International Journal of Neonatal Screening

11 pages, 859 KB

Open AccessArticle

Quebec Spinal Muscular Atrophy Newborn Screening Program: The First Year Experience

by Emilie Groulx-Boivin, Ariane Belzile, Cam-Tu Émilie Nguyen, Amélie Gauthier, Nicolas Chrestian, Catherine Michaud-Gosselin, Yves Giguère, Marie-Thérèse Berthier, Jean-François Soucy, Anne-Marie Laberge and Maryam Oskoui

Int. J. Neonatal Screen. 2025, 11(4), 89; https://doi.org/10.3390/ijns11040089 - 5 Oct 2025

Abstract

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s [...] Read more.

Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s first-year experience, focusing on screening yield, birth prevalence, clinical outcomes, and challenges. In the first year, 6 of 67,933 newborns screened positive for SMA, all subsequently confirmed by diagnostic testing. Of these, 4 newborns (67%) had two SMN2 copies and 2 newborns (33%) had four copies. Additionally, one symptomatic compound heterozygote infant presented during this period, indicating a provincial birth prevalence of 1 in 9705 live births (95% CI: 1:20,032–1:4701). Two newborns with two SMN2 copies were symptomatic at initial consultation; one transitioned to palliative care and died at 43 days of life. Surviving newborns initiated treatment at a median age of 30 days (range: 9–103 days), with four receiving onasemnogene abeparvovec and one nusinersen. Motor outcomes at three or six months were stable or improved among treated infants. Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program’s impact, which is expected with full automation. Full article

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22 pages, 1531 KB

Open AccessCommentary

Reflections on 50 Years of Cystic Fibrosis Newborn Screening Experience with Critical Perspectives, Assessment of Current Status, and Predictions for Future Improvements

by Philip M. Farrell

Int. J. Neonatal Screen. 2025, 11(4), 88; https://doi.org/10.3390/ijns11040088 - 30 Sep 2025

Abstract

The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to [...] Read more.

The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to other genetic disorders and immunoassay methods became routine, the discovery of immunoreactive trypsinogen (IRT) led to numerous CF NBS programs around the world. Excellent laboratorians led the way, but CF clinicians rightly questioned the benefit–risk relationship and unanswered questions about IRT. These issues were resolved by the combination of a positive randomized clinical trial and the discovery of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and its principal pathogenic variant, F508del. Recommendations for universal screening and then the proliferation of IRT/DNA screening programs followed. But more knowledge has brought more complexity, including an enigmatic, distracting condition known as cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) or cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). Recently, with the recognition that CF is not a “white person’s disease,” and that over 1000 CFTR pathogenic variants occur, attention has turned to achieving equity and timeliness for all babies. Continuous quality improvement has characterized the past decade, as greatly expanded CFTR panels in the DNA tier through next-generation sequencing offer promise and raise the prospect of a primary genetic screening test. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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15 pages, 2219 KB

Open AccessArticle

Evaluating Georgia’s Cystic Fibrosis Newborn Screening Algorithm to Inform Improvement Recommendations

by Brittany Truitt, Eileen Barr, Angela Wittenauer, Andrew Jergel, Shasha Bai, Rossana Sanchez Russo, Kathryn E. Oliver, Kathleen McKie and Rachel W. Linnemann

Int. J. Neonatal Screen. 2025, 11(4), 87; https://doi.org/10.3390/ijns11040087 - 29 Sep 2025

Abstract

Early diagnosis by newborn screening (NBS) has contributed to improved outcomes in children with cystic fibrosis (CwCF). Georgia’s two-tiered algorithm consists of a fixed immunoreactive trypsinogen (IRT) cut-off followed by a 39-variant CFTR genetic panel. We conducted a retrospective review of CwCF born [...] Read more.

Early diagnosis by newborn screening (NBS) has contributed to improved outcomes in children with cystic fibrosis (CwCF). Georgia’s two-tiered algorithm consists of a fixed immunoreactive trypsinogen (IRT) cut-off followed by a 39-variant CFTR genetic panel. We conducted a retrospective review of CwCF born in Georgia from 2007 to 2022 to evaluate false negative NBS frequency. We characterized CwCF whose diagnosis was delayed beyond 28 days of age despite positive NBS. Six cases were detailed demonstrating the impact of missed and delayed diagnoses. We examined IRT trends from 2018 to 2022 and cut-off approaches. Missed case detection by expanded CFTR variant assays was assessed. Of 390 CwCF born in Georgia, 18 (4.6%) had false negative NBS—6 due to lack of CFTR variant detection and 12 due to low IRT values. Thirty children had delayed diagnosis, with the majority related to sweat testing. Minoritized children made up 19% of the population but 43% of missed and 44% of delayed diagnoses. Black and Hispanic infants had higher odds of missed or delayed diagnosis compared to non-Hispanic White infants (OR = 2.7, p = 0.027 and OR = 6.1, p < 0.001, respectively). Average IRT values varied across kits and were lower in warmer seasons. Expanded CFTR assays would reduce missed cases. Our results informed recommendations for improvement at multiple steps in the NBS process. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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19 pages, 632 KB

