Newborn Screening For Lysosomal Storage Disorders Research Articles

Establishment of Cutoff Values for Newborn Screening of Six Lysosomal Storage Disorders by Tandem Mass Spectrometry.

ObjectiveLysosomal storage disorders (LSDs) are becoming increasingly important in newborn screening, and tandem mass spectrometry (MS/MS) is widely used in newborn screening for LSDs through measurement of enzymatic activities in dried blood spots (DBSs). Overall, the determination of the cutoff value is important in such screening, and different laboratories have different methods of determining this value; most do not use a fixed cutoff value but rather calculate the corresponding batch cutoff value based on each batch of experimental data. In this study, we used MS/MS to screen for LSDs and sought to find an appropriate method to establish the cutoff value for LSD screening.MethodsA total of 38,945 samples from newborn blood tablets collected from various maternity hospitals in six cities in Shandong province, including Jinan, Dezhou, Heze, Linyi, Weifang, and Zibo, were tested using a Waters Xevo TQD tandem mass spectrometer; the experimental data were analyzed with MassLynx V4.1. The laboratory used 30% of the median GLA enzyme activity and 20% of the median ABG, ASM, GALC, IDUA, and GAA enzyme activities in every test as the cutoff values for that batch of experiments.ResultsThere were 254 suspicious positives in the initial screening test, including one case of Gaucher disease, one of Niemann-Pick disease, 47 of Krabbe disease, four of MPS-I, 21 of Fabry disease, and 180 of Pompe disease. After genetic screening, 11 children were diagnosed, including three with Pompe disease, three with Fabry disease, and five with Krabbe disease. In addition, the enzyme activity cutoff value of this experiment showed seasonal variation, which was initially believed to be related to the ambient temperature, such as the effect of ambient temperature on the human body or the temperature when the blood tablets dried naturally.ConclusionOverall, MS/MS can be used in LSD screening, and using different cutoff values in each batch of experiments is feasible. The ambient temperature might be a reason why the enzyme activity cutoff value has seasonal variation. More samples are needed to develop a method of determining cutoff values in laboratories.

The New York pilot newborn screening program for lysosomal storage diseases: Report of the First 65,000 Infants

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 (LSD) for public health mandated screening.Methods:At five participating high-birth-rate, ethnically diverse New York City hospitals, recruiters discussed the study with post-partum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long term outcome.Results:65,605 infants participated over four years, representing an overall consent rate of 74%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status.Conclusion:Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

Newborn Screening for Lysosomal Storage Disorders

Lysosomal storage disorders (LSDs) are a heterogeneous group of approximately 50 rare inherited metabolic conditions that result from enzyme deficiencies that interfere with lysosome function. Although often grouped together, there is great variability regarding age of onset, severity, treatment, and outcomes for each disorder and subtype. Currently, laboratory methods are available to test newborns for seven of these conditions. Although newborn screening programs remain state-based, each at a different phase of condition review and implementation, if newborn screening for LSDs has not yet been adopted by the state within which you practice, it likely will. Given the extremely low prevalence and limited provider familiarity with these conditions, this article provides an overview of LSDs and the seven conditions for which newborn screening is available. It offers information about each of the conditions including enzyme deficiency, mode of inheritance, incidence rates, types, clinical course, and available as well as potential treatment options.

The D313Y variant in the GLA gene - no evidence of a pathogenic role in Fabry disease in 2 Danish families

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.At five participating high–birth rate, ethnically diverse New York City hospitals, recruiters discussed the study with postpartum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long-term outcome.Over 4 years, 65,605 infants participated, representing an overall consent rate of 73%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status.Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

Heritability of hair cortisol and genetic overlap with psychological variables

Lysosomal storage disorders (LSDs) are a heterogeneous group of approximately 50 rare inherited metabolic conditions that result from enzyme deficiencies that interfere with lysosome function. Although often grouped together, there is great variability regarding age of onset, severity, treatment, and outcomes for each disorder and subtype. Currently, laboratory methods are available to test newborns for seven of these conditions. Although newborn screening programs remain state-based, each at a different phase of condition review and implementation, if newborn screening for LSDs has not yet been adopted by the state within which you practice, it likely will. Given the extremely low prevalence and limited provider familiarity with these conditions, this article provides an overview of LSDs and the seven conditions for which newborn screening is available. It offers information about each of the conditions including enzyme deficiency, mode of inheritance, incidence rates, types, clinical course, and available as well as potential treatment options.

The management of lysosomal disorders

Lysosomal storage disorders (LSDs) are a group of genetic disorders resulting from defective lysosomal metabolism/export of a range of naturally occurring compounds. Although individually rare, as a group they constitute a significant burden on society and are expensive to manage. In addition to general palliative care, treatment options for patients with LSDs now include haematopoetic stem cell therapy (HSCT), enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). The exact treatment regimen preferred depends upon the disease, the age at presentation and the presence or absence of central nervous system involvement. As therapy is likely to be most successful at an early stage in the natural history of a disorder, there is greater pressure upon clinicians to diagnose disorders as early as possible. As more treatments become available, newborn screening for LSDs may be the next essential development for this group of conditions.

Diagnosis of lysosomal storage disorders: evaluation of lysosome-associated membrane protein LAMP-1 as a diagnostic marker

Early diagnosis of lysosomal storage disorders (LSDs), before the onset of irreversible pathologies, will be a key factor in the development of effective therapies for many of these disorders. Newborn screening offers a potential mechanism for the early detection of these disorders. From studies of both normal and LSD-affected human skin fibroblasts we identified the lysosome-associated membrane protein LAMP-1 as a potential diagnostic marker. We have developed a sensitive method for the quantification of this protein with a time-resolved fluorescence immunoassay. A soluble form of LAMP-1 was observed in plasma samples, and determination of 152 unaffected individuals gave a median value of 303 micrograms/L with the 5th and 95th percentile at 175 and 448 micrograms/L respectively. Plasma samples from 320 LSD-affected individuals representing 25 different disorders were assayed. We observed that 17 of the 25 disorder groups tested had > 88% of individuals above the 95th percentile of the control population, with 12 groups having 100% above the 95th percentile. Overall, 72% of patients had LAMP-1 concentrations above the 95th percentile of the unpartitioned control population. We suggest that LAMP-1 may be a useful marker in newborn screening for LSDs.