Search Results (1,280)

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

Newborn screening for congenital adrenal hyperplasia (CAH) is effective in identifying patients with severe forms before a potentially lethal crisis, but has a relatively high false-positive rate. The aim of this study was to improve the national neonatal screening program in Sweden and the positive predictive value by implementing LC-MS/MS second-tier testing. A combination of two independent parameters, the steroid hormone ratio (androstenedione+17-hydroxyprogesterone)/cortisol and the concentration of 21-deoxycortisol and adjustment of cut-off levels resulted in an increase in the positive predictive value (PPV) from 14% to 84% for full-term infants. In total, the false-positive screening cases decreased by 88%. CYP21A2 genotyping was used to determine the severity of CAH in identified cases. We report on the stepwise approach that was used to optimize the cut-off levels for full-term and preterm infants in order not to miss any true cases in the process. Full article

(1) Background: The characteristics of rare diseases (RDs) vary considerably—not only between different disease types but also between individual patients with the same condition. In the Roma community, we analyzed the most frequent rare genetic disorders related to the founder effect. (2) Methods: This retrospective study, conducted between January 2019 and January 2025 at the Clinical Genetics and Metabolics Outpatient Clinic in Košice, included 61 patients aged from infancy to 25 years diagnosed with hypomyelinating leukodystrophy 14, pontocerebellar hypoplasia type 1B, neuronal ceroid lipofuscinosis 7, or TMEM70 deficiency. (3) Results: This study includes the largest known cohort of patients with hypomyelinating leukodystrophy 14 caused by the UFM1 c.-273_-271delTCA mutation, predominantly affecting males (n = 17). The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly. In a separate group with pontocerebellar hypoplasia type 1B, six Roma patients (three males, three females) shared the same EXOSC3 mutation. Diagnosis occurred at an average age of 8.8 months, and most children did not survive beyond three years. Common features included microcephaly, severe hypotonia, and spastic quadriplegia. Thirteen children from eight families were diagnosed with neuronal ceroid lipofuscinosis 7, all carrying the same MFSD8 mutation. Symptoms typically began with psychomotor regression between ages 3 and 4, along with intellectual disability and seizures, which were more frequent in males. The mean age at diagnosis was 4.5 years, and eight children died before age nine. Finally, 25 patients with TMEM70 deficiency associated with Roma ancestry were identified, predominantly females, with a mean age of 9.95 years and the oldest patient aged 25. Four children died due to severe metabolic crises. Common findings included intellectual disability, global hypotonia, hypertrophic cardiomyopathy, epilepsy, and failure to thrive. (4) Conclusions: Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available. Their increased prevalence in the Roma population reflects founder effects and high consanguinity. Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management. Full article

Increasing ethnic diversity raises potential inequalities within screening programmes. In the UK, newborns are screened for CF by initially measuring IRT. Dried blood spot IRT levels above a set cut-off require follow-up testing to establish a screening result. Variation exists in IRT levels between different ethnicities and therefore impacts the number of potentially false positive results obtained from ethnic groups. Over a 4-year period, IRT data was collected, and the 99.5th centile was calculated for different ethnic groups. Significant differences were noticed between ethnic groups, and the CF outcome data over a 10-year period were then analysed to establish the effect this had on positive predictive values. The largest difference in IRT 99.5th centile values was seen between the White British and Black African groups. Positive predictive values for Black African and Indian ethnic groups were much lower than the other groups. Rather than try to incorporate ethnicity into the UK CF screening algorithm, we suggest making CF clinicians aware of the differences between different ethnic groups to inform counselling families who receive screen-positive results. Full article