Open AccessArticle

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) Newborn Screening in Italy: Five Years’ Experience from a Nationwide Program

by Margherita Ruoppolo, Cristina Cereda, Teresa Giovanniello, Sabrina Malvagia, Sara Boenzi, Francesca Teofoli, on behalf of the SIMMESN Italian Newborn Screening Group and Alberto Burlina

Int. J. Neonatal Screen. 2025, 11(4), 86; https://doi.org/10.3390/ijns11040086 - 26 Sep 2025

Abstract

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation that can have life-threatening consequences if not promptly treated. Early diagnosis by means of newborn screening (NBS) has the potential to reduce morbidity and mortality. This study investigates the [...] Read more.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation that can have life-threatening consequences if not promptly treated. Early diagnosis by means of newborn screening (NBS) has the potential to reduce morbidity and mortality. This study investigates the incidence and molecular characteristics of MCADD in Italy over a five-year period within the framework of the expanded NBS program. Between January 2019 and December 2023, a total of 1,976,473 newborns were screened. Ninety unrelated neonates were diagnosed with MCADD, providing an estimated incidence of 1/21,960 live births (95% CI: 1:17,780–1:27,200), comparable to rates reported in other Mediterranean populations. Molecular analysis identified c.985A>G (p.Lys329Glu) as the most frequent pathogenic ACADM gene variant, observed in 56 patients (63%), including eighteen patients (20%) who were homozygous and thirty-eight (43%) who were compound heterozygotes for this variant. To our knowledge, this study represents the first comprehensive investigation to document the high prevalence of MCADD among the Italian population. Full article

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14 pages, 3285 KB

Open AccessArticle

CFTR Variant Frequencies and Newborn Screening Panel Performance in the Diverse CF Population Receiving Care in the State of Georgia

by Eileen Barr, Brittany Truitt, Andrew Jergel, Shasha Bai, Kathleen McKie, Rossana Sanchez Russo, Kathryn E. Oliver and Rachel W. Linnemann

Int. J. Neonatal Screen. 2025, 11(4), 85; https://doi.org/10.3390/ijns11040085 - 26 Sep 2025

Abstract

Cystic fibrosis (CF) newborn screening (NBS) aims to improve outcomes through early diagnosis, yet disparities in time to diagnosis remain. This study examines CFTR allele frequencies and variant panel performance among a diverse CF population in Georgia to inform recommendations for updating the [...] Read more.

Cystic fibrosis (CF) newborn screening (NBS) aims to improve outcomes through early diagnosis, yet disparities in time to diagnosis remain. This study examines CFTR allele frequencies and variant panel performance among a diverse CF population in Georgia to inform recommendations for updating the NBS algorithm and improving equity. This cross-sectional study includes 969 people with CF (PwCF) from Georgia’s accredited CF centers. CFTR variant frequencies were calculated according to race and ethnicity. Panel performance was evaluated for Georgia’s current Luminex-39 variant test and three expanded panels. Statistical analyses compared detection rates across panels and demographic groups. Georgia’s diverse CF population demonstrates a unique CFTR allelic variability compared to national data. Increasing panel size enhances case identification. A panel including 719 CF-causing variants from the CFTR2 database significantly improves case detection from 93% to 97% (p = 0.002), as well as two-variant detection from 69% to 86% (p < 0.001). Detection of minoritized PwCF also improves with increasing panel size. However, even using the 719-variant panel, detection of non-Hispanic Black PwCF remains significantly lower compared to non-Hispanic White PwCF (case detection: p = 0.003; two-variant detection: p < 0.001). In conclusion, the use of expanded CFTR panels for NBS in Georgia would enhance timely diagnosis and improve equity. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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19 pages, 1554 KB

