Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I

Herbst, Zackary M.; Urdaneta, Leslie; Klein, Terri; Fuller, Maria; Gelb, Michael H.

doi:10.3390/ijns6030069

Cited by 28 publications

(52 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pathogenicity of new mutations identified in the asymptomatic newborn screening positive neonates cannot be defined only by the molecular analysis; however, the recent reports suggest the clinical severity can be predicted by assaying specific GAGs as a second-tier screening. Therefore, it is critical to measure both enzyme and primary stored GAGs to define the phenotype (pseudodeficiency, attenuated, or severe) along with the molecular analysis [ 157 , 183 , 184 ]. In general, traditional methods cannot identify all patients before the patient becomes symptomatic; however, we need early diagnosis and early treatment for MPS patients since some symptoms are irreversible or hard to improve.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Epidemiology of Mucopolysaccharidoses Update

Çelik

Tomatsu

et al. 2021

Diagnostics

View full text Add to dashboard Cite

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a lysosomal enzyme deficiency or malfunction, which leads to the accumulation of glycosaminoglycans in tissues and organs. If not treated at an early stage, patients have various health problems, affecting their quality of life and life-span. Two therapeutic options for MPS are widely used in practice: enzyme replacement therapy and hematopoietic stem cell transplantation. However, early diagnosis of MPS is crucial, as treatment may be too late to reverse or ameliorate the disease progress. It has been noted that the prevalence of MPS and each subtype varies based on geographic regions and/or ethnic background. Each type of MPS is caused by a wide range of the mutational spectrum, mainly missense mutations. Some mutations were derived from the common founder effect. In the previous study, Khan et al. 2018 have reported the epidemiology of MPS from 22 countries and 16 regions. In this study, we aimed to update the prevalence of MPS across the world. We have collected and investigated 189 publications related to the prevalence of MPS via PubMed as of December 2020. In total, data from 33 countries and 23 regions were compiled and analyzed. Saudi Arabia provided the highest frequency of overall MPS because of regional or consanguineous marriages (or founder effect), followed by Portugal, Brazil, the Netherlands, and Australia. The newborn screening is an efficient and early diagnosis for MPS. MPS I has been approved for newborn screening in the United States. After the newborn screening of MPS I, the frequency of MPS I increased, compared with the past incidence rates. Overall, we conclude that the current identification methods are not enough to recognize all MPS patients, leading to an inaccurate incidence and status. Differences in ethnic background and/or founder effects impact on the frequency of MPS, which affects the prevalence of MPS. Two-tier newborn screening has accelerated early recognition of MPS I, providing an accurate incidence of patients.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Most LSDs could benefit from an early diagnosis since the availability of treatments leads to better consequences when starting at an early stage [ 184 , 185 , 186 ]. ERT and HSCT are clinically used for some MPS types, while gene therapy, SRT, and pharmacologic chaperons are under development.…”

Section: Discussionmentioning

confidence: 99%

Epidemiology of Mucopolysaccharidoses Update

Çelik

Tomatsu

et al. 2021

Diagnostics

View full text Add to dashboard Cite

show abstract

“…Most of these programs do not have the capability to perform 2TT using either molecular or biochemical methods in house, and therefore outsource such testing to external laboratories. Biochemical genetics testing by analysis of glycosaminoglycans (GAGs) in DBS [ 23 ] is primarily utilized to detect severe MPS I (Hurler syndrome), which is the main target of NBS, and may be sufficiently sensitive to detect at least some cases of attenuated MPS I [ 24 ]. Molecular testing, performed either as a 2TT or after case referral for follow-up testing, appears to be the preferred option in the United States for short-term follow-up of presumptive positives, regardless of the platform used for LSD enzyme testing [ 25 ].…”

Section: Prospective Screening Results From States Using Dmfmentioning

confidence: 99%

Digital Microfluidics in Newborn Screening for Mucopolysaccharidoses: A Progress Report

