to an initially low lymphocyte count with recovery in the following months, and three patients are still under study. The results obtained provide further evidence of the benefits of including this disease in newborn screening programs. Longer follow-up is needed to define the exact incidence of SCID in Catalonia.

GTP-Cyclohydrolase I deficiency presenting as malignant hyperphenylalaninemia, recurrent hyperthermia and progressive neurological dysfunction in a South Asian child \u2013 a case report

BackgroundTetrahydrobiopterin (BH4) deficiencies are disorders affecting phenylalanine homeostasis, and catecholamine and serotonin biosynthesis. GTP-Cyclohydrolase I deficiency (OMIM 600225) is an extremely rare variant of inborn error of BH4 synthesis which exists in recessive and dominant forms. The recessive form presents with complex neurological and autonomic dysfunction whilst the dominant form presents as Dopa-responsive dystonia.Case presentationWe describe a South Asian child who initially presented with neurological dysfunction and recurrent vomiting and later developed recurrent hyperthermia for several months. The child did not have screening for hyperphenylalaninemia at birth and was found to have marked hyperphenylalaninemia after clinical presentation at 5 months. Further evaluation revealed BH4 deficiency. GTP-Cyclohydrolase I deficiency (GTPCH) was identified based on normal dihydro pteridine reductase activity and markedly reduced neopterin in dried blood spot test. After institution of treatment and control of high phenylalanine levels, clinical deterioration decelerated yet with noticeable residual neurological dysfunction.ConclusionTo authors’ knowledge, this is first report of GTPCH deficiency in a South Asian child. The case highlights practical issues regarding diagnosis of GTPCH deficiency, especially in countries without broader universal newborn screening programs for early detection of inherited metabolic disorders. Testing for GTPCH deficiency should be considered for patients with unexplained neurological and autonomic symptoms following initial metabolic screen.

Results of a multicenter universal newborn screening program for sickle cell disease in Italy: A call to action.

Sickle cell disease (SCD) is a chronic multisystem disorder requiring comprehensive care that includes newborn screening (NBS) as the first step of care. Italy still lacks a national SCD NBS program and policy on blood disorders. Pilot single-center screening programs and a regional targeted screening have been implemented so far, but more evidence is needed in order to impact health policies. NBS was offered to parents of newborns in gynecology clinics in Padova and Monza, tertiary care university hospitals in northern Italy. High-performance liquid chromatography (HPLC) was performed as the first test on samples collected on Guthrie cards. Molecular analysis of the beta-globin gene was performed on positive samples. A total of 5466 newborns were enrolled; for 5439, informed consents were obtained. A similar family origin was seen in the two centers (65% Italians, 9% mixed couples, 26% immigrants). Compared with SCD NBS programs in the United States and Europe, our results show a similar incidence of SCD patients and carriers. All SCD patients had a Sub-Saharan family background; HbS carriers were 15% Caucasians (Italian, Albanians) and 10% from other areas (North Africa-India-South America); carriers of other hemoglobin variants were mainly (47%) from other areas. Our results demonstrate the feasibility of a multicentric NBS program for SCD, give information on HbS epidemiology in two Northern Italian Areas, and support previous European recommendation for a universal NBS program for SCD in Italy: a high incidence of patients and carriers has been detected, with a high percentage of Caucasian carriers, impossible to identify in a targeted NBS.

Newborn Screening for SCD in the USA and Canada.

Sickle cell disease (SCD) encompasses a group of inherited red cell disorders characterized by an abnormal hemoglobin, Hb S. The most common forms of SCD in the United States and Canada are identified through universal newborn screening (NBS) programs. Now carried out in all fifty U.S. states and 8 Canadian provinces, NBS for SCD represents one of the major public health advances in North America. The current status of NBS programs for hemoglobinopathies and the screening techniques employed in many regions worldwide reflect in large part the U.S. and Canadian experiences. Although the structure, screening algorithms and laboratory procedures, as well as reporting and follow up, vary between NBS programs, the overall workflow is similar. The current review summarized the historical background, current approaches, and methods used to screen newborns for SCD in the United States and Canada.

Sickle cell disease.

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.

Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency in Sichuan, China.