Open AccessArticle

Newborn Screening of X-Linked Adrenoleukodystrophy in Italy: Clinical and Biochemical Outcomes from a 4-Year Pilot Study

by Eleonora Bonaventura, Fabio Bruschi, Luisella Alberti, Clara Antonello, Filippo Arrigoni, Marina Balestriero, Barbara Borsani, Laura Cappelletti, Elisa Cattaneo, Matilde Ferrario, Giulia Fiore, Maria Iascone, Giana Izzo, Simona Lucchi, Cecilia Parazzini, Michela Perrone Donnorso, Luigina Spaccini, Ylenia Vaia, Pierangelo Veggiotti, Elvira Verduci, Gianvincenzo Zuccotti, Cristina Cereda, Davide Tonduti and XALD-NBS Study Group Show full author list Hide full author list

Int. J. Neonatal Screen. 2025, 11(4), 84; https://doi.org/10.3390/ijns11040084 - 24 Sep 2025

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched [...] Read more.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched in Lombardy, Italy. From September 2021 to June 2025, 138,116 newborns (≥37 weeks’ gestational age) were screened for elevated C26:0-lysophosphatidylcholine (C26:0-LPC) levels using a two-tier algorithm. Genetic testing was performed in non-negative cases. Males found to be ABCD1 variant carriers were enrolled in multidisciplinary follow-up, including neurological, endocrinological, and nutritional assessments. Eleven individuals (six males, five females) carried pathogenic or likely pathogenic ABCD1 variants. Three males were diagnosed with adrenal insufficiency and started hydrocortisone therapy between 1 and 2 years of age. Growth parameters were within normal range overall, but two children showed signs of stunting associated with poor dietary compliance. Additionally, three patients were diagnosed with Zellweger spectrum disorders (ZSDs). No patients affected with Aicardi-Goutières Syndrome were identified. Newborn screening for X-ALD in Italy is feasible and enables early detection and intervention. Biochemical markers and genetic analysis are reliable tools for identifying affected males and female carriers. Multidisciplinary management is essential to address medical and psychosocial challenges during follow-up. Full article

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12 pages, 691 KB

Open AccessArticle

Prevalence and Mutation Analysis of Medium-Chain Acyl-CoA Dehydrogenase Deficiency Detected by Newborn Screening in Hefei, China

by Haili Hu, Qingqing Ma, Yong Huang, Wangsheng Song, Hongyu Xu, Peng Zhu and Yan Wang

Int. J. Neonatal Screen. 2025, 11(3), 83; https://doi.org/10.3390/ijns11030083 - 22 Sep 2025

Abstract

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is a metabolic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid oxidation. The present study aims to analyze the prevalence and genetic mutation characteristics of MCADD among newborns in Hefei, China, providing insights [...] Read more.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is a metabolic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid oxidation. The present study aims to analyze the prevalence and genetic mutation characteristics of MCADD among newborns in Hefei, China, providing insights for the diagnosis, treatment, and prevention of MCADD. A retrospective analysis was conducted on data from newborns diagnosed with MCADD at the Hefei Newborn Disease Screening Center between January 2016 and December 2024. Screening was performed using tandem mass spectrometry (MS/MS), complemented by next-generation sequencing (NGS) for genetic testing. Out of 880,224 screened newborns, 16 cases of MCADD were diagnosed, resulting in a prevalence of 1 in 55,014. A total of 31 mutation sites in the ACADM gene were identified, with 18 different mutation types. The hotspot mutations were c.449-452del (p.T150Rfs*4) and c.1085G>A (p.G362E), each with a mutation frequency of 16.13% (5 out of 31). Additionally, three novel mutations were identified: c.468+5G>A, c.854C>G, and c.428_431delinsTCTTCTTTTGTT. Following diagnosis, patients received health education, dietary guidance, and symptomatic treatment, all resulting in favorable prognoses without any acute metabolic decompensation events. The prevalence of MCADD is lower in Asia compared to Europe and America. The hotspot mutations for MCADD in Hefei are c.449-452del and c.1085G>A. Diagnosis should integrate results from both octanoylcarnitine (C8) levels and genetic testing. Early screening, diagnosis, treatment, and scientific prevention strategies are essential for reducing adverse outcomes in children with MCADD. Full article

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12 pages, 1335 KB

Open AccessArticle

The Impact of Cystic Fibrosis Algorithm Changes: A Case Study of Challenges and Strategies

by Jerusalem Alleyne, Kenneth Coursey, Kimberly Noble Piper, Cynthia Cass and Michael Pentella

Int. J. Neonatal Screen. 2025, 11(3), 82; https://doi.org/10.3390/ijns11030082 - 19 Sep 2025

Abstract

The State Hygienic Lab at the University of Iowa (SHL) performs newborn blood spot screening (NBS) for IA, AK, ND, and SD. In October 2022, we halted in-house CFTR DNA testing due to the unexpected nonperformance of our newly expanded variant panel. Samples [...] Read more.

