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Source publication
Purpose:
We conducted a consented pilot newborn screening (NBS) for Pompe, Gaucher, Niemann-Pick A/B, Fabry, and MPS 1 to assess the suitability of these lysosomal storage disorders (LSDs) for public health mandated screening.
Methods:
At five participating high-birth rate, ethnically diverse New York City hospitals, recruiters discussed the stu...
Contexts in source publication
Context 1
... diagnoses and phenotypic predictions were based on results of confirmatory testing (Table 1), using a combination of enzyme activity and genotype information for all five disorders, plus biomarker quantification for MPS 1 and Pompe disease. Predicted early-onset phenotypes were defined as classic infantile Pompe disease, types 2 or 3 Gaucher disease, Niemann-Pick type A, type 1 Fabry disease, and severe MPS 1. Predicted late-onset phenotypes were defined as late-onset Pompe disease, type 1 Gaucher, Niemann-Pick type B, type 2 Fabry disease, and attenuated MPS 1. ...
Context 2
... referral numbers and results of confirmatory testing are summarized in Table 2. Sixty-nine infants were screen- positive, and of these, 23, or 33%, were determined to be true positive based on the criteria shown in Table 1. All true positives were determined to be at risk for late-onset disease; all of these infants had genotypes known to be associated with late-onset phenotypes, low enzyme activity, and none had relevant clinical symptoms at the most recent evaluation. ...
Citations
... The incidental variant in the IDUA gene (c.1577T > C p.L526P) in case 8 was reported in a previous study in association with Mucopolysaccharidosis type 1 and conflicting interpretation of pathogenicity in ClinVar (Donati et al. 2018;Wasserstein et al. 2019;Polo et al. 2020;Bosfield et al. 2021;Zhang et al. 2022). Similarly, in case 12, we found homozygous causative variant c.274C > T (p.R83C) in G6PC and an incidental heterozygous variant c.4591A > G (p.M1531V) in CACNA1G. ...
Glycogen storage diseases (GSDs) are a group of rare inherited metabolic disorders characterized by clinical, locus, and allele heterogeneity. This study aims to investigate the phenotype and genotype spectrum of GSDs in a cohort of 14 families from Iran using whole-exome sequencing (WES) and variant analysis. WES was performed on 14 patients clinically suspected of GSDs. Variant analysis was performed to identify genetic variants associated with GSDs. A total of 13 variants were identified, including six novel variants, and seven previously reported pathogenic variants in genes such as AGL, G6PC, GAA, PYGL, PYGM, GBE1, SLC37A4, and PHKA2. Most types of GSDs observed in the cohort were associated with hepatomegaly, which was the most common clinical presentation. This study provides valuable insights into the phenotype and genotype spectrum of GSDs in a cohort of Iranian patients. The identification of novel variants adds to the growing body of knowledge regarding the genetic landscape of GSDs and has implications for genetic counseling and future therapeutic interventions. The diverse nature of GSDs underscores the need for comprehensive genetic testing methods to improve diagnostic accuracy. Continued research in this field will enhance our understanding of GSDs, ultimately leading to improved management and outcomes for individuals affected by these rare metabolic disorders.
... Only a few states have reported their experience, such as Missouri and Illinois (43,701 and 219,973 newborns, respectively), which found an incidence of about 1:43,000 [52,53]. In New York State (65,605 newborns), a very high incidence was found (1:4374), and this probably reflects New York City's large Jewish population, in which the p.Asn409Ser allele is frequent [54]. Several NBS programs for GD have been conducted in East Asia, where, due to the presence of different ethnic backgrounds, a lower incidence of disease was reported (1:73,743 to 1:103,134), and most of the patients suffered from neuronopathic forms (GD2/3), for which few therapeutic options are available [37,[55][56][57][58]. ...
In the last two decades, the development of high-throughput diagnostic methods and the availability of effective treatments have increased the interest in newborn screening for lysosomal storage disorders. However, long-term follow-up experience is needed to clearly identify risks, benefits and challenges. We report our 8-year experience of screening and follow-up on about 250,000 neonates screened for four lysosomal storage diseases (Pompe disease, mucopolysaccharidosis type I, Fabry disease, Gaucher disease), using the enzyme activity assay by tandem mass spectrometry, and biomarker quantification as a second-tier test. Among the 126 positive newborns (0.051%), 51 infants were confirmed as affected (positive predictive value 40%), with an overall incidence of 1:4874. Of these, three patients with infantile-onset Pompe disease, two with neonatal-onset Gaucher disease and four with mucopolysaccharidosis type I were immediately treated. Furthermore, another four Gaucher disease patients needed treatment in the first years of life. Our study demonstrates the feasibility and effectiveness of newborn screening for lysosomal storage diseases. Early diagnosis and treatment allow the achievement of better patient outcomes. Challenges such as false-positive rates, the diagnosis of variants of uncertain significance or late-onset forms and the lack of treatment for neuronopathic forms, should be addressed.
