Sialidosis type I (ST-1) is a rare lysosomal storage disease (LSD) caused by NEU1 gene mutations, leading to progressive neurological and visual dysfunction. The classical macular cherry-red spot (CRS) is considered a hallmark ocular sign, but its diagnostic value, particularly in older patients, remains unclear. This study aimed to characterize ocular manifestations and evaluate optical coherence tomography (OCT) reflectivity as a potential structural biomarker of neurological function. In this 2-year prospective cohort study, 15 genetically confirmed ST-1 patients underwent neurological evaluations every 6 months and annual ophthalmic assessments including best-corrected visual acuity (BCVA), fundus photography, OCT, and visual evoked potential (VEP). OCT reflectivity of the inner retina (Rin) and ellipsoid zone at the foveola (Rez) was quantified using greyscale analysis. Fifteen age-matched healthy controls were included for comparison. CRS was present in 46.7% of patients, predominantly in younger individuals. OCT revealed significantly elevated Rin and Rez in ST-1 patients compared to controls (p < 0.0001), including in those without clinically visible CRS. OCT reflectivity was strongly associated with neurological severity but not with BCVA. Conversely, BCVA correlated with parafoveal and ganglion cell complex thinning and with delayed VEP latency. Age-related declines in reflectivity, retinal thickness, and BCVA were observed in ST-1 but not in controls. These findings highlight OCT reflectivity is a more sensitive biomarker than the CRS for diagnosing ST-1 and reflects neurological severity even in patients without visible CRS. Importantly, the structure-function relationship between OCT parameters and neurological outcomes suggests broader applicability in LSD and other neurodegenerative conditions.

ABSTRACT Background Severe hypertriglyceridemia (HTG) is rare in children and is often caused by monogenic disorders. However, autoimmune mechanisms, particularly antibodies against glycosylphosphatidylinositol‐anchored high‐density lipoprotein‐binding protein 1 (GPIHBP1), have emerged as rare causes. Pediatric‐onset GPIHBP1 autoantibody‐related HTG remains poorly characterized. Methods We evaluated two 3‐year‐old children with extreme HTG (triglyceride level > 3000 mg/dL). Whole‐exome sequencing was performed to investigate monogenic etiologies. Autoimmune testing included antinuclear antibodies (ANAs) and anti‐Sjögren's syndrome‐related antigen A (SSA) antibodies, as well as an enzyme‐linked immunosorbent assay (ELISA) for anti‐GPIHBP1 antibodies. A clinical response to immunosuppressive therapy was assessed. A literature review of previously reported pediatric cases was conducted. Results No pathogenic variants were identified by whole‐exome sequencing. Both patients were positive for ANAs (1:320, speckled), and one had high‐titer anti‐SSA antibodies. The ELISA confirmed the presence of anti‐GPIHBP1 antibodies in both cases. Immunosuppressive therapy with hydroxychloroquine effectively reduced the triglyceride level in one patient, while the other required additional prednisolone. At follow‐ups (ages 9 and 10), neither patient developed overt systemic autoimmune disease. A literature review revealed 13 previously reported pediatric cases, most of which were diagnosed after the age of 11 years and were frequently associated with systemic lupus erythematosus or other autoimmune disorders. Conclusion GPIHBP1 autoantibody‐related HTG is important and potentially treatable severe pediatric HTG, representing an early manifestation of autoimmune dysregulation that requires an accurate diagnosis and longitudinal surveillance.

