Evidence and recommendation for mucopolysaccharidosis type II newborn screening in the United States.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.

Newborn screening for mucopolysaccharidosis type II: Lessons learned.

We describe our experience with population-based newborn screening for mucopolysaccharidosis type II (MPS II) in 586,323 infants by measurement of iduronate-2-sulfatase activity in dried blood spots between December 12, 2017 and April 30, 2022. A total of 76 infants were referred for diagnostic testing, 0.01% of the screened population. Of these, eight cases of MPS II were diagnosed for an incidence of 1 in 73,290. At least four of the eight cases detected had an attenuated phenotype. In addition, cascade testing revealed a diagnosis in four extended family members. Fifty-three cases of pseudodeficiency were also identified, for an incidence of 1 in 11,062. Our data suggest that MPS II may be more common than previously recognized with a higher prevalence of attenuated cases.

Clinical characteristics and genotypes of 201 patients with mucopolysaccharidosis type II in China: A retrospective, observational study.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal storage disease caused by a disease-associated variant in the IDS gene, which encodes iduronate 2-sulfatase (IDS). We aimed to characterize the clinical characteristics and genotypes of the largest cohort of Chinese patients with MPS II and so gain a deeper understanding of natural disease progression. Patients with confirmed MPS II and without treatment were included. The disease was classified as severe in patients with neurological impairment, and as attenuated in patients aged >6 years without neurological impairment. Of the 201 male patients, 78.1% had severe MPS II. Cognitive regression occurred before age 6 years in 94.3% of patients. Of 122 IDS variants identified, 37 were novel. Among the large gene alteration types identified, only the frequency of IDS-IDS2 recombination was significantly higher in severe versus attenuated MPS II (P = 0.032). Some identified point variants could inform the understanding of genotype-phenotype correlations. In conclusion, this study showed that classification of the disease as attenuated should only be made in patients aged >6 years. Our findings expand the understanding of the genotype-phenotype relationship, inform the diagnostic process, and provide an indication of the likely prognosis.

Transferrin Receptor-Targeted Iduronate-2-sulfatase Penetrates the Blood-Retinal Barrier and Improves Retinopathy in Mucopolysaccharidosis II Mice.

Mucopolysaccharidoses (MPSs) make up a group of lysosomal storage diseases characterized by the aberrant accumulation of glycosaminoglycans throughout the body. Patients with MPSs display various signs and symptoms, such as retinopathy, which is also observed in patients with MPS II. Unfortunately, retinal disorders in MPS II are resistant to conventional intravenous enzyme-replacement therapy because the blood-retinal barrier (BRB) impedes drug penetration. In this study, we show that a fusion protein, designated pabinafusp alfa, consisting of an antihuman transferrin receptor antibody and iduronate-2-sulfatase (IDS), crosses the BRB and reaches the retina in a murine model of MPS II. We found that retinal function, as assessed by electroretinography (ERG) in MPS II mice, deteriorated with age. Early intervention with repeated intravenous treatment of pabinafusp alfa decreased heparan sulfate deposition in the retina, optic nerve, and visual cortex, thus preserving or even improving the ERG response in MPS II mice. Histological analysis further revealed that pabinafusp alfa mitigated the loss of the photoreceptor layer observed in diseased mice. In contrast, recombinant nonfused IDS failed to reach the retina and hardly affected the retinal disease. These results support the hypothesis that transferrin receptor-targeted IDS can penetrate the BRB, thereby ameliorating retinal dysfunction in MPS II.

Retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome.

PURPOSE: To describe a case of retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome. METHODS: Fundus photography, total field electroretinogram, ultrasound, computerized visual field examination, biochemical examination and genetic testing were obtained. RESULTS: The fundus exam showed diffuse arteriolar attenuation, optic disc with regular contours, and pigment agglomerates like "bone spicules" in the middle periphery. Ultrasound examination revealed scleral thickening and short axial diameter in both eyes. The total field electroretinogram exam showed a subnormal result with greater impairment of the scotopic phase of the exam. Computerized visual field examination demonstrated a diffuse reduction in retinal sensitivity in the periphery. Biochemical examination showed increased urine glycosaminoglycan excretion and iduronate-2-sulphatase activity (IDS) deficiency in leukocytes, confirming the type II mucopolysaccharidosis. Molecular analysis revealed a novel missense mutation (p.A77D) in the IDS gene. CONCLUSION: The case report is about a patient presented an attenuated form of the syndrome, with no cognitive impairment. Ophthalmologic follow-up is still an important part of multidisciplinary treatment for Hunter's syndrome.