... A previous NBS pilot study conducted by ScreenPlus investigators enrolled and screened over 65,000 infants for five lysosomal storage disorders (LSDs). The study demonstrated that it is not only possible to implement a multi-site, multi-disorder pilot program, but that most parents are amenable to participate and have their child screened [18]. These findings led to the conceptualization of ScreenPlus, a comprehensive, multi-disorder pilot NBS program. ...
... Eligible newborns are recruited primarily through active, on-site recruitment, which our previous study found as the most effective in engaging parents right after birth [18]. All newborns (0-4 weeks old) born at a pilot hospital are eligible to participate, regardless of sex, gestational age, or health status. ...
The increasing availability of novel therapies highlights the importance of screening newborns for rare genetic disorders so that they may benefit from early therapy, when it is most likely to be effective. Pilot newborn screening (NBS) studies are a way to gather objective evidence about the feasibility and utility of screening, the accuracy of screening assays, and the incidence of disease. They are also an optimal way to evaluate the complex ethical, legal and social implications (ELSI) that accompany NBS expansion for disorders. ScreenPlus is a consented pilot NBS program that aims to enroll over 100,000 infants across New York City. The initial ScreenPlus panel includes 14 disorders and uses an analyte-based, multi-tiered screening platform in an effort to enhance screening accuracy. Infants who receive an abnormal result are referred to a ScreenPlus provider for confirmatory testing, management, and therapy as needed, along with longitudinal capture of outcome data. Participation in ScreenPlus requires parental consent, which is obtained in active and passive manners. Patient-facing documents are translated into the ten most common languages spoken at our nine pilot hospitals, all of which serve diverse communities. At the time of consent, parents are invited to receive a series of online surveys to capture their opinions about specific ELSI-related topics, such as NBS policy, residual dried blood spot retention, and the types of disorders that should be on NBS panels. ScreenPlus has developed a stakeholder-based, collective funding model that includes federal support in addition to funding from 14 advocacy and industry sponsors, all of which have a particular interest in NBS for at least one of the ScreenPlus disorders. Taken together, ScreenPlus is a model, multi-sponsored pilot NBS program that will provide critical data about NBS for a broad panel of disorders, while gathering key stakeholder opinions to help guide ethically sensitive decision-making about NBS expansion.
... Symptoms in the later-onset phenotype appear in adulthood and have less multi-organ involvement but can still be life-limiting [6, 10,11]. Variants associated with this phenotype are observed in 1:1390-1:9372 individuals across different populations [13,14]. ...
Background: Fabry disease (FD) is a rare, progressive disorder caused by pathogenic variants of the GLA gene resulting in the accumulation of toxic metabolites. Pain is a hallmark of FD, and patients often present with heterogeneous pain profiles. This cross-sectional, web-based survey was conducted to characterize pain and pain crises in patients with FD in the United States and explore the effects of sex, disease phenotypes, and treatment on pain.
Results: A total of 66 participants (mean [±SD] age: 44.0 [±12.7] years; females: 59.1%) completed the survey. Participants reported experiencing pain in upper (34.8%) and lower (43.9%) extremities several times a day and abdominal pain (31.8%) a few times a week. Overall, participants reported the nature of their pain as triggered (upper extremities: 47.0%; abdomen: 51.5%) or sudden (lower extremities: 57.6%). Female participants reported experiencing pain in upper (46.2%) and lower (48.7%) extremities several times a day and described it as sudden or triggered (48.7%) in upper extremities and sudden (61.5%) in lower extremities. Pain crises were reported in the lower extremities (80.0%), followed by the upper extremities (66.7%) and the abdomen (51.1%), and were often characterized as burning, tingling, or stabbing. A higher proportion of female participants (84.6%) than that of male participants (73.7%) reported pain crises in lower extremities. The duration of pain crises varied from 30 minutes to several days for different subgroups depending on sex and FD phenotypes. Most participants (81.0%) reported symptom improvement after 12 months of FD-specific treatment. With agalsidase beta as the most recent medication, participants reported improvement in neuropathic symptoms (burning in hands, 45.9%), with an overall mean (±SD) satisfaction score of 7.2 (±1.7).
Conclusions: Pain was largely reported to be triggered across all subgroups. Consistent pain profiles were noted in participants across sex and FD phenotypes. Female participants reported pain burden similar to that of male participants, and pain crisis experience was heterogeneous across the subgroups. Most participants reported improvement in symptoms after FD-specific treatment and a high treatment satisfaction score with agalsidase beta.
... Fifteen studies performing screening in newborns met the inclusion criteria, [100][101][102][103][104][105][106][107][108][109][110][111][112][113][114] providing data on the prevalence of FD among 1 108 793 newborns screened. ...