Background In addition to the main goal of T cell engraftment, the functional reconstitution of B cell function is an important indicator of successful hematopoietic stem cell transplantation (HSCT) for severe combined immunodeficiency (SCID) patients. Objective Poor functional reconstitution of B cell function may relate to lower degree of Major Histocompatibility Complex (MHC) compatibility in children with SCID after HSCT. Study Design We aimed to analyze the outcomes of HSCT in children with SCID in a referral tertiary center in southern Taiwan. We collected data retrospectively from all seven infants with SCID who received HSCT and were followed-up at the center during 2005-2025. Results All patients survived with reconstituted T cells during the follow-up period. One hundred percent T cell engraftment of donor cells are noted in all patients while variable degrees of chimerism were noted in other leukocytes. However, the extent of B cell chimerism does not appear to determine the outcome of B cell functional recovery. Two haploidentical-transplant patients required regular immunoglobulin supplement to prevent frequent infections. Conclusion Newborn screening for SCID may successfully identified patients with SCID and early HSCT helped them to survive the previously fatal disease. However, poor immunoglobulin recovery requiring lifelong immunoglobulin replacement was observed in the two patients who underwent haploidentical HSCT. Haploidentical transplantation as a potential cause of compromised B cell recovery in SCID treatment should be further investigated.

BACKGROUND:Prader‒Willi syndrome (PWS) is a genetic disorder characterized by hypotonia, feeding difficulties in infancy, excessive eating in childhood, intellectual disability and short stature. Growth hormone therapy (GHT) improves body composition and decreases fat percentage in patients with PWS. However, the effect of GHT on cognitive function is not clear. OBJECTIVES:The aim of this study was to evaluate the beneficial effects of GHT on cognition in younger patients with PWS. METHODS:A retrospective analysis of patients with PWS who received GHT in four hospitals was conducted in Taiwan. Patient demographics, molecular diagnosis, age at GHT initiation, GHT dose, developmental quotient/full-scale intelligence quotient (DQ/FSIQ) scores, and verbal intelligence quotient/verbal comprehension index (VIQ/VCI) scores were analyzed. RESULTS:This retrospective study included a total of 61 patients. Seven patients who did not receive growth hormone treatment were assigned to the control group, while the remaining 54 patients composed the treatment group. After applying the exclusion criteria, 47 patients were ultimately included in the analysis. Twenty-nine patients were treated before 3 years of age, and eighteen patients were treated after 3 years of age. The DQ/FSIQ score was significantly greater in the younger age group (p < 0.05). Specifically, in the nondeletion type and female groups, younger patients presented significantly higher DQ/FSIQ scores (p < 0.05). Compared with the untreated group, the early GH treatment group had significantly higher VIQ/VCI scores (p < 0.05). According to linear regression, the age at GHT initiation was significantly negatively correlated with the DQ/FSIQ score (β1 = -1.264, R2 = 0.184, F = 4.16, p < 0.05) and the VIQ/VCI score (β(VIQ)1 = -1.981, R2 = 0.242, F = 4.09, p < 0.05). CONCLUSION:The initiation of GHT before 3 years of age and as early as possible had a significant effect on cognitive development after adjustments were made for sex and molecular type.

Background and Objectives:Enzyme replacement therapy has not only significantly improved motor outcome and survival in patients with classic infantile Pompe disease, but also revealed previously unrecognized central nervous system (CNS) involvement. In this international study, involving patients from the Netherlands, Italy, Argentina, Germany, the United Kingdom, and Taiwan, we investigated whether epilepsy should be considered part of the CNS phenotype. Methods:We included patients with classic infantile Pompe disease, defined by the presence of hypertrophic cardiomyopathy, symptom onset < 6 months of age, complete acid α-glucosidase (GAA) deficiency, and/or 2 severe variants in the GAA gene, who developed epilepsy. Data on epilepsy characteristics, electroencephalogram (EEG), cognitive testing, serum neurofilament light chain (NfL), and brain magnetic resonance imaging (MRI) were retrospectively collected. Results:Seventeen patients from 10 centers were identified. The median follow-up duration was 13.7 years (range 3.3-19). Seven patients had deceased at the time of analysis. The median age at first seizure was 11.5 years (range 2.5-17.5). Seizure semiology was variable: six patients experienced generalized tonic-clonic seizures and 3 focal seizures with impaired consciousness only; 6 had multiple seizure types, and 7 experienced seizures during fever or infection. Seizure frequency varied considerably (in 9 occasionally, 5 monthly, 2 weekly, 1 daily). The most common EEG findings were a slowed background activity and focal epileptiform discharges, not substantially activated by sleep. Levetiracetam was most frequently used as antiseizure medication. Overall, 70% of patients became seizure-free. Serum NfL was elevated in all 6 patients in whom it was measured, and 8 of 10 patients had an intelligence quotient ≤66 at onset of epilepsy. Although brain MRI was not always performed at the age of first seizure, 14 of 15 patients showed white matter abnormalities, which were extensive in 11 of 14 (score ≥7/12). Brain atrophy was present in 9 cases and calcifications in 4. Discussion:Our findings suggest a potential increased frequency of seizures in classic infantile Pompe disease in comparison with unaffected children, occurring predominantly after the age of 7, and that epilepsy is part of the CNS phenotype. The risk of seizures should be evaluated during follow-up in long-term survivors with classic infantile Pompe disease.

