Gaucher disease (GD) is a lysosomal storage disorder (LSD) characterized by glycosphingolipid accumulation. Age of symptomonset and disease progression varies across types of disease. Newborn screening (NBS) for Gaucher disease facilitates early identification of affected individuals and enables pre-symptomatic monitoring with the goal of starting therapies early and improving clinical outcomes. This multi-center study involved New Jersey NBS referral centers. Data regarding initial NBS results, confirmatory testing, diagnosis, and treatment were collected. For patients on therapy, monitoring biomarkers and exam findings are available as of the last clinical evaluation. Between July 2019 and December 2023, 438,515 newborns were screened, with 60 screen-positive cases. Of those positive screens, 19 cases with positive screens did not undergo confirmatory testing due to parental refusal, loss to follow-up, or death; 23 cases were false positives; 14 newborns were diagnosed with GD type I; 2 newborns were diagnosed with suspected type I GD; 2 newborns were diagnosed with GD type II; and 1 case is still pending. Three type I GD patients started enzyme replacement therapy, with the youngest starting at 28 months of age. Post-treatment data are available for these individuals. One type II case was referred to experimental gene therapy, and one was started on ERT. Our results demonstrate that NBS for GD is a valuable public health tool that can facilitate early diagnosis and intervention.

Pennsylvania started newborn screening for Pompe disease (PD) in 2016. As a result, the prevalence of PD has increased with early detection, primarily of late-onset Pompe disease (LOPD). No clear guidelines exist regarding if and when to initiate enzyme replacement therapy (ERT) in patients identified through a newborn screen (NBS). To help define the natural history and indications for starting ERT, we present the long-term follow-up data of 45 patients identified through NBS from 2016 to 2021. These patients were evaluated at regular intervals through our multi-disciplinary clinic at the Children’s Hospital of Philadelphia (CHOP) with physical examinations, physical therapy evaluations, muscle biomarkers including creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hexosaminidase 4 levels (Hex4), as well as cardiac evaluation at certain points in time. We found that newborn screening of acid alpha-glucosidase (GAA) enzyme detected primarily LOPD. One case of infantile-onset PD (IOPD) was detected. Muscle biomarkers in LOPD were elevated at birth and showed a general downward trend over time. NBS GAA levels and initial CK levels helped to differentiate LOPD cases from unaffected infants (carriers, pseudodeficiency alleles), while Hex4 was not a meaningful discriminator. On repeat NBS, there was a significant difference between mean GAA levels for the unaffected vs. compound heterozygote groups and unaffected vs. homozygote groups for the common splice site pathogenic variant (c.-32-13T>G). Echocardiogram and electrocardiogram (EKG) are essentially normal at the first evaluation in LOPD. One LOPD patient was started on ERT at age 4.5 months. Continued data collection on these patients is critical for developing management guidelines, including timing of ERT and improved genotype–phenotype correlation.

Type 1 Gaucher disease is a lysosomal storage disorder associated with marked phenotypic heterogeneity, including among individuals carrying genotypes historically defined as “mild”. Early diagnosis, workup and follow-up care are crucial to avoid irreversible complications. We present a case series of 5 pediatric patients with type 1 Gaucher disease who had been identified based on newborn screening (NBS), parental carrier status, or clinical presentation. They were followed over time for monitoring of clinical status, hematologic indices, biomarkers including glucopsychosine, and imaging studies. Enzyme replacement therapy (ERT) was started when rising trends of biomarkers and/or new clinical symptoms appeared. Three patients were identified by NBS, one at birth due to parental carrier status, and one after symptomatic presentation with femoral fracture. All patients required initiation of ERT between 9 months and 5 years of age due to evidence of disease progression. Early diagnosis via NBS and proactive monitoring enabled timely ERT initiation in four cases, preventing irreversible organ damage and clinical complications. In contrast, the unscreened case presented with severe skeletal and hematologic involvement at baseline. Rising glucopsychosine was a sensitive early marker of disease activity and MRI was more sensitive at detecting organomegaly than ultrasound. These cases emphasize the vital importance of NBS, regular biomarker surveillance, and early intervention, even in presumed mild cases based on genotype. Early diagnosis via NBS, individualized monitoring and timely treatment are fundamental to optimizing outcomes in Gaucher disease type 1.

Mucopolysaccharidosis (MPS) type II, or Hunter syndrome, is an X-linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase. Glycosaminoglycan (GAG) accumulation leads to progressive multisystemic involvement, with coarse facial features, hepatosplenomegaly, short stature, recurrent upper respiratory infections, hearing loss, hernias, dysostosis multiplex, joint contractures, and cardiac valve disease. Individuals with the neuronopathic form of the disease also have central nervous system (CNS) involvement with developmental delay and progressive cognitive decline. Enzyme replacement therapy (ERT), idursulfase, is the only FDA-approved treatment for MPS II. MPS II was added to the Recommended Uniform Screening Panel (RUSP) in the United States in 2022, and screening is ongoing in several other countries, including Taiwan. Here, we report seven individuals from four families identified through newborn screening sharing the same IDS variant: c.817C>T, p.Arg273Trp. Confirmatory testing demonstrated low iduronate-2-sulfatase activity level and elevated GAGs in every individual, but they had no signs or symptoms of MPS II. They were aged 8 months to 60 years old according to the most recent assessment and all remained asymptomatic. ERT was not initiated for any of them. Our findings suggest that the IDS c.817C>T variant is associated with abnormal biochemical findings but no clinical phenotype of MPS II. Newborn screening will likely identify additional cases and provide a better understanding of the clinical significance of this variant.