A Case of Mucopolysaccharidosis II Caused by a Novel Variant with Skin Linear Hyperpigmented Streaks along Blaschko's Lines.

We report a case of an eight-year-old boy with mucopolysaccharidosis (MPS) II with atypical skin lesions of hyperpigmented streaks along Blaschko's lines. This case presented with mild symptoms of MPS such as hepatosplenomegaly, joint stiffness, and quite mild bone deformity, which was the reason for the delay in diagnosis until the age of seven years. However, he showed an intellectual disability that did not meet the diagnostic criteria for an attenuated form of MPS II. Iduronate 2-sulfatase activity was reduced. Clinical exome sequencing of DNA from peripheral blood revealed a novel pathogenic missense variant (NM_000202.8(IDS_v001):c.703C>A, p.(Pro235Thr)) in the IDS gene, which was confirmed in the mother with a heterozygous state. His brownish skin lesions differed from the Mongolian blue spots or "pebbling" of the skin that are observed in MPS II.

A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II.

Pabinafusp alfa (JR-141) is a novel enzyme drug that crosses the blood-brain barrier by transcytosis via transferrin receptors. In order to establish its efficacy and safety, a multicenter, single-arm, open-label phase 2/3 clinical trial was conducted in 28 Japanese patients with mucopolysaccharidosis II (MPS-II, Hunter syndrome) by intravenous administrations of 2.0 mg/kg of pabinafusp alfa for 52 weeks. The primary efficacy endpoint was changes in heparan sulfate (HS) concentrations in the cerebrospinal fluid (CSF). Secondary endpoints included assessments of neurocognitive development for central efficacy, and changes in plasma HS and dermatan sulfate (DS) concentrations for peripheral efficacy. HS concentrations in the CSF significantly decreased from baseline to week 52 (p < 0.001), suggesting continuous inhibition of substrate accumulations in the CNS, i.e., hitherto unaddressed progressive neurodegeneration. Evaluations of neurocognitive developments showed positive changes in 21 of the 28 patients. Serum HS and DS concentrations, liver and spleen volumes, and other assessments suggested the peripheral efficacy of pabinafusp alfa was comparable to that of idursulfase. Drug-related adverse events were mild or moderate in severity, transient, and manageable. The results establish delivery across the BBB of pabinafusp alfa as an effective therapeutic for treating both the CNS and peripheral symptoms of patients with MPS-II.

[Clinical characteristics and analysis of IDS gene variant in a child with mucopolysaccharidosis type â ¡].

OBJECTIVE: To summarize the clinical features, laboratory examination and genetic analysis of a patient with mucopolysaccharidosis type Ⅱ (MPS Ⅱ). METHODS: Clinical manifestations, results of urine glycosaminoglycans (GAGs) and dermatan sulfate assay, metabolites related to MPS in peripheral blood leukocytes were analyzed. Meanwhile, the child and his mother were subjected to next-generation sequencing and Sanger sequencing. RESULTS: The boy has presented with global development delay, coarse facies, frequent upper-respiratory infections, hearing loss, indirect inguinal hernia, hepatosplenomegaly, and skeletal deformities. His urine GAGs were significantly elevated, and the urinary dermatan sulfate (DS) was positive. Meanwhile, the activity of idose-2-sulfatase was extremely reduced. The patient was found to harbor a hemizygote c.676C>G (p. His226Asp) missense variant in exon 5 of IDS gene, for which his mother was heterozygous. CONCLUSION: The novel c.676C>G variant of the IDS gene probably underlay the MPS Ⅱ in this child. Genetic testing combined with enzymatic analysis can enable effective diagnosis and classification of MPS.

[Genetic analysis and prenatal diagnosis of a Chinese pedigree affected with mucopolysaccharidosis type II due to deletion of exon 2 of IDS gene].

