Newborn Screening for Sickle Cell Disease and other Haemoglobinopathies is a Special Issue of the International Journal of Neonatal Screening. Sickle cell disease is one of the most common inherited ...blood disorders, with a huge impact on health care systems due to high morbidity and high mortality associated with the undiagnosed disease. Newborn screening helps to make the diagnosis early and to prevent fatal complications and diagnostic odysseys. This book gives an overview of diagnostic standards in newborn screening for sickle cell disease and examples of existing newborn screening programs.
•NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA.•All infants were ≥25 months old, and alive without permanent ventilation.•All infants achieved independent sitting ...and 88% (22/25) were walking alone.•Nusinersen demonstrated durability of effect with a median 2.9 years of follow up.•Nusinersen was well tolerated with no new safety concerns over extended follow up.
Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 25.7–45.4 months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prospective/retrospective protocols of the PIDTC have collected detailed data from children undergoing allogeneic hematopoietic cell transplantation (HCT) for SCID at 33 North American centers since ...1982. We previously reported that from 1982 to 2009, overall survival (OS) after HCT was unchanged. Newborn screening (NBS) for SCID, initiated in 2010, was hypothesized to improve SCID OS following HCT.
Children born and receiving HCT during 4 time intervals (1982–89; 1990–99; 2000–09; and 2010–18) were analyzed for categorial variables (chi-square test), continuous outcomes (Kruskal-Wallis test), and OS (Kaplan-Meier method).
902 children with typical (n = 747) and atypical (n = 155) SCID were included. Unlike years 1982–2009 when 5-year OS after HCT was stagnant (72–73%), improvement was seen for the first time beginning in 2010, when 5-year OS increased to 87% (p < 0.001). To determine what contributed to this finding, multiple factors were evaluated to identify differences between children transplanted between 2010–18 compared to prior time intervals. Significant differences (all p < 0.001) were found in the trigger for diagnosis being NBS or family history as opposed to clinical illness, age at HCT, active infection at HCT, and transplant characteristics including conditioning intensity, stem cell source, and donor source. On multivariable analysis, which excluded matched sibling donors due to their consistently high rates of OS (≥92%) in all time intervals, active infection (HR 2.41, 95% CI 1.53–3.72; p < 0.001), age ≥3.5 months at HCT (HR 2.21, 95% CI 1.38–3.24; p = 0.001), certain genotypes (ADA, DCLRE1C/LIG4/NHEJ, and other rare genotypes) (HR 2.22–3.67, 95% CI 1.23–7.45; p < 0.001), and Black/African American race (HR 2.33, 95% CI 1.56–3.54; p < 0.001) were associated with lower survival rates. A subgroup multivariable analysis examining the effect of trigger for diagnosis in the era of NBS, adjusting for genotype and race, confirmed that improved OS with NBS was related to earlier age and fewer infections at time of HCT.
This study confirmed for the first time the direct benefit of population-based SCID NBS in improving OS after HCT. Our findings support adoption of SCID NBS worldwide, but also point out that persistent racial disparities in survival despite universal availability of screening must be addressed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Newborn screening (NBS) measures T cell receptor excision circle (TREC) counts in infants to identify infants with potential primary immunodeficiency. Low TREC counts are associated with T cell ...lymphopenia (TCL). Infants are considered to have idiopathic TCL if no cause for the lymphopenia is found. By convention, infants whose T cell counts normalize within 12 months of birth are considered to have transient TCL. This study aimed to characterize and differentiate infants with transient and persistent idiopathic TCL across demographic, immunologic, perinatal, and postnatal factors.
There were 53 infants referred to an academic medical center for idiopathic TCL between September 2010 and August 2021, following abnormal NBS at a gestational age of at least 37 weeks. They were evaluated for CD3+, CD4+, and CD8+ T cell counts. Demographic, immunologic, perinatal, and postnatal data were collected from the electronic health record. Chi-square analysis was performed for mode of delivery, neonatal intensive care unit (NICU) stay, and hospitalization within 12 months of birth. Descriptive statistics were calculated and Mann-Whitney tests performed for assessing initial TREC counts, initial T cell counts, and birth weight by gestational age percentile.
Of the 53 infants evaluated, 28 had transient while 25 had persistent idiopathic TCL. The transient cohort was 60.7% male and 28.6% African-American, and 35.7% had Medicaid. The persistent cohort was 60.0% male and 32.0% African-American, and 56.0% had Medicaid. The cohorts did not differ by mode of delivery (χ2(1,N = 52) = 3.71, p = 0.054), NICU stay (χ2(1,N = 51) = 0.11, p = 0.735), or postnatal hospitalization (χ2(1, N = 49) = 0.82, p = 0.365). Persistent lymphopenic infants had significantly lower median CD3+ (1176 vs. 2144 cells/µL; p < 0.001), CD4+ (866 vs. 1460 cells/µL; p < 0.001), and CD8+ (293 vs. 539 cells/µL; p = 0.003) counts than transient lymphopenic infants, but did not differ by median TREC count (73 vs. 52 TRECs/µL; p = 0.219) or birth weight percentile (41st vs. 20th percentile; p = 0.363).
In our cohort, persistent idiopathic TCL infants had lower initial T cell counts than transient infants. None of the other factors differed between the groups. Future research should evaluate for differences across other relevant factors, including maternal health factors and other relevant perinatal and postnatal factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Efficacy of new treatments in SMA is better in pre than in post-symptomatic patients.•NBS is complementary of carrier screening, with different false negatives.•Pilot projects of SMA NBS have ...started or are planned to start in several countries.•Questions remain on SMN2 quantification and management of patients with 4 copies.•A strategy is proposed to launch an evidence-based approach for these patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic ...diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Population newborn screening (NBS) for phenylketonuria began in the United States in 1963. In the 1990s electrospray ionization mass spectrometry permitted an array of pathognomonic metabolites to be ...identified simultaneously, enabling up to 60 disorders to be recognized with a single test. In response, differing approaches to the assessment of the harms and benefits of screening have resulted in variable screening panels worldwide. Thirty years on and another screening revolution has emerged with the potential for first line genomic testing extending the range of screening conditions recognized after birth to many hundreds. At the annual SSIEM conference in 2022 in Freiburg, Germany, an interactive plenary discussion on genomic screening strategies and their challenges and opportunities was conducted. The Genomics England Research project proposes the use of Whole Genome Sequencing to offer extended NBS to 100 000 babies for defined conditions with a clear benefit for the child. The European Organization for Rare Diseases seeks to include "actionable" conditions considering also other types of benefits. Hopkins Van Mil, a private UK research institute, determined the views of citizens and revealed as a precondition that families are provided with adequate information, qualified support, and that autonomy and data are protected. From an ethical standpoint, the benefits ascribed to screening and early treatment need to be considered in relation to asymptomatic, phenotypically mild or late-onset presentations, where presymptomatic treatment may not be required. The different perspectives and arguments demonstrate the unique burden of responsibility on those proposing new and far-reaching developments in NBS programs and the need to carefully consider both harms and benefits.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene, continues to present diagnostic challenges. Newborn screening and an evolving ...understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project ( http://www.cftr2.org/index.php ) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR - related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR - related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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