Our goals were to screen newborns and characterize the occurrence of glucose-6-phosphate dehydrogenase (G6PD) deficiency in southwestern China. Meanwhile, we would like to analyze the factors that might affect the results of neonatal dried blood spots for glucose-6-phosphate dehydrogenase screening test, to improve the clinical quality control level, effectively reduce the external factors in the process of detection. This study involved an evaluation of G6PD data for 20,644 newborns from a universal newborn screening program. Heel prick blood specimens were collected around 72 hours after birth and were dried on filter papers. For G6PD deficiency the fluorescent spot test was employed. We studied the association between incidence of G6PD deficiency and influence factors. This study involved an evaluation of G6PD data for 20,644 neonatal heel prick blood samples from 10,984 males and 9,660 females. There were 503 positive results for G6PD deficiency (299 males and 204 females), and the G6PD deficiency-positive rate was estimated to be around 2.4%. The gender-specific prevalence for males was 2.7%, and for females 2.1%. Multiple factors may influence the result of the G6PD test, such as season, temperature, and specimen of indwelling time. This study analyzed the prevalence of G6PD deficiency in Sichuan, China. Accelerating the speed of sample delivery and ensuring availability of screening results can aid the screening and diagnosis.

Substituting Sodium Hydrosulfite with Sodium Metabisulfite Improves Long-Term Stability of a Distributable Paper-Based Test Kit for Point-of-Care Screening for Sickle Cell Anemia.

Sickle cell anemia (SCA) is a genetic blood disorder that is particularly lethal in early childhood. Universal newborn screening programs and subsequent early treatment are known to drastically reduce under-five SCA mortality. However, in resource-limited settings, cost and infrastructure constraints limit the effectiveness of laboratory-based SCA screening programs. To address this limitation our laboratory previously developed a low-cost, equipment-free, point-of-care, paper-based SCA test. Here, we improved the stability and performance of the test by replacing sodium hydrosulfite (HS), a key reducing agent in the hemoglobin solubility buffer which is not stable in aqueous solutions, with sodium metabisulfite (MS). The MS formulation of the test was compared to the HS formulation in a laboratory setting by inexperienced users (n = 3), to determine visual limit of detection (LOD), readout time, diagnostic accuracy, intra- and inter-observer agreement, and shelf life. The MS test was found to have a 10% sickle hemoglobin LOD, 21-min readout time, 97.3% sensitivity and 99.5% specificity for SCA, almost perfect intra- and inter-observer agreement, at least 24 weeks of shelf stability at room temperature, and could be packaged into a self-contained, distributable test kits comprised of off-the-shelf disposable components and food-grade reagents with a total cost of only $0.21 (USD).

The Sweat Metabolome of Screen-Positive Cystic Fibrosis Infants: Revealing Mechanisms beyond Impaired Chloride Transport.

The sweat chloride test remains the gold standard for confirmatory diagnosis of cystic fibrosis (CF) in support of universal newborn screening programs. However, it provides ambiguous results for intermediate sweat chloride cases while not reflecting disease progression when classifying the complex CF disease spectrum given the pleiotropic effects of gene modifiers and environment. Herein we report the first characterization of the sweat metabolome from screen-positive CF infants and identify metabolites associated with disease status that complement sweat chloride testing. Pilocarpine-stimulated sweat specimens were collected independently from two CF clinics, including 50 unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted metabolite profiling was performed using multisegment injection–capillary electrophoresis–mass spectrometry as a high throughput platform for analysis of polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic acids, amino acid derivatives, dipeptides, purine derivatives, and unknown exogenous compounds were identified in sweat when using high resolution tandem mass spectrometry, including metabolites associated with affected yet asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid, and a plasticizer metabolite from environmental exposure, mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at significantly lower concentrations relative to unaffected CF screen-positive controls. These results indicated a deficiency in human paraoxonase, an enzyme unrelated to mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) and impaired chloride transport, which is a nonspecific arylesterase/lactonase known to mediate inflammation, bacterial biofilm formation, and recurrent lung infections in affected CF children later in life. This work sheds new light into the underlying mechanisms of CF pathophysiology as required for new advances in precision medicine of orphan diseases that benefit from early detection and intervention, including new molecular targets for therapeutic intervention.