OBJECTIVE: To explore the genetic etiology of a patient with mucopolysaccharidosis type II (MPSII). METHODS: The IDS gene of the proband and his mother was detected by Sanger sequencing, agarose gel electrophoresis, real-time PCR and multiple ligation-dependent probe amplification (MLPA). Prenatal diagnosis was performed on amniotic fluid sample. RESULTS: Agarose gel electrophoresis, real-time PCR, and MLPA all showed that exon 2 of IDS gene of the proband was deleted, for which his mother was normal. Prenatal diagnosis showed that the fetus was a normal male. CONCLUSION: The de novo deletion of exon 2 of the IDS gene probably underlay the MPSII in this patient. Above finding has broadened the mutation spectrum of the IDS gene. The combined methods for the detection of IDS gene mutations could make accurate prenatal diagnosis for MPSII.

[The combination of recurrent otitis media and adenotomy in early childhood as diagnostic marker of mucopolysaccharidosis type II (Hunter syndrome)]. / Sochetanie retsidiviruyushchego srednego otita i adenotomii v rannem detskom vozraste kak diagnosticheskii marker mukopolisakharidoza II tipa (sindroma Khantera).

Mucopolysaccharidoses are a group of rare lysosomal accumulation diseases caused by a deficiency of the lysosomal enzyme and the accumulation of mucopolysaccharides in various organs and tissues. Children with mucopolysaccharidosis type II (Hunter syndrome) develop multisystem dysfunction, including severe airway obstruction. At the same time, 34% of patients already at an early age (2-3 years) undergo surgical manipulations related to ENT organs (tonsillectomy, adenotomy). The article describes a clinical case of diagnosis of type II mucopolysaccharidosis by a pediatric otorhinolaryngologist. The main manifestations of the disease are discussed in detail, including the presence of indications for adenotomy at the age of 2 years, episodes of otitis media, which served as diagnostic markers for suspected orphan disease mucopolysaccharidosis type II. The leading role of the pediatric otorhinolaryngologist in the early diagnosis of the rare disease mucopolysaccharidosis type II is substantiated.

Clinical assessment of upper airway and its complications in Hunter syndrome.

BACKGROUND: Hunter syndrome (HS) is an X-linked, recessive, lysosomal storage disease caused by a deficiency of the lysosomal enzyme, iduronate sulfatase (IDS). It is characterized by multisystem accumulations of glycosaminoglycans and upper airway obstruction is one of the major causes of death. While the current disease severity classifications for HS are mainly based on the degree of neurocognitive impairment, its association with the level of upper airway obstruction has not been assessed. METHODS: A retrospective chart review of HS patients who were followed at the Jikei University School of Medicine was performed. Association between the degree of airway obstruction and the currently used disease severity scores was evaluated. RESULTS: We identified eight HS patients and they were enrolled in the study. The Modified Mallampati classification (MMC) score, used to predict difficulties for oropharyngeal procedures, was significantly correlated with the HS severity. It was also correlated with the Apnea-Hypopnea Index (AHI). No significant correlation between IDS enzymatic activity and the severity of HS disease was identified. CONCLUSIONS: Variable clinical expressivities exist in HS, but the risk of respiratory complications is likely to be associated with disease severity, assessed by the previously recognized neurocognitive function-based severity scoring systems. MMC can be a simple supplementary tool to evaluate disease severity as well as predict difficulties for oropharyngeal procedures and respiratory function complications in HS, such as sleep apnea.

Severe central airway stenosis and tracheomalacia in hunter syndrome.

Hunter Syndrome is a genetic disease characterized by deficiency of Iduronate-2-Sulfatase enzyme activity, resulting in accumulation of glycoaminoglycans in various organs including the central airways. We report a case of severe tracheomalacia and airway stenosis at Hospital Sultanah Aminah, Johor Bahru, Malaysia requiring mechanical ventilation in a middle aged gentleman who was previously undiagnosed of mucopolysaccharidosis. The patient underwent emergency tracheostomy for failed intubation, when he presented with shortness of breath and acute respiratory failure. A contrast-enhanced computed tomography of the neck and thorax revealed that the trachea distal to the tracheostomy tube had collapsed with narrowed right and left main bronchus. These findings were confirmed via direct visualization of the airway through a flexible bronchoscopy. Eventually, a tracheal stenting were performed to maintain the airway patency and assist in weaning off from mechanical ventilation. Further investigations to identify the aetiology of the central airway stenosis revealed elevated urinary glycoaminoglycans and the absence of iduronate-2-Sulfatase activity tested on dried blood spots, thus confirming the diagnosis of Hunter Syndrome. Managing mucopolysacharidosis with central airway obstruction requires multidisciplinary team effort in handling the difficult airway, anaesthesiology risk, potential comorbidities and providing genetic counselling.

