Maria Luz Couce

Background: Conventional newborn screening (NBS) relies on mainly biochemical assays and remains limited by its dependence on detectable biomarkers within a narrow postnatal window, leaving many treatable genetic disorders unidentified. Advances in next-generation sequencing have enabled projects of genomic newborn screening, which may expand the spectrum of detectable conditions. However, challenges persist regarding variant interpretation, reporting criteria, and integration into public healthcare systems. Methods: NBGenS is a prospective, single-center pilot study in Spain that will evaluate the feasibility of integrating whole exome sequencing (WES) into routine NBS. The study will recruit 550 newborns at the University Clinical Hospital of Santiago de Compostela. DNA will be extracted from residual dried blood spots (DBS) obtained through NBS. WES and clinical interpretation will be restricted to a virtual panel of genes associated with severe, highly-penetrant, pediatric-onset diseases for which early intervention is available. Variant interpretation will follow ACMG/AMP and ClinGen recommendations, and only pathogenic or likely pathogenic variants will be considered reportable. Untargeted metabolomics using DBS will be applied in selected cases, particularly for prioritised variants of uncertain significance (VUS), to provide complementary biochemical evidence that may contribute to variant classification. Clinical follow-up, psychosocial assessment, pharmacogenetic analysis, and health economic evaluation will also be incorporated into the study design. Outcomes: The project will establish and evaluate a comprehensive clinical workflow encompassing recruitment, sequencing, interpretation, reporting, and follow-up. Key outcomes will include diagnostic yield, parental acceptance, psychological impact, cost-effectiveness, clinical utility, and the added value of metabolomic integration for resolving VUS. Conclusion: NBGenS represents one of the first prospective public healthcare pilot studies integrating genomic sequencing and untargeted metabolomics within an established NBS program. The study will generate empirical evidence on the clinical, ethical, psychosocial, and economic implications of neonatal genomic screening and may inform future policy decisions regarding its implementation within national health systems.

Glycogen storage disease type Ia (GSDIa) is a rare, life‐threatening inherited carbohydrate metabolism disorder caused by biallelic pathogenic G6PC gene variants resulting in deficiency of glucose‐6‐phosphatase. DTX401 is an investigational AAV8 vector containing the human G6PC gene. DTX401‐CL301 is a pivotal, phase 3, double‐blind, randomized, placebo‐controlled trial of DTX401 in patients ≥ 8 years with GSDIa. The primary endpoint was percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 versus placebo group. Participants were randomly assigned (1:1) to blinded DTX401 or placebo. After the 48‐week Primary Efficacy Analysis Period (PEAP), participants crossed over in a blinded manner for an additional 48‐week blinded Crossover Period. Following randomization: 21 participants received DTX401; 25 received placebo. At Week 48, DTX401 treatment resulted in a statistically significant least squares (LS) mean (SE) daily cornstarch intake reduction of 41% (4.6) versus 10% (4.1) for Placebo ( p < 0.0001). Clinical meaningfulness was evidenced by a mean desired percent reduction in daily cornstarch intake among those reporting in Baseline interviews ( n = 33) of 45% (median = 41%). Greater and faster reductions in cornstarch were observed at Week 96 for the Crossover DTX401 group compared with the DTX401 group in the PEAP. The DTX401 safety profile was acceptable, and expected hepatic reactions consisting of transaminase elevations were managed with prophylactic corticosteroids. Treatment with DTX401 resulted in both a statistically significant and clinically meaningful reduction in cornstarch intake in the 48‐week PEAP versus placebo, with greater cornstarch reductions in both groups at Week 96.

Newborn screening (NBS) is a cornerstone of preventive medicine, enabling early diagnosis and treatment of severe congenital disorders. In Spain, despite the existence of a Basic Common Portfolio, the absence of a harmonized national panel has led to significant inter-regional variability, affecting equity in access to early diagnosis. The Spanish Uniform Screening Panel (SUSP) was developed through a structured nationwide consensus process involving all NBS centers in Spain, with additional input from Portugal. The process included a comprehensive survey of current practices, expert workshops, multiple consensus rounds, and predefined inclusion criteria. Disease nomenclature was standardized using OMIM and ORPHAcode identifiers. Conditions were classified as primary screening targets or secondary findings, and consensus was reached on confirmatory biochemical and genetic testing pathways. The operational dataset comprised 48 biomarker-based screening entries. Because some conditions can be detected through multiple primary markers, duplicate analytical routes were retained but counted once, resulting in a total 189 unique clinical conditions, including 87 primary and 102 secondary conditions. The SUSP represents the first nationwide harmonized framework for newborn screening in Spain and constitutes a major step toward equitable and standardized implementation. It provides a scalable model that may inform other countries facing similar disparities.