BACKGROUND:Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal disorder with diverse clinical presentations and often delayed diagnosis. This study investigates the clinical features, genetic variants, and treatment outcomes in Taiwanese patients. METHODS:We retrospectively reviewed nine ASMD cases in Taiwan, including genetic data and responses to olipudase alfa. Newborn screening data using the NeoLSD MS/MS kit for dried blood spot enzyme activity, followed by lyso-sphingomyelin and molecular testing, were also analysed. RESULTS:The SMPD1 c.1497_1498inv variant was found in 62.5% of alleles among chronic neurovisceral ASMD cases, while c.995C > G appeared in 37.5% of chronic visceral ASMD cases and was also frequent in partial ASMD from newborn screening. Four patients received olipudase alfa; Patient 1, treated for 3 years starting at age 41, showed improved pulmonary function despite persistent thrombocytopenia and splenomegaly. Patients 2, 6, and 7, treated from early childhood, exhibited marked improvements in hepatosplenomegaly, interstitial lung disease, and growth within 1 year of therapy. CONCLUSION:This study highlights distinct genotype-phenotype correlations in ASMD and supports the clinical benefits of olipudase alfa. Increased awareness and early diagnosis, potentially through newborn screening, are essential for optimizing outcomes in ASMD.

Niemann-Pick type C (NP-C) disease is a fatal, neurodegenerative disorder caused by lysosomal lipid accumulation with variable symptomatic penetrance at the primary disease locus encoded by the NPC1 gene. We identified genetic modifiers of disease progression by integrating genetic, genomic, and lipidomic analyses across yeast, mice, and human patients. A yeast screen identified 45 candidate modifiers of disease severity, including phosphatidic acid hydrolase (PAH1), a key enzyme in triacylglycerol (TAG) synthesis. Lipidomic profiling of liver, cerebral cortex, and cerebellum from Npc1-/- mice at multiple ages demonstrated that dysregulation of TAG metabolism strongly correlates with disease progression. Deletion of the murine PAH1 orthologues Lpin1 or Lpin2 in Npc1-/- mice reduced lifespan, accelerated Purkinje cell loss, and increased hepatic lipid accumulation. In NP-C patients, two LPIN3 variants were associated with early childhood onset. These findings identify lipins as modifiers of NP-C disease and expand our understanding of lipid metabolism in neurodegeneration.