Background: Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by hyperargininemia and progressive neurological impairment, including spasticity, loss of motor function, and reduced quality of life. Conventional management based on dietary protein restriction and ammonia scavengers rarely achieves adequate metabolic control or prevents neurological deterioration. Pegzilarginase, a recombinant human arginase 1 enzyme, is the first disease-modifying therapy for ARG1-D. Methods: We report the first Italian real-world experience with pegzilarginase in three pediatric patients with genetically confirmed ARG1-D enrolled in the phase 3 PEACE trial. Clinical, biochemical, functional, nutritional and quality-of-life data were retrospectively collected over a long-term follow-up (2003–2025). Outcomes were evaluated across three phases: treatment initiation (Start), a 13-month treatment interruption due to trial closure (Stop), and therapy re-initiation through an early access program (Restart). Results: Pegzilarginase rapidly normalized plasma arginine levels and was associated with improvements in motor function, spasticity, walking endurance, dietary protein tolerance, bone mineral density, and quality of life. During treatment interruption, all patients experienced biochemical worsening and clinical deterioration, including increased spasticity, reduced mobility, and emotional distress. Re-initiation of pegzilarginase restored metabolic control and led to progressive neurological and functional recovery, including partial reversal of long-standing motor deficits. Conclusions: This real-world experience supports pegzilarginase as a disease-modifying therapy for ARG1-D. Sustained normalization of plasma arginine, rather than subthreshold biochemical control, correlates with functional and neurological improvement and may partially reverse non-lesional metabolic brain injury. Early initiation of pegzilarginase, including in newborn-screened patients, may further modify the natural history of ARG1-D. Full article

21-deoxycortisol is a sensitive and specific blood marker for congenital adrenal hyperplasia (CAH). We postulated that 21-deoxycortisone, the 11β-hydroxysteroid dehydrogenase metabolite of 21-deoxycortisol, may also be an accurate bloodspot marker of CAH. Measurement of 21-deoxycortisone was performed on 42 residual NBS specimens with a true positive result for CAH, 11 with a false negative result, and 439 specimens with a false positive result. For this study, the test was considered positive if 21-deoxycortisone was detected. The sensitivity and specificity of 21-deoxycortisone as a marker for classical CAH was calculated and compared to 21-deoxycortisol data from a previous New Zealand study. The method for 21-deoxycortisone measurement was linear to 1000 nmol/L and precision was 7.3–10.3%. The lower limit of quantification was 2 nmol/L, and recovery was 99%. 21-deoxycortisone was ≥2 nmol/L in all 42 true positive samples and in 10 false negative samples, and was not detected in the false positive group of specimens. The sensitivity of 21-deoxycortisone was 98.1%, and specificity was 100%. In a previous study, the sensitivity of 21-deoxycortisol was 88.7% and specificity was 99.8% in 1910 newborn screening tests carried out between 2018 and 2021. Incorporating 21-deoxycortisone into a second-tier test and adjustment of primary screening protocols could improve the accuracy of newborn screening for CAH. Longer term prospective studies on the performance of 21-deoxycortisone are warranted. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article

Objectives: The purpose of this study was to compare the incidence of hearing loss at three months of age in a cohort of newborns with hypoxic-ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) with that reported in the literature. We also evaluated potential risk factors associated with audiological impairment and changes in hearing threshold during follow-up. Methods: This retrospective observational cohort study was conducted at the Neonatal Intensive Care Unit of the Fondazione Policlinico Universitario A. Gemelli, IRCCS in Rome, Italy, between January 2017 and December 2023. Infants underwent audiological screening and a full diagnostic evaluation at three months of age and were followed during the first year of life. Results: A total of 149 infants were enrolled, and hearing loss was identified in six (4.0%) at three months of age. Two of these six infants showed an improvement in their hearing threshold, resulting in a prevalence of permanent bilateral sensorineural hearing loss (SNHL) of four out of 149 infants (2.7%), with no cases of late-onset hearing loss detected. Gestational age was identified as an independent protective factor against SNHL (OR 0.49; 95% CI 0.22–0.91). Conclusions: The audiological screening program demonstrates effectiveness in early intervention for diagnosing and treating hearing loss. Infants with HIE are at high risk for hearing disorders and require increased attention in neonatological and audiological management. Management should be individualized based on specific risk factors. The association between gestational age and susceptibility to cochlear damage should be confirmed by further studies. Full article