The State Hygienic Lab at the University of Iowa (SHL) performs newborn blood spot screening (NBS) for IA, AK, ND, and SD. In October 2022, we halted in-house CFTR DNA testing due to the unexpected nonperformance of our newly expanded variant panel. Samples were sent to a reference laboratory to ensure uninterrupted testing and by December 2022, SHL had selected an alternative test that enabled CFTR panel expansion as envisioned. However, due to circumstances beyond our control, test implementation was severely delayed, and in-house testing was paused. These events were consequential. Firstly, our prolonged utilization of reference labs and fees was a financial strain on the lab. Secondly, our timeliness decreased significantly, and lastly, these issues were burdensome for staff. The lab overcame these problems using three strategies: effective communication; technical expertise; and staff perseverance. Finally, in Aug 2023, SHL successfully resumed in-house testing. As state labs ponder major CFTR algorithm changes, such as the addition of next generation sequencing, the strategies we utilized can be useful during sudden setbacks. Our experience of replacing our CFTR assay underscores the importance of emergency preparedness and partnership within the NBS community. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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11 pages, 1333 KB

Open AccessArticle

Early Screening for Developmental Dysplasia of the Hip: Sonographic Reference Values, Risk Factors, and Treatment Considerations

by Bjoern Vogt, Stella S. Tureck, Georg Gosheger, Adrien Frommer, Andrea Laufer, Henning Tretow, Robert Roedl and Gregor Toporowski

Int. J. Neonatal Screen. 2025, 11(3), 81; https://doi.org/10.3390/ijns11030081 - 19 Sep 2025

Abstract

Developmental dysplasia of the hip (DDH) is a common neonatal musculoskeletal disorder. In Germany, sonographic screening is recommended at 1–10 days of life for neonates with specific risk factors. This study aims to determine reference values for early sonographic screening and to evaluate [...] Read more.

Developmental dysplasia of the hip (DDH) is a common neonatal musculoskeletal disorder. In Germany, sonographic screening is recommended at 1–10 days of life for neonates with specific risk factors. This study aims to determine reference values for early sonographic screening and to evaluate associated risk factors. Between 2007 and 2022, 3383 neonates (6766 hips) underwent hip ultrasound according to Graf. Of these, 967 neonates were screened universally (2007–2015) and 1900 based on predefined risk factors (2015–2022). DDH was defined as ≥type IIc, according to Graf. A subgroup of 20 neonates with borderline alpha angles (51–52°) was followed up after 3–6 weeks. The mean alpha angle was 61.2° ± 5.3° (range 50.5–71.9°), and beta angle 70.8° ± 8.6° (range 53.6–88.0°). DDH prevalence was 2.5% in the universal and 3.2% in the risk-based cohort (p = 0.350). Logistic regression revealed associations with abnormal birth presentation (OR = 3.09, p < 0.001) and female sex (OR = 3.77, p < 0.001), not with Cesarean section or familial predisposition. In the follow-up subgroup, all hips showed a sufficient maturation to an alpha angle of 61.0° (range 57–66°). This study provides reference values for early DDH screening and confirms abnormal birth presentation and female sex as relevant risk factors. Full article

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4 pages, 149 KB

Open AccessOpinion

Newborn Screening—A Worldwide Endeavour to Protect

by James R. Bonham, Dianne Webster, Amy Gaviglio, Aysha Habib Khan, R. Rodney Howell and Peter C. J. I. Schielen

Int. J. Neonatal Screen. 2025, 11(3), 80; https://doi.org/10.3390/ijns11030080 - 18 Sep 2025

Abstract

For more than 60 years, newborn (or neonatal) screening has flourished through global collaboration, demonstrating that collective action is key to success. This unity proved to be especially vital during the COVID-19 pandemic, when, despite severe disruptions, NBS services were largely preserved, reflecting [...] Read more.