... Studies reporting the prevalence of FD among newborns undergoing metabolic screening started in 2006 when Spada et al 100 screened 37 104 consecutive Italian male neonates by determination of α-Gal A activities in DBS, observing a prevalence of 1 in 3100 newborns. Since then, screening programs in different countries [100][101][102][103][104][105][106][107][108][109][110][111][112][113][114] reported a prevalence ranging between 1 in 1250 101 and 1 in 18 436, 112 according to ethnicity, gender, and predicted disease phenotype. In this study, we showed that variable assignment of GLA variant pathogenicity has an impact on the estimated prevalence. ...
BACKGROUND
The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of GLA variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different GLA variant classifications on the estimated prevalence of FD.
METHODS
We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified GLA variants were included. GLA variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
RESULTS
Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the GLA variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q.
CONCLUSIONS
This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the GLA variants in the context of recent clinical, biochemical, and histological data.
REGISTRATION
URL: https://crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42023401663.
... Only a few States have reported their experience, such as Missouri and Illinois (43,701 and 219,973 newborns, respectively), which found an incidence of about 1:43,000 [52,53]. In New York State (65,605 newborns), a very high incidence was found (1:4374), and this likely reflects New York City's large Jewish population, in which the p.Asn409Ser allele is frequent [54]. Several NBS programs for GD have been conducted in East Asia where, due to different ethnic backgrounds, a lower incidence of disease was reported (1:73,743 to 1:103,134), and most patients suffered from neuronopathic forms (GD2/3), for which few therapeutic options are available [37,[55][56][57][58]. ...
In the last two decades, the development of high-throughput diagnostic methods and availabil-ity of effective treatments has increased interest in newborn screening for lysosomal storage disorders. However, long-term follow-up experience is needed to clearly identify risks, benefits and challenges. We report our 8-year experience of screening and follow up on about 250,000 neonates screened for four lysosomal storage diseases (Pompe disease, mucopolysaccharidosis type I, Fabry dis-ease, Gaucher disease), using enzyme activity assay by tandem mass spectrometry, and bi-omarker quantification as second tier test. Among the 126 positive newborns (0.051%), 51 infants were confirmed as affected (positive pre-dictive value 40%), with an overall incidence of 1:4,874. Of these, 3 infantile-onset Pompe dis-ease, 2 neonatal-onset Gaucher disease and 4 mucopolysaccharidosis type I patients were imme-diately treated. Furthermore, another four Gaucher disease patients needed treatment in the first years of life. Our study demonstrated the feasibility and effectiveness of newborn screening for lysosomal storage diseases. Early diagnosis and treatment allow the achievement of better patient out-comes. Challenges such as false positive rates, the diagnosis of variants of uncertain significance or late-onset forms, and the lack of treatment for neuronopathic forms, should be addressed.
... Over a course of 4-years 65,605 infants were screened for 3 LSD. Of those infants 69 screened positive, 23 were true positives (all late onset phenotype), 8 were carriers, 31 were unaffected, 6 were categorized as undetermined disease status, and one individual was lost to follow up despite molecular testing being part of the NBS results provided [7]. Studying biomarkers can also be helpful for diagnosis. ...
... Newborn screening for ASMD has presented with similar challenges as screening for other lysosomal storage disorders. A New York pilot study consented 65,605 infants for participation in a broad panel including several other LSD [7]. Of those infants, 69 screened positive, and two of those were screen positive for ASMD. ...
... Both infants' disease status was indeterminate. Results such as these highlight the difficulty of interpreting low enzymes when variants of uncertain significance are identified [7]. The biomarker lysosphingomyelin (lyso-SM) may be helpful in the future to determine the clinical utility of these variants [28]. ...
Lysosomal storage disorders (LSD) are caused by enzymatic failure to degrade specific cellular byproducts of metabolism within the lysosome. They have a wide range of presentations involving multiple body systems and can manifest from infancy through adulthood. As treatments have become available for many of these disorders, newborn screening has been adapted for early identification and pre-symptomatic treatment. This article will review some of the LSD that are now being added to newborn screening panels, including globoid cell leukodystrophy (Krabbe), Gaucher disease, Fabry disease, Mucopolysaccharidosis Type I (Hurler; MPSI), Mucopolysaccharidosis Type II (Hunter; MPSII), Acid Sphingomyelinase deficiency (ASMD), and Pompe disease.
... This could be attributed to the rarity of the disease, the phenotypes of which are likely to be unrecognized, let alone precisely diagnosed before disease progression. In our cohort, all except one patient diagnosed by NBS were asymptomatic, which concurs with a previous pilot study on NBS for LSDs [35]. The only symptomatic GD2 patient at the time of diagnosis by NBS initially presented with hepatosplenomegaly, anemia, thrombocytopenia, oculomotor apraxia, and ichthyosis and expired at 3 months of age. ...