The project aimed to explore the psychosocial impact on parents of receiving a false-positive outcome following a positive newborn bloodspot screening (NBS) result for SCID for their child. A mixed-methods design was employed using semi-structured interviews and standardised health-related questionnaires (EQ-5D-5L, ITQOL-47, and GAD-7). The participants were recruited from six National Health Service hospital trusts in England involved in the NHS England In-Service Evaluation of Screening for SCID. A total of 22 interviews were conducted with 28 parents. Health-related questionnaire data were collected from 26 of these parents. The interviews were analysed using a reflexive deductive approach to thematic analysis. For the health-related questionnaire data, a comparison of group means against population norms was undertaken using t-tests with unequal variances. The findings from the interviews showed that receiving a false-positive outcome following a positive NBS SCID result could cause parents to have an enhanced view of their child’s vulnerability in the short term. However, negative sequelae were largely mitigated as parents viewed their child’s exposure to ‘normal’ infections as evidence of a functional immune system. The health-related questionnaire data showed that the parents had significantly worse health than the population norm (as indicated by EQ-VAS: p = 0.0296); however, all the other measures were non-significant. More research is needed to explore the potential longer-term psychosocial impact of a false-positive screening result for SCID on parents beyond their child’s first year of life. Full article

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results. Full article

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is among the most common inherited enzymatic disorders worldwide and is an important risk factor for neonatal hyperbilirubinemia. Regional data from Western Saudi Arabia based on universal newborn screening remain limited. Objectives: To determine the prevalence of G6PD deficiency among newborns delivered at a tertiary center in Jeddah, Saudi Arabia, and to evaluate its association with clinically relevant outcomes, including early-onset jaundice (<24 h), need for phototherapy, admission for hyperbilirubinemia management, and readmission after discharge. Methods: We conducted a retrospective cohort study at King Abdulaziz Medical City, Western Region, Jeddah, Saudi Arabia, between January 2020 and May 2025. Cord blood samples from live-born infants were screened using a qualitative fluorescent spot test. Demographic variables (sex, gestational age, birth weight) and jaundice-related outcomes were extracted from the electronic medical record. Categorical variables were compared using chi-square testing, with p < 0.05 considered statistically significant. Results: Among 14,964 screened newborns, 489 were identified as G6PD deficient, yielding a prevalence of 3.3%. Prevalence was higher in males than in females (5.6% vs. 0.9%). Among the G6PD-deficient infants, early-onset jaundice occurred in 17.2%, phototherapy was required in 36.0%, and 16.5% were admitted for hyperbilirubinemia management. Readmission for worsening jaundice requiring phototherapy occurred in 11.0%, and no exchange transfusions were required. Compared with term infants, late preterm infants had higher rates of early-onset jaundice (11/49, 22.4% vs. 73/440, 16.6%) and phototherapy use (22/49, 45.0% vs. 154/440, 35.0%) (p < 0.01). Conclusions: G6PD deficiency was identified in a substantial proportion of newborns in this large screened cohort and was associated with clinically significant jaundice-related outcomes, particularly among late preterm infants. These findings underscore the importance of universal screening and structured postnatal follow-up to reduce the risk of severe hyperbilirubinemia and its complications. Early identification of G6PD-deficient infants should be accompanied by careful bilirubin monitoring, clear discharge planning, and timely post-discharge follow-up, especially for those born late preterm. Full article

Sickle cell disease (SCD) is a major public health concern in Tanzania where approximately 11,000 children are born with the condition annually. Newborn screening (NBS) enables early diagnosis and timely intervention. Despite the proven effectiveness of NBS in reducing early mortality from SCD, implementation in Tanzania remains limited to pilot programs at facilities such as Temeke and Amana Regional Referral Hospitals (RRHs) in the city of Dar-es-salaam. This study evaluated the implementation of NBS for the SCD Program at Temeke and Amana RRHs. An explanatory mixed-methods process evaluation was conducted between January 2022 and December 2024. Quantitative data were extracted from hospital registries and REDCap, while qualitative data were obtained from key informant interviews with 17 healthcare workers. Quantitative data were analyzed using SPSS v29.0, while qualitative transcripts were thematically analyzed using NVivo software version 15 to explore operational factors influencing implementation. A total of 10,711 newborns were screened across the two hospitals. Seventy-four (0.70%) newborns had homozygous SCD (HbS/S), whereas 1325 (12.53%) had sickle cell trait (HbA/S). Enrolment of infants diagnosed with SCD into comprehensive care declined substantially over time, from 65.6% in 2022 to 10.5% in 2024 at Temeke RRH, while Amana RRH recorded no enrolments beyond the first year of implementation. Qualitative findings highlighted facilitators for NBS such as maternal awareness, interdepartmental collaboration, and the availability of trained staff. However, implementation was hindered by inadequate refresher training, delayed staff incentives, supply shortages, and parental hesitancy influenced by cultural beliefs. This evaluation found a substantial decline in enrolment of newborns diagnosed with SCD into comprehensive care, driven by key operational challenges. Although early implementation benefited from trained, committed staff and interdepartmental collaboration, sustainability was limited by inadequate refresher training, delayed incentives, supply shortages, and parental hesitancy. Addressing these gaps through regular capacity building, strengthened supply chains, timely incentives, and culturally sensitive community education is critical to improving enrolment, continuity of care, and informing national scale-up of NBS for SCD in Tanzania. Full article