For more than 60 years, newborn (or neonatal) screening has flourished through global collaboration, demonstrating that collective action is key to success. This unity proved to be especially vital during the COVID-19 pandemic, when, despite severe disruptions, NBS services were largely preserved, reflecting the high value placed on early detection and care for vulnerable newborns. Today, the International Society for Neonatal Screening (ISNS) recognises that NBS programmes face increasing challenges due to global instability. While direct assistance is not always possible, ISNS emphasises the strength of the international NBS community—scientists, clinicians, patient groups, and industry partners—who are committed to mutual support and knowledge-sharing. Building on the proud legacy inspired by pioneers like Bob Guthrie, this community is enriched by diverse voices and is unified by a shared vision: to ensure that all children with rare disorders have access to life-saving screening and care. Safeguarding and advancing this foundation is a responsibility owed to future generations. Full article

7 pages, 1699 KB

Open AccessCase Report

The Success of Newborn Screening Beyond War: An International Collaborative Case of Purine Nucleoside Phosphorylase (PNP) Deficiency

by Alessandra Bettiol, Roberta Damiano, Nataliia Mytsyk, Nataliia Samonenko, Gabriella Cericola, Carsten Speckmann, Nataliia Olkhovich, Renzo Guerrini and Giancarlo la Marca

Int. J. Neonatal Screen. 2025, 11(3), 79; https://doi.org/10.3390/ijns11030079 - 16 Sep 2025

Abstract

Ukraine’s healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)–purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on [...] Read more.

Ukraine’s healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)–purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on a neonatal dried blood spot (DBS) by real-time PCR, which showed remarkably reduced T-cell receptor and kappa-deleting recombination excision circles (TREC/KREC). Retesting was delayed due to communication difficulties with the family. Whole exome sequencing on a new DBS confirmed the diagnosis. The newborn was a candidate for allogeneic hematopoietic stem cell transplantation (HSCT), the only curative treatment. HSCT is a complex procedure still ongoing in Ukraine despite the conflict. However, due to the psychosocial strain, the family sought medical support in Germany, where HSCT was performed successfully at 6 months. As part of a collaborative initiative with Italy, PNP biomarkers were quantified on the same DBSs using tandem mass spectrometry, according to the protocols established for SCID NBS in Tuscany, serving as a proof of concept of its diagnostic performance. This case highlights the importance of sustaining preventive and life-saving healthcare services, and reflects the key role of international partnerships in upholding the right to healthcare in times of crisis. Full article

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20 pages, 2405 KB

Open AccessArticle

The Burden of Congenital Hypothyroidism Without Newborn Screening: Clinical and Cognitive Findings from a Multicenter Study in Algeria

by Adel Djermane, Yasmine Ouarezki, Kamelia Boulesnane, Sakina Kherra, Fadila Bouferoua, Mimouna Bessahraoui, Nihad Selim, Larbi Djahlat, Kahina Mohammedi, Karim Bouziane Nedjadi, Hakima Abes, Meriem Bensalah, Dyaeddine Lograb, Foued Abdelaziz, Dalila Douiri, Soumia Djebari, Mohamed Seghir Demdoum, Nadira Rouabeh, Meriem Oussalah, Guy Van Vliet and Asmahane Ladjouze Show full author list Hide full author list

Int. J. Neonatal Screen. 2025, 11(3), 78; https://doi.org/10.3390/ijns11030078 - 15 Sep 2025

Abstract

The absence of biochemical newborn screening (NBS) delays the diagnosis and treatment of congenital hypothyroidism (CH), resulting in irreversible neurodevelopmental damage. To determine the age at diagnosis for CH among Algerian children and to describe its clinical and biological characteristics, etiology, and outcome, [...] Read more.

The absence of biochemical newborn screening (NBS) delays the diagnosis and treatment of congenital hypothyroidism (CH), resulting in irreversible neurodevelopmental damage. To determine the age at diagnosis for CH among Algerian children and to describe its clinical and biological characteristics, etiology, and outcome, we conducted a multicenter retrospective cohort study involving 288 children with CH across 20 pediatric centers between 2005 and 2023. The median age at diagnosis was 1.6 months, and only 28% of patients started treatment before 30 days. Prolonged neonatal jaundice was the most frequently presented symptom (58%), severe CH (fT₄ < 5 pmol/L) was observed in 35% and 52% received an insufficient initial dose of L-T₄. The median IQ of the 47 patients tested was 86; 11% had an IQ < 70, and a negative correlation was found between age at diagnosis and IQ (r = −0.48, p = 0.001). In children reassessed at age 3, 51% had normal thyroid function, indicating transient CH. Delayed diagnosis and suboptimal treatment of CH remain major challenges in Algeria, leading to substantial neurodevelopmental deficits. Pediatricians must remain cognizant of early clinical signs of CH to allow for timely diagnosis and intervention. Biochemical NBS for CH in Algeria is needed. Full article

(This article belongs to the Special Issue Newborn Screening for Congenital Hypothyroidism)