BACKGROUND:Newborn screening (NBS) for severe combined immunodeficiency (SCID) using T-cell receptor excision circles in dried blood spots has been implemented in the United States and many other regions and countries globally. The Clinical Immunology Society and the Association of Public Health Laboratories jointly formed the SCID Harmonization Initiative to facilitate comparison of NBS reporting practices to promote global consensus and collaboration. OBJECTIVE:To assess current NBS SCID practices using a global survey and to report the findings from the phase 1 component. METHODS:An 18-question survey was distributed to all known SCID screening programs worldwide. Only 1 response per region was analyzed. Examples of international screening algorithms were also solicited and included. RESULTS:A total of 200 responses were received, of which 80 responses were unique and used for further analysis. Of the 39 non-US countries, 15 (38%) reported national universal screening and 24 (62%) reported regional, pilot, or other screening. Additional questions pertained to methodology and reporting, with particular emphasis on communication of the clinical urgency of an abnormal T-cell receptor excision circle result. CONCLUSIONS:This global survey confirmed that the approach to NBS SCID varies widely, underscoring the need for harmonization at multiple steps, particularly for reporting and interpretation. This is the first study to capture global NBS SCID practices, and these findings provide the basis for creation of a phase 2 consensus reporting framework, which will be developed by the same SCID Harmonization Committee that created the current study.

Aromatic ʟ-amino acid decarboxylase (AADC) deficiency is a rare pediatric neurotransmitter disorder that typically necessitates lifelong care, and that carries a risk of childhood mortality. Eladocagene exuparvovec gene therapy is designed to restore AADC production. Study GT-002 (NCT04903288) is a phase 2, multicenter, open-label trial assessing the pharmacodynamics, safety, and efficacy of eladocagene exuparvovec administered to the putamen bilaterally in pediatric patients with AADC deficiency using a magnetic resonance (MR)-compatible cannula. Patients received eladocagene exuparvovec at 1.8 × 1011 vector genomes via the SmartFlow MR-compatible cannula in a single operative session. Endpoints include the change from baseline in cerebrospinal fluid homovanillic acid levels, motor milestone achievement, and safety. Here we report results from 48 weeks of follow-up. Mean (SD) cerebrospinal fluid homovanillic acid levels increased from baseline (22.5 [32.3] nmol/L; n = 13) to week 48 (55.3 [45.6] nmol/L; change from baseline: 28.3 [13.7] nmol/L; p = 0.0003; n = 9), indicating de novo dopamine production. At baseline (n = 13), all patients showed severe motor developmental delay; at week 48 (n = 12), nine achieved full head control, four could sit unassisted, two could stand with support, and two could walk independently to a toy. Overall, 260 treatment-emergent adverse events were reported in 13 patients; 259 were deemed unrelated and one likely unrelated to the MR-compatible cannula. No treatment-emergent adverse events led to study withdrawal and no deaths occurred. This study provides further evidence of the favorable pharmacodynamic, efficacy, and safety profile of eladocagene exuparvovec in children with AADC deficiency; intraputaminal administration using an MR-compatible cannula was well tolerated. Study GT-002 (NCT04903288) provides further evidence of the favourable pharmacodynamic, efficacy and safety profile of eladocagene exuparvovec gene therapy in children with AADC deficiency over 48 weeks and demonstrates that intraputaminal administration using an MR-compatible cannula was well tolerated, allowing for real-time MRI confirmation of cannula placement and infusate coverage, and for accurate dosing to the putamen.