Research programs can interface with public health programs to generate innovation, yet it is critical to ensure processes that support research activities without infringing on protected data. Genomic newborn screening (gNBS) research programs require reliable methods to link parental consents to the correct newborn screening (NBS) specimen. Early Check is a gNBS research program in North Carolina that uses the residual dried bloodspot (DBS) samples stored at the North Carolina State Laboratory of Public Health (NCSLPH) to screen babies for serious health conditions. Early Check created a systematic approach to match research consents with NBS DBS samples utilizing a fuzzy matching algorithm and manual review of prospective matches utilizing a decision tree. Between 28 September 2023, and 10 June 2025, Early Check received parental consents for 4279 newborns. Of those, 614 (14%) had discrepancies that required further review. More than half of these (349, 57%) required outreach to the consenting parent to resolve differences in information such as name, infant sex, or contact details. The use of probabilistic matching, a decision tree, and structured staff review provides a feasible approach for accurately identifying samples from consented NBS participants. Full article

Acid sphingomyelinase deficiency (ASMD) is currently treatable with olipudase alfa, increasing the need for early newborn screening (NBS). We conducted a two-center pilot cohort study to characterize dried blood spot (DBS) acid sphingomyelinase (ASM) activity in Japanese neonates in the neonatal intensive care unit (NICU). ASM activity was measured by flow injection-tandem mass spectrometry in 244 NICU-admitted neonates (gestational age 25–41 weeks; birth weight 773–4201 g); longitudinal paired samples were available in 34 neonates with birth weight < 2000 g and concurrent hematology in 43 neonates. The mean ASM activity was 3.7 ± 1.2 μmol/h/L (95% confidence interval, 3.54–3.84; range, 1.7–11.6), with a right-skewed distribution. ASM activity correlated positively with birth weight (r = 0.184, p = 0.0039), gestational age (r = 0.219, p = 0.0006), and lymphocyte count (ρ = 0.394, p = 0.0089) and negatively with hematocrit (ρ = −0.372, p = 0.014). In neonates with a birth weight < 2000 g, ASM increased significantly on repeat sampling (mean difference, 1.60 μmol/h/L; p < 0.0001; Cohen’s d = 0.912). These findings support NICU-specific reference ranges, hematology-informed interpretations, repeat testing after maturation, and the use of second-tier biomarkers for ASMD NBS implementation in Japan. Full article

We conducted a cost-effectiveness analysis of a universal newborn screening (NBS) program for infantile-onset Pompe disease (IOPD) compared with clinical identification in newborns. The analytical model combined a decision tree and a Markov model. The incremental cost-effectiveness ratio (ICER) was estimated over a lifetime horizon, applying a 2% annual discount rate from the public healthcare payer’s perspective. In a cohort of 727,288 individuals, 2.4 patients were expected to have IOPD. The cumulative quality-adjusted life years (QALYs) gained per patient were estimated to be 7.9 when clinically diagnosed and treated with enzyme replacement therapy, and 28.9 when identified through universal NBS. The ICER was 174 million JPY per QALY. Sensitivity and scenario analyses indicated that the parameters most affecting the ICER were the NBS test cost, the quality-of-life value for ambulatory patients, the prevalence of IOPD, and the cost of enzyme replacement therapy. Although considerable uncertainty exists in the analysis, the findings suggest that implementing NBS solely for detecting infantile-onset cases poses challenges in terms of cost-effectiveness, primarily due to the rarity of the disease and the high costs associated with testing and treatment. Full article