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9 pages, 593 KB

Open AccessArticle

Milder Form of Cobalamin C Disease May Be Missed by Newborn Screening: The Importance of Methylmalonic Acid Assessment

by Francesca Nardecchia, Agnese De Giorgi, Silvia Santagata, Teresa Giovanniello, Manuela Tolve, Antonio Angeloni, Vincenzo Leuzzi, Francesco Pisani and Claudia Carducci

Int. J. Neonatal Screen. 2025, 11(3), 77; https://doi.org/10.3390/ijns11030077 - 12 Sep 2025

Abstract

CblC deficiency is the most common intracellular disorder of vitamin B12 metabolism. Expanded newborn screening (NBS) plays a key role in early diagnosis, allowing timely treatment and preventing serious complications. However, traditional first-tier markers—such as propionylcarnitine (C3) and its ratios with other metabolites [...] Read more.

CblC deficiency is the most common intracellular disorder of vitamin B12 metabolism. Expanded newborn screening (NBS) plays a key role in early diagnosis, allowing timely treatment and preventing serious complications. However, traditional first-tier markers—such as propionylcarnitine (C3) and its ratios with other metabolites (e.g., methionine, carnitine, and acetylcarnitine)—have limited sensitivity, particularly for mild forms, leading to missed or delayed diagnoses. In this study, we analyzed data from the NBS Center of the Lazio region (Italy) and identified nine newborns with confirmed CblC deficiency. All were recalled due to abnormalities in C3 or related ratios, along with elevated methylmalonic acid (MMA) levels. Notably, three infants had completely normal C3 levels and ratios during the second screening test, yet they showed MMA levels above the cut-off value (2 µmol/L), enabling a diagnosis of otherwise undetectable mild CblC cases. Our center regularly measures MMA in dried blood spots, even when first-tier markers return to normal on the second sample. This approach allows for early diagnosis and immediate treatment with hydroxocobalamin in patients with mild CblC deficiency, resulting in early intervention, effective metabolic control, and, based on current follow-up, normal neurodevelopmental outcomes. Our findings highlight the essential role of second-tier MMA testing in improving the detection of mild CblC deficiency during NBS. Full article

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8 pages, 606 KB

Open AccessCase Report

Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Three New Cases Detected by Newborn Screening Confirming the Significance of C4OH Elevation

by Alessandra Vasco, Clarissa Berardo, Simona Lucchi, Laura Cappelletti, Giulio Tamburello, Salvatore Fazzone, Alessia Mauri, Francesca Fiumani, Diana Postorivo, Luisella Alberti, Michela Perrone Donnorso, Serena Gasperini, Francesca Furlan, Laura Fiori, Stephana Carelli, Laura Assunta Saielli, Cristina Montrasio and Cristina Cereda

Int. J. Neonatal Screen. 2025, 11(3), 76; https://doi.org/10.3390/ijns11030076 - 6 Sep 2025

Abstract

Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation [...] Read more.

Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation of isoleucine and acetoacetyl-CoA, leading to the accumulation of toxic metabolites. We describe three cases of BKTD. The first newborn showed increase in C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. Urinary organic acids (uOAs) revealed marked excretion of 2-methyl-3-hydroxybutyrate. Tiglylglycine was absent. Genetic testing identified the compound heterozygosity for two pathogenic ACAT1 variants. The second patient showed increased levels of C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. uOAs revealed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous VUS in ACAT1 was identified. The third case showed elevation of C4DC/C5OH, C3DC/C4OH in the NBS, with a slight increase in C5:1. uOAs showed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous missense VUS was identified in the ACAT1 gene. BKTD exhibited variable NBS biochemical phenotypes across the three cases. While C5OH and C5:1, the primary markers, were not consistently elevated in all our cases, C4OH strongly increased in all three. Our findings support the use of C4OH in a combined marker strategy to improve BKTD NBS. Full article

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16 pages, 2770 KB

Open AccessArticle

Comparing DNA Isolation and Preparation Protocols for Dried Blood Spots in the Context of Genomic Newborn Screening

by Annelotte J. Duintjer, Sandra Imholz, Ingrid Pico-Knijnenburg, Adinda Heuperman, Hennie Hodemaekers, Eva S. Deutekom, Els Voorhoeve, Martijn E. T. Dollé and Mirjam van der Burg

Int. J. Neonatal Screen. 2025, 11(3), 75; https://doi.org/10.3390/ijns11030075 - 3 Sep 2025

Abstract

Due to rapid technical advancements and increasing cost-effectiveness, the potential application of next-generation sequencing (NGS) in newborn screening (NBS) has raised great interest worldwide. Genomic NBS offers the possibility to improve current NBS programs when applied as follow-up tier, and, as first-tier, allows [...] Read more.