OBJECTIVE:To evaluate the long-term safety and efficacy of avalglucosidase alfa in children with infantile-onset Pompe disease experiencing clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3) to prestudy alglucosidase alfa. STUDY DESIGN:The Mini-COMET clinical trial, a phase 2, open-label, ascending-dose, 3-cohort study, has a 25-week primary analysis period (PAP) and an extension treatment period (ETP). In the PAP, cohorts 1 (n = 6) and 2 (n = 5) received avalglucosidase alfa 20 or 40 mg/kg every other week (qow), respectively. Cohort 3 received avalglucosidase alfa 40 mg/kg qow (n = 5) or alglucosidase alfa (prestudy [>6 months] stable dose: 20 mg/kg qow to 40 mg/kg weekly; n = 6). All children completed the PAP and entered the ETP. Children receiving avalglucosidase alfa in the PAP continued the same dose in the ETP. Those receiving alglucosidase alfa in the PAP received avalglucosidase alfa 40 mg/kg qow in the ETP. RESULTS:At baseline, children were 1-12 years old. Interim data (≥97 weeks) are presented from all 22 children, 20 receiving avalglucosidase alfa 40 mg/kg qow and 2 receiving 20 mg/kg qow in the ETP. Among the 6 who received 20 mg/kg qow avalglucosidase alfa in PAP (cohort 1), 4 had their dose increase to 40 mg/kg qow because of further clinical decline in the ETP. No child died or discontinued at data cutoff. PAP and ETP safety profiles were similar; no treatment-related serious or severe treatment-emergent adverse events occurred. Avalglucosidase alfa was well-tolerated, with no increased safety risk or immunogenicity concerns post-treatment switch. Echocardiography revealed persistent left ventricular mass z score normalization. Compared with baseline, biomarkers of Pompe disease burden decreased, and motor function improved or stabilized. CONCLUSIONS:Results support the positive clinical impact of long-term avalglucosidase alfa in children with infantile-onset Pompe disease. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03019406.

Fabry disease (FD) is a rare inherited X-linked lysosomal disorder caused by the deficiency or dysfunction of the enzyme α-galactosidase. This leads to a detrimental accumulation of globotriaosylceramide (Gb3) within multiple cell types. Enzyme replacement therapies (ERTs), including agalsidase alfa and agalsidase beta, can diminish Gb3 levels. Published real-world data on the time, cost and burden associated with the administration of ERTs are limited. These evidence gaps were addressed by generating real-world data quantifying the burden of agalsidase alfa and beta infusions for FD treatment. The study (ClinicalTrials.gov number: NCT04281537) comprised a prospective time-and-motion and a cross-sectional evaluation of self-reported burden and outcomes associated with ERT administration (including work productivity and out-of-pocket costs) from multiple perspectives (healthcare professionals [HCPs], patients, and caregivers). To assess patient/caregiver experience and burden of ERT, the primary objective was to quantify the total time spent by HCPs in the preparation and administration of a single dose of ERT. Overall, 76 patients and 6 caregivers were included. Of the 76 patients, (Brazil [n = 23], Japan [n = 4], Taiwan [n = 30] and Turkey [n = 19]), 41

Background/Objectives: Achondroplasia is the most common skeletal dysplasia, affecting 1 in 25,000 births. Limited research exists on the assessment of functional independence using standardized tools in children and adolescents with achondroplasia. The WeeFIM scale provides a comprehensive evaluation of daily living skills across multiple functional domains. This study aimed to assess the functional independence levels in children and adolescents with achondroplasia using WeeFIM and analyze functional capabilities. Methods: This multicenter cross-sectional study included 46 participants aged 6–18 years with confirmed achondroplasia. Data were collected through standardized WeeFIM assessments from medical centers and online surveys (2021–2024). WeeFIM evaluates 18 functional items across 3 domains: self-care (8 items), mobility (5 items), and cognition (5 items), scored 1–7 (complete dependence to independence). Results: Participants included 26 males (56.5%) and 20 females (43.5%). Most (78.3%) were diagnosed during infancy. The mean functional scores were highest for cognition (34.0/35, 97.1%), followed by self-care (51.2/56, 91.4%) and mobility (31.5/35, 90.0%). Most participants achieved near-complete independence in cognitive functions. Mobility tasks, particularly stair climbing and bathtub transfers, showed the greatest challenges. Functional independence increased with age, with significant improvements during early childhood to adolescence transition. Conclusions: Children and adolescents with achondroplasia demonstrate high functional independence across daily activities, with cognitive abilities largely unaffected. Although specific mobility challenges exist, most participants achieve independence with appropriate accommodations. These findings provide valuable baseline data for clinical care planning and support optimistic functional outcomes for pediatric patients with achondroplasia.