Pompe disease (PD) is a rare, autosomal recessive neuromuscular disorder caused by mutations in the gene encoding acid alpha-glucosidase (GAA). The resulting deficiency in GAA, a lysosomal enzyme, leads to the pathological accumulation of glycogen, primarily in cardiac and skeletal muscles. PD presents as a clinical continuum spanning two major phenotypes: infantile-onset Pompe disease (IOPD), the most severe form, typically characterized by onset before 12 months of age, rapid hypertrophic cardiomyopathy, and severe hypotonia; and late-onset Pompe disease (LOPD), which manifests between 12 months of age and adulthood, and is characterized by progressive axial and proximal muscle weakness and respiratory insufficiency. Enzyme replacement therapy (ERT), available since 2006, has improved survival, particularly in IOPD, but is limited by variable efficacy and limited penetration of the blood–brain barrier, necessitating new approaches. In this comprehensive review, we focus on advances in the understanding and management of PD. First, we explore recent diagnostic advances and the characterization of multisystem involvement in PD. Next, we critically discuss the advantages and limitations of current ERT approaches, and advances achieved with next-generation ERT (avalglucosidase alfa, cipaglucosidase alfa + miglustat). Finally, we summarize cutting-edge, potentially curative strategies, including substrate reduction therapy and novel experimental therapies (e.g., gene therapy) that seek to circumvent the limitations of ERT, provide durable effects, and potentially penetrate the central nervous system.

Mucopolysaccharidosis type I (MPS-I) is a rare, multisystemic lysosomal storage disease (LSD) caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT), administered via weekly intravenous infusions. ERT is of limited efficacy owing to its inability to reach critical tissues such as the brain and bone. To address these limitations, this study explores a novel method to improve drug delivery to target organs and simplify administration: oral administration of enzyme encapsulated within nanostructured lipid carriers (NLC). Encapsulation of ERT within NLC enabled effective oral administration. In vitro analysis showed that our NLC formulation was as effective as intravenous ERT in correcting enzyme activity and reducing glycosaminoglycan (GAG) accumulation in fibroblasts from MPS-I patients, when administered periodically. Permeability studies confirmed passage across the intestinal barrier. Proteomic analyses demonstrated normalization of protein expression in energetic pathways related to hexose metabolism, and significant improvements in protein dysregulation in the cytoskeleton, cellular trafficking, lysosomal function, GAG biosynthesis and degradation, and the extracellular matrix. Furthermore, in vivo studies in MPS-I knockout (KO) mice demonstrated biodistribution of NLC-encapsulated enzymes to all tissues affected by the disease, including passage across the blood-brain barrier and access to poorly vascularized bone. These findings suggest that oral administration of ERT via NLC encapsulation represents a significant advancement in MPS-I treatment, enabling drug delivery to previously inaccessible areas. This study opens important avenues of research for future therapeutic strategies targeting LSDs.

Urea cycle disorders (UCDs) are rare inherited metabolic diseases associated with toxic hyperammonemia, leading to severe neurological damage and early mortality. Early diagnosis of distal UCDs through newborn screening (NBS) enables presymptomatic intervention; however, comparative real-world outcome data remain limited. We conducted a retrospective, multicenter study using data from the Spanish UCD Registry to describe the clinical characteristics and compare health outcomes between patients diagnosed through NBS (n = 40) and those diagnosed after clinical presentation (n = 53). Patients identified by NBS showed a markedly more favorable clinical prognosis, with a mortality rate of 2.5% compared with 15.1% in the unscreened cohort, as well as significantly lower rates of neurological involvement, fewer hospital admissions due to metabolic decompensation, and a reduced need for liver transplantation. Screening also identified a high prevalence of argininosuccinate synthetase deficiency (ASS1D) cases with attenuated biochemical profiles, highlighting the relevance of sensitive screening cutoffs. These findings provide real-world evidence that presymptomatic diagnosis through NBS is associated with improved survival and long-term neurological outcomes in patients with distal UCDs.

Background/Objectives: Hereditary fructose intolerance (HFI) is an inherited metabolic disorder caused by a deficiency of the enzyme fructose-1,6-bisphosphate aldolase. Treatment consists of a lifelong diet restricted in fructose, sucrose, and sorbitol (FSS). The aim of this study was to determine dietary intake of FSS and to analyze the consumption patterns of vegetables, fruit, legumes, pulses, and dried fruit in a nationwide cohort of HFI patients. Methods: Overall, 36 HFI patients and 28 age-, sex- and BMI-matched healthy control subjects participated in this study. A self-administered three-day dietary record and an adapted quantitative food frequency questionnaire (FFQ) including frequency and portion sizes were collected. FSS intake was calculated using the DIAL Nutritional Calculation Program (ALCE INGENIERÍA). Total fructose intake was calculated as the sum of free fructose, 50% of sucrose, and sorbitol. Results: Protein intake was significantly higher in HFI patients compared to the controls (92.43 g/day [65.1–165.03] vs. 70.39 g/day [35.21–133.83]; p = 0.001). In most patients, total fructose intake was within the recommended limits (9.79 mg/kg bw/day [0.29–59.09]), with no significant differences between children and adults (p = 0.325). Although the established dietary recommendations did not always match the actual intake observed in a real-life setting, in general, foods with higher fructose content were consumed less frequently and in smaller quantities. Conclusions: Further research on the fructose content of various foods, particularly fruits and vegetables, and updated dietary recommendations for HFI patients are warranted to provide the best tools for the nutritional management of the disease.