Due to rapid technical advancements and increasing cost-effectiveness, the potential application of next-generation sequencing (NGS) in newborn screening (NBS) has raised great interest worldwide. Genomic NBS offers the possibility to improve current NBS programs when applied as follow-up tier, and, as first-tier, allows for inclusion of conditions lacking a detectable biomarker for conventional NBS. Obtaining enough high-quality DNA from typically limited dried blood spot (DBS) material to meet NGS requirements can be challenging. Selecting a DNA isolation method for genomic NBS requires balancing technical performance and laboratory feasibility with optimal cost-effectiveness. Ten DNA isolation protocols, including two column-based, five lysis-based, and three semi-automated magnetic bead-based protocols, were evaluated on technical outcomes and performance in targeted amplicon sequencing. Additionally, estimated costs, hands-on time, turnaround time, scalability, and plastic footprint were assessed. Although technical outcomes, including yield, purity, and molecular weight, differed between methods, qualitative results in amplicon sequencing, as defined by read output, mapping, and coverage depth, were found sufficient and comparable for various protocols. In conclusion, both technical requirements and operational parameters are crucial when selecting a DNA isolation protocol and will depend on the NGS application as well as the NBS approach, as either first-tier or follow-up tier. Full article

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16 pages, 1147 KB

Open AccessArticle

Umbilical Cord Blood Sampling for Newborn Screening of Pompe Disease and the Detection of a Novel Pathogenic Variant and Pseudodeficiency Variants in an Asian Population

by Fook-Choe Cheah, Sharifah Azween Syed Omar, Jasmine Lee, Zheng Jiet Ang, Anu Ratha Gopal, Wan Nurulhuda Wan Md Zin, Beng Kwang Ng, Shu-Chuan Chiang and Yin-Hsiu Chien

Int. J. Neonatal Screen. 2025, 11(3), 74; https://doi.org/10.3390/ijns11030074 - 3 Sep 2025

Abstract

Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase (GAA) deficiency. The use of umbilical cord blood (UCB) for newborn screening (NBS) of Pompe disease, compared to heel-prick sampling, has not been widely studied. This study compared GAA activity in [...] Read more.

Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase (GAA) deficiency. The use of umbilical cord blood (UCB) for newborn screening (NBS) of Pompe disease, compared to heel-prick sampling, has not been widely studied. This study compared GAA activity in UCB from term newborns with peripheral or heel-prick blood samples obtained on days 1, 2, and 3 after birth. Enzyme assays were performed using UPLC-MS/MS. Sanger sequencing was conducted in infants with low GAA activity to identify pathogenic variants. Among 4091 UCB samples analyzed over 18 months, the mean GAA activity was 10.04 ± 5.95 μM/h, higher in females than males [Median (IQR): 9.83 (5.45) vs. 9.08 (4.97) μM/h, respectively, p < 0.001], and similar across ethnicities. GAA levels in UCB and Day 3 heel-prick samples were comparable. A GAA cut-off value of 1.54 μM/h (0.1% of study population) identified one infant (0.024% prevalence) with a novel bi-allelic variant—c.2005_2010del (p.Pro669_Phe670del) and c.1123C>T (p.Arg375Cys), and 12 infants with non-pathogenic pseudodeficiency alleles. This study supports GAA measurement in UCB as a viable alternative for NBS, with enzyme activity remaining stable for up to 72 h post-collection. Larger-scale multicenter nationwide studies are warranted to confirm this prevalence in our population. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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11 pages, 216 KB

Open AccessArticle

Next-Generation Sequencing in the Diagnostic Workup of Neonatal Dried Blood Spot Screening in Sweden 2015–2023

by Lene Sörensen, Jorge Asin-Cayuela, Michela Barbaro, Helene Bruhn, Martin Engvall, Nicole Lesko, Karin Naess, Mikael Oscarson, Yan Shen, Malin Ueberschär, Anna Wredenberg, Fredrik H. Sterky, Anna Wedell and Rolf H. Zetterström

Int. J. Neonatal Screen. 2025, 11(3), 73; https://doi.org/10.3390/ijns11030073 - 3 Sep 2025

Abstract

Sweden has one neonatal screening laboratory and two centers conducting diagnostic workup for inborn errors of metabolism (IEM). Next-generation sequencing (NGS) has been gradually introduced as a confirmatory diagnostic test in the Swedish newborn screening program. Here, we describe the use of NGS [...] Read more.