Treatment of mucopolysaccharidosis type II (Hunter syndrome): a Delphi derived practice resource of the American College of Medical Genetics and Genomics (ACMG).

Mucopolysaccharidosis, type II (MPS II, MIM 309900) is a severe lysosomal storage disease with multisystem involvement. There is one product approved by the FDA, an enzyme replacement therapy, based on a phase III trial in older, attenuated MPS II individuals. Guidance on treatment of MPS II is lacking, not only in general, but for specific clinical situations. A previous systematic evidence-based review of treatment for MPS II demonstrated insufficient strength in all data analyzed to create a definitive practice guideline based solely on published evidence. The American College of Medical Genetics and Genomics (ACMG) Therapeutics Committee conducted a Delphi study to generate an MPS II clinical practice resource of the treatment for these individuals for the genetics community, based on the evidence-based review and subsequent literature. This report describes the process, including consensus development and areas where consensus could not be obtained due to lack of quality evidence. Recommendations from the Delphi process were generated, and areas were highlighted that need further study to help guide clinical care of these individuals.

The mutational spectrum of hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients.

BACKGROUND: Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs). METHODS: A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material. RESULTS: All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients. Five previously reported mutations were identified in this study patients: one splice site mutation, c.240 + 1G > A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C > T (p.T214M), c.438 C > T (p.T146T), c.709-87G > A, and c.1006 + 38 T > C. CONCLUSIONS: The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients' phenotypic classification and the detection of carriers.

Treatable lysosomal storage diseases in the advent of disease-specific therapy.

Lysosomal storage diseases (LSD) comprise a rare and heterogeneous group of nearly 50 heritable metabolic disorders caused by mutations in proteins critical for cellular lysosomal function. Defects in the activity of these proteins in multiple organs leads to progressive intra-lysosomal accumulation of specific substrates, resulting in disruption of cellular functions, extracellular inflammatory responses, tissue damage and organ dysfunction. The classification and clinical presentation of different LSD are dependent on the type of accumulated substrate. Some clinical signs and symptoms are common across multiple LSD, while others are more specific to a particular syndrome. Due to the rarity and wide clinical diversity of LSD, identification and diagnosis can be challenging, and in many cases diagnosis is delayed for months or years. Treatments, such as enzyme replacement therapy, haemopoietic stem cell transplantation and substrate reduction therapy, are now available for some of the LSD. For maximum effect, therapy must be initiated prior to the occurrence of irreversible tissue damage, highlighting the importance of prompt diagnosis. Herein, we discuss the clinical presentation, diagnosis and treatment of four of the treatable LSD: Gaucher disease, Fabry disease, Pompe disease, and two of the mucopolysaccharidoses (I and II). For each disease, we present illustrative case studies to help increase awareness of their clinical presentation and possible treatment outcomes.

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) was first described by Dr. Charles Hunter in 1917. Since then, about one hundred years have passed and Hunter syndrome, although at first neglected for a few decades and afterwards mistaken for a long time for the similar disorder Hurler syndrome, has been clearly distinguished as a specific disease since 1978, when the distinct genetic causes of the two disorders were finally identified. MPS II is a rare genetic disorder, recently described as presenting an incidence rate ranging from 0.38 to 1.09 per 100,000 live male births, and it is the only X-linked-inherited mucopolysaccharidosis. The complex disease is due to a deficit of the lysosomal hydrolase iduronate 2-sulphatase, which is a crucial enzyme in the stepwise degradation of heparan and dermatan sulphate. This contributes to a heavy clinical phenotype involving most organ-systems, including the brain, in at least two-thirds of cases. In this review, we will summarize the history of the disease during this century through clinical and laboratory evaluations that allowed its definition, its correct diagnosis, a partial comprehension of its pathogenesis, and the proposition of therapeutic protocols. We will also highlight the main open issues related to the possible inclusion of MPS II in newborn screenings, the comprehension of brain pathogenesis, and treatment of the neurological compartment.

High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Quantification of Glycosaminoglycans as Biomarkers of Mucopolysaccharidosis II.