Washburn

Millington

2020

IJNS

View full text Add to dashboard Cite

Newborn screening (NBS) for mucopolysaccharidosis type I (MPS I, Hurler syndrome) is currently conducted in about two-fifths of the NBS programs in the United States and in a few other countries. Screening is performed by measurement of residual activity of the enzyme alpha-l-iduronidase in dried blood spots using either tandem mass spectrometry or digital microfluidic fluorometry (DMF). In this article, we focus on the development and practical experience of using DMF to screen for MPS I in the USA. By means of their responses to a questionnaire, we determined for each responding program that is screening for MPS I using DMF the screen positive rate, follow-up methods, and classification of confirmed cases as either severe or attenuated. Overall, the results show that at the time of reporting, over 1.3 million newborns in the US were screened for MPS I using DMF, 2094 (0.173%) of whom were screen positive. Of these, severe MPS I was confirmed in five cases, attenuated MPS I was confirmed in two cases, and undetermined phenotype was reported in one case. We conclude that DMF is an effective and economical method to screen for MPS I and recommend second-tier testing owing to high screen positive rates. Preliminary results of NBS for MPS II and MPS III using DMF are discussed.

show abstract

“…Measurement of enzyme activity serves as the primary standard for the diagnosis of many lysosomal storage conditions. More recently, second tier GAG testing from dried blood spots has been employed as a means of confirming or ruling out an MPSI positive screen [ 6 , 7 , 8 ]. This testing is advantageous since it does not require IDUA sequencing to help address the validity of the NBS activity measurement.…”

Section: Introductionmentioning

confidence: 99%

“…This testing is advantageous since it does not require IDUA sequencing to help address the validity of the NBS activity measurement. Nonetheless, there is still a subset of cases described in two of the papers cited above where the GAG testing does not provide clear support for the enzyme analysis and further molecular testing is necessary [ 7 , 8 ]. Moreover, enzyme activity in some clinically normal individuals can be below the established normal range, and in some cases the reduction in enzyme activity may be similar to what is found in affected patients [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

A Biochemical Platform to Define the Relative Specific Activity of IDUA Variants Identified by Newborn Screening

Yu¹,

Pollard²,

Wood³

et al. 2020

IJNS

View full text Add to dashboard Cite

The lysosomal storage disorder, mucopolysaccharidosis I (MPSI), results from mutations in IDUA, the gene that encodes the glycosaminoglycan-degrading enzyme α-L-iduronidase. Newborn screening efforts for MPSI have greatly increased the number of novel IDUA variants identified, but with insufficient experimental evidence regarding their pathogenicity, many of these variants remain classified as variants of uncertain significance (VUS). Defining pathogenicity for novel IDUA variants is critical for decisions regarding medical management and early intervention. Here, we describe a biochemical platform for the characterization of IDUA variants that relies on viral delivery of IDUA DNA into IDUA-deficient HAP1 cells and isolation of single cell expression clones. The relative specific activity of wild-type and variant α-iduronidase was determined using a combination of Western blot analysis and α-iduronidase activity assays. The specific activity of each variant enzyme was consistent across different single cell clones despite variable IDUA expression and could be accurately determined down to 0.05–0.01% of WT α-iduronidase activity. With this strategy we compared the specific activities of known pseudodeficiency variants (p.His82Gln, p.Ala79Thr, p.Val322Glu, p.Asp223Asn) or pathogenic variants (p.Ser633Leu, p.His240Arg) with variants of uncertain significance (p.Ser586Phe, p.Ile272Leu). The p.Ser633Leu and p.His240Arg variants both show very low activities consistent with their association with Scheie syndrome. In our experiments, however, p.His240Arg exhibited a specific activity five times higher than p.Ser633Leu in contrast to other reports showing equivalent activity. Cell clones expressing the p.Ser586Phe and p.Ile272Leu variants had specific activities in the range of other pseudodeficiency variants tested. Our findings show that pseudodeficiency and pathogenic variants can be distinguished from each other with regard to specific activity, and confirms that all the pseudodeficiency variants variably reduce α-iduronidase activity. We envision this platform will be a valuable resource for the rigorous assessment of the novel IDUA variants emerging from the expansion of newborn screening efforts.

show abstract

Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I

Cited by 28 publications

References 18 publications

Epidemiology of Mucopolysaccharidoses Update

Epidemiology of Mucopolysaccharidoses Update

Digital Microfluidics in Newborn Screening for Mucopolysaccharidoses: A Progress Report

A Biochemical Platform to Define the Relative Specific Activity of IDUA Variants Identified by Newborn Screening

Contact Info

Product

Resources

About