Sweden has one neonatal screening laboratory and two centers conducting diagnostic workup for inborn errors of metabolism (IEM). Next-generation sequencing (NGS) has been gradually introduced as a confirmatory diagnostic test in the Swedish newborn screening program. Here, we describe the use of NGS in the diagnostic workup of IEM in screening-detected babies in Sweden between 2015 and 2023. During this period, 1,023,344 newborn children were screened, and 81 of 290 IEM cases were genetically confirmed using NGS. Planned improvements to the program are to perform genetic validation directly on the initial dried blood spot (DBS). As whole-genome sequencing (WGS) is superior in detecting causative genetic variants compared to Sanger sequencing, targeted NGS, and whole-exome sequencing (WES), it will likely become the method of choice more broadly in the future. A strong focus is to consolidate the nationally coordinated DBS newborn screening program, with all its individual components, including screening, targeted diagnostics, individualized treatment, and follow-up. This challenges the current regionalized organization of Swedish healthcare, which hinders close national collaboration between experts and sharing of data, as well as equal access to advanced treatments for identified patients, regardless of their place of birth. Full article

5 pages, 983 KB

Open AccessCorrection

Correction: Kuypers et al. Evaluation of Neonatal Screening Programs for Tyrosinemia Type 1 Worldwide. Int. J. Neonatal Screen. 2024, 10, 82

by Allysa M. Kuypers, Marelle J. Bouva, J. Gerard Loeber, Anita Boelen, Eugenie Dekkers, Konstantinos Petritis, C. Austin Pickens, The ISNS Representatives, Francjan J. van Spronsen and M. Rebecca Heiner-Fokkema

Int. J. Neonatal Screen. 2025, 11(3), 72; https://doi.org/10.3390/ijns11030072 - 1 Sep 2025

Abstract

The authors wish to make the following correction to their paper published in the International Journal of Neonatal Screening [...] Full article

14 pages, 1122 KB

Open AccessArticle

Optimization of the Performance of Newborn Screening for X-Linked Adrenoleukodystrophy by Flow Injection Analysis Tandem Mass Spectrometry

by Chengfang Tang, Minyi Tan, Yanna Cai, Sichi Liu, Ting Xie, Xiang Jiang, Li Tao, Yonglan Huang and Fang Tang

Int. J. Neonatal Screen. 2025, 11(3), 71; https://doi.org/10.3390/ijns11030071 - 29 Aug 2025

Abstract

The aim of this study was to improve screening efficiency by establishing reasonable interpretation criteria for the use of flow injection analysis tandem mass spectrometry (FIA-MS/MS) in newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD). FIA-MS/MS was employed to analyze very-long-chain acylcarnitines (ACs) and [...] Read more.

The aim of this study was to improve screening efficiency by establishing reasonable interpretation criteria for the use of flow injection analysis tandem mass spectrometry (FIA-MS/MS) in newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD). FIA-MS/MS was employed to analyze very-long-chain acylcarnitines (ACs) and lysophosphatidylcholines (LPCs) and their ratios in dried blood spot (DBS) obtained from five X-ALD patients in the neonatal period (0–7 days old) and 7123 healthy neonate controls. By comparing these results and analyzing receiver operating characteristic (ROC) curves, we identified sensitive indicators for X-ALD screening in newborns. To evaluate the performance of different FIA-MS/MS screening indicators, we simultaneously analyzed 7712 neonatal DBS samples obtained for X-ALD screening using FIA-MS/MS and the established liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantitative detection of C26:0-lysophosphatidylcholine (C26:0-LPC). Furthermore, 84,268 newborn X-ALD screening results were retrospectively analyzed to further evaluate the screening performance of FIA-MS/MS. After the three-step optimization evaluation, the optimized first-tier sensitive screening indicators of FIA-MS/MS were C24:0-AC, C26:0LPC, and C24:0/C22:0-AC. Among the 7712 newborns screened, one case was confirmed to be double-positive. Within separate statistical analyses, based on LC-MS/MS screening alone (positive cutoff > 0.17 µmol/L), only seven cases (0.09%) were initially positive, with a positive predictive value (PPV) of 42.8%, and two additional ABCD1 VUS hemizygous males were detected. Through the retrospective analysis of 84,268 newborns, eight ABCD1 variants (six hemizygous males and two heterozygous females) were ultimately identified. Our study showed that the optimization of first-tier screening performance is particularly important if second-tier screening is not performed. Using LC-MS/MS for second-tier screening for X-ALD can significantly reduce the number of false positives, but the method still misses some false negatives. If it is used as a first-tier assessment, more VUS variant neonates can be detected. Full article

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International Journal of Neonatal Screening

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