Background
Gaucher disease (GD) is a lysosomal storage disorder characterized by deficient glucocerebrosidase activity that results from biallelic mutations in the GBA1 gene. Its phenotypic variability allows GD to be classified into 3 subtypes based on the presence and extent of neurological manifestations. Enzyme replacement therapy (ERT) has been available for all patients with GD in Taiwan since 1998. Newborn screening (NBS) for GD has been available since 2015. This study attempted to unveil the clinical features of patients diagnosed with GD during different eras in Taiwan.
Materials and methods
Data from the health records of two tertiary hospitals responsible for two-thirds of the patients with GD in Taiwan were used. The study population included all patients identified as having GD between 1998, and April 2022, in these two hospitals for review. A total of 42 individuals were included, six of whom were diagnosed by NBS.
Results
Our cohort presented a higher proportion of GD3 individuals, both by clinical suspicion and by NBS diagnosis, than that reported worldwide. The major subtypes that were recognized following NBS diagnosis were GD2 and GD3. The majority of GD patients carry at least one p.Leu483Pro variant. The 5-year survival rates were 0% for GD2 patients and 100% for patients with other subtypes. Patients diagnosed during the post-NBS era were free of symptoms on initial presentation, except for those with the GD2 subtype. For those diagnosed earlier, ERT was shown to be effective in terms of improved hemograms and prevented bone crises. However, the neurological symptoms in GD3 patients progressed despite ERT intervention.
Conclusion
ERT is essential in reversing the hematological presentations and preventing the skeletal complications of GD. Timely diagnosis of GD with NBS allows for early intervention with ERT to prevent disease progression and complications. However, the need for effective intervention for neurological dysfunction remains unmet.
... NBS for MPS I has been studied in several pilot programs and is already implemented in several countries. Most results of NBS programs are shared publicly but little is known about the long-term outcome of MPS I patients diagnosed by NBS [42][43][44][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. Nationwide NBS programs have been implemented in Taiwan since 2015 and the age at diagnosis has decreased significantly, as reported by a retrospective multicenter study by Lin et al. [58]. ...
... With the implementation of NBS, MPS I patients will be diagnosed before the onset of phenotype-distinguishing disease characteristics. Current NBS studies reported that one of the most important problems with NBS is identifying patients with an uncertain clinical phenotype and identifying individuals with a positive NBS that cannot be identified as affected or unaffected [40,42,52,55,69]. ...
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase α-L-iduronidase. MPS I is characterized by a broad range of disease manifestations. This includes devastating neurocognitive and bone manifestations and a short life expectancy in severely affected MPS I patients. Neurocognitive manifestations are typically limited in more attenuated MPS I, but patients may still suffer from severe somatic and bone manifestations. Severe MPS I patients are primarily treated with hematopoietic stem cell transplantation (HSCT) and more attenuated patients with enzyme replacement therapy. HSCT should be initiated before irreversible disease manifestations, preferably before 9 months, but may be initiated in patients up to 2 years. Early diagnosis of MPS I is challenging at best, and newborn screening (NBS) has already been initiated in several countries to diagnose and treat patients early. This article summarizes the history, benefits, methods and challenges that have to be addressed before NBS can be used most effectively.
... For GBA and GAA the percentage of daily mean used was 15%, for ASM 11%, for GALC 12%, for GLA 18%, and IDUA 6%. The percentages for GBA, ASM, GALC, GAA, GLA, and IDUA were similar to the percentages used in other centers [11,33,37,38]. ...
Background:
Lysosomal diseases (LDs) are progressive life-threatening disorders that are usually asymptomatic at birth. Specific treatments are available for several LDs, and early intervention improves patient's outcomes. Thus, these diseases benefit from newborn screening (NBS). We have performed a pilot study for six LDs in Brazil by tandem mass spectrometry.
Methods:
Dried blood spot (DBS) samples of unselected newborns were analyzed by the Neo-LSD™ kit (Perkin-Elmer) by MS/MS. Samples with low enzyme activity were submitted to the evaluation of specific biomarkers by ultra-performance liquid chromatography tandem-mass spectrometry as the second-tier, and were analyzed by a next-generation sequencing (NGS) multi-gene panel as the third-tier. All tests were performed in the same DBS sample.
Results:
In 20,066 newborns analyzed, 15 samples showed activity of one enzyme below the cutoff. Two newborns had biochemical and molecular results compatible with Fabry disease, and five newborns had biochemical results and pathogenic variants or variants of unknown significance (VUS) in GAA.
Conclusions:
This study indicates that the use of enzyme assay as the first-tier test gives an acceptably low number of positive results that requires second/third tier testing. The possibility to run all tests in a DBS sample makes this protocol applicable to large-scale NBS programs.