We recently developed a blood-brain barrier (BBB)-penetrating enzyme transport vehicle (ETV) fused to the lysosomal enzyme iduronate 2-sulfatase (ETV:IDS) and demonstrated its ability to reduce glycosaminoglycan (GAG) accumulation in the brains of a mouse model of mucopolysaccharidosis (MPS) II. To accurately quantify GAGs, we developed a plate-based high-throughput enzymatic digestion assay coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to simultaneously measure heparan sulfate and dermatan sulfate derived disaccharides in tissue, cerebrospinal fluid (CSF) and individual cell populations isolated from mouse brain. The method offers ultra-high sensitivity enabling quantitation of specific GAG species in as low as 100,000 isolated neurons and a low volume of CSF. With an LOD at 3 ng/mL and LLOQs at 5-10 ng/mL, this method is at least five times more sensitive than previously reported approaches. Our analysis demonstrated that the accumulation of CSF and brain GAGs are in good correlation, supporting the potential use of CSF GAGs as a surrogate biomarker for brain GAGs. The bioanalytical method was qualified through the generation of standard curves in matrix for preclinical studies of CSF, demonstrating the feasibility of this assay for evaluating therapeutic effects of ETV:IDS in future studies and applications in a wide variety of MPS disorders.

Case report: a rare case of Hunter syndrome (type II mucopolysaccharidosis) in a girl.

BACKGROUND: Hunter syndrome (mucopolysaccharidosis type II) is a recessive X-linked disorder due to mutations in the iduronate 2-sulfatase (IDS) gene. The IDS gene encodes a lysosomal enzyme, iduronate 2-sulfatase. The disease occurs almost exclusively in males. However, in the literature, 12 cases of the disease in females are known due to structural anomalies, a non-random chromosome X inactivation or chromosome X monosomy. The purpose of this article is to demonstrate a rare case of Hunter syndrome in a girl caused by a mutation in the IDS gene inherited from the mother and the presence of chromosome X of paternal origin, partially deleted in the long arm region - 46,X,del(X)(q22.1). CASE PRESENTATION: Girl M., 4 years old, entered the hospital with growth retardation, pain in the lower limbs, and joint stiffness, noted from the age of 18 months. After the karyotype analysis, which revealed a partial deletion of the long arm of chromosome X - 46, X, del (X) (q 22.1), Turner syndrome was diagnosed. However, due to the hurler-like facial phenotype, Hurler syndrome or type I mucopolysaccharidosis (MPS) was suspected. The study of lysosomal enzymes showed normal alpha-L-iduronidase activity and a sharp decrease in the activity of iduronate sulfatase in the blood: 0.001 µM/l/h, at a rate of 2.5-50 µM/l/h. Molecular genetic analysis revealed a hemizygous deletion in the IDS gene, which was not registered in the international Human Gene Mutation Database (HGMD) professional. This deletion was not detected in the girl's father, but was detected in her mother in the heterozygous state. CONCLUSIONS: Thus, the girl confirmed comorbidity - Turner syndrome with a partial deletion of the long arm of chromosome X of paternal origin, affecting the Xq28 region (localization of the IDS gene), and Hunter syndrome due to a deletion of the IDS gene inherited from the mother. The structural defect of chromosome X in the girl confirmed the hemizygous state due to the mutation in the IDS gene, which has led to the formation of the clinical phenotype of Hunter syndrome.

Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience.

OBJECTIVES: To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois. STUDY DESIGN: Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. RESULTS: One case of MPS II and 14 infants with pseudodeficiency for I2S were identified. CONCLUSIONS: Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois.

Taiwan National Newborn Screening Program by Tandem Mass Spectrometry for Mucopolysaccharidoses Types I, II, and VI.

OBJECTIVE: To evaluate the initial cutoff values, rates of screen positives, and genotypes for the large-scale newborn screening program for multiple mucopolysaccharidoses (MPS) in Taiwan. STUDY DESIGN: More than 100 000 dried blood spots were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry from dried blood spot punches. Genotypes were obtained when a second newborn screening specimen again had a decreased enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. RESULTS: Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic alpha-L-iduronidase mutations, 3 newborns with pathogenic iduronate-2-sulfatase mutations, and 1 newborn was a carrier of an arylsulfatase B mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. CONCLUSIONS: The highly robust tandem mass spectrometry-based enzyme assays for MPS-I, MPS-II, and MPS-VI allow for high-throughput newborn screening for these lysosomal storage disorders. Optimized cutoff values combined with second tier testing could largely eliminate false-positive results. Accordingly, newborn screening for these lysosomal storage disorders is possible.