Spondyloepiphyseal Dysplasias and Bilateral Legg-Calvé-Perthes Disease: Diagnostic Considerations for Mucopolysaccharidoses

Mendelsohn, Nancy J.; Wood, Timothy C.; Olson, Rebecca; Temme, Renee; Hale, Susan; Zhang, Haoyue; Read, Lisa; White, Klane K.

doi:10.1007/8904_2013_231

Cited by 23 publications

(21 citation statements)

References 30 publications

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“…Neurologic function is typically not affected. The age of onset is often in early childhood but milder variants may present in adolescence (Mendelsohn et al 2013). Recently, enzyme replacement therapy with recombinant human N-acetyl-galactosamine-6-sulfatase (rhGALNS, elosulfase alfa) for the treatment of MPS IVA (Lyseng-Williamson 2014) has been approved by the Food and Drug Administration.…”

Section: Introductionmentioning

confidence: 99%

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

et al. 2016

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Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n ¼ 9), MPS II (n ¼ 13), MPS III (n ¼ 23), MPS VI (n ¼ 7), betagalactosidase deficiency (n ¼ 7), mucolipidosis (ML) type II, II/III and III (n ¼ 51), alpha-mannosidosis (n ¼ 11), fucosidosis (n ¼ 4), sialidosis (n ¼ 5), Pompe disease (n ¼ 3), aspartylglucosaminuria (n ¼ 4), and galactosialidosis (n ¼ 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.

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Section: Introductionmentioning

confidence: 99%

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

et al. 2016

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“…Although patients of non-classical phenotype may not have the typical, pronounced manifestations that would lead to a clinical suspicion of a MPS disease [23-25], awareness of the unique and distinguishing features of orthopedic diseases may contribute to earlier diagnosis of Morquio A. There are subtle radiographic differences between Morquio A (Figure 2a-d) and other skeletal dysplasia, such as pseudoachondroplasia (Figure 3a-d) and SED (image not shown), which could help clinicians distinguish between these diagnoses.…”

Section: Discussionmentioning

confidence: 99%

Overcoming the barriers to diagnosis of Morquio A syndrome

Bhattacharya

Balasubramaniam

Fietz

et al. 2014

Orphanet J Rare Dis

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BackgroundMorquio A syndrome is an autosomal recessive lysosomal storage disease often resulting in life-threatening complications. Early recognition and proficient diagnosis is imperative to facilitate prompt treatment and prevention of clinical complications.MethodsExperts in Asia Pacific reviewed medical records focusing on presenting signs and symptoms leading to a diagnosis of Morquio A syndrome.ResultsEighteen patients (77% female) had a mean (median; min, max) age of 77.1 (42.0; 0.0, 540.0) months at symptom onset, 78.9 (42.0; 4.5, 540.0) months at presentation and 113.8 (60.0; 7.0, 540.0) months at diagnosis. Orthopedic surgeons and pediatricians were most frequently consulted pre-diagnosis while clinical geneticists/metabolic specialists most frequently made the diagnosis. Delayed diagnoses were due to atypical symptoms for 5 patients (28%), while 4 patients (22%) experienced each of subtle symptoms, symptoms commonly associated with other diseases, or false-negative urine glycosaminoglycan analysis. Two patients (11%) each experienced overgrowth within the first year of life. Two patients with Morquio A syndrome (11%) were diagnosed with craniosynostosis and 1 (6%) for each of Legg-Calvé-Perthes disease, Leri-Weill syndrome, and pseudoachondroplasia. Early radiographic features of Morquio A syndrome led to more efficient diagnosis.ConclusionsIncreased awareness of clinical symptomology overlapping with Morquio A syndrome is essential. Clinicians encountering patients with certain skeletal dysplasia should consider Morquio A syndrome in their differential diagnosis. Atypical or subtle symptoms should not eliminate Morquio A syndrome from the differential diagnosis, especially for patients who may have non-classical phenotype of Morquio A syndrome.

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“…Age at diagnosis (reported in 172 individuals) ranged from <1 year to 45 years of age, with a mean of 7.8 years and median of 5.0 years. Two patients, both with an older affected sibling, were diagnosed at birth (Furujo, Kubo, Kosuga, & Okuyama, ; Mendelsohn et al., ). Approximately one‐third (31.7%) of unique variants appeared only once in the population assessed, with an additional 28.5% appearing twice.…”

Section: Variantsmentioning

confidence: 99%

“…As such, patients with the p.(Tyr210Cys) mutation generally exhibit a non‐classical, slowly progressing form of MPS VI, and the p.(Tyr210Cys) mutation may reduce the severity of other ARSB pathogenic variants when present in a compound heterozygous state (Bradford et al., ; Brands et al., ; Litjens, Brooks, Peters, Gibson, & Hopwood, ; Saito et al., ). Interestingly, this allele has only been reported in a homozygous state twice (Gottwald et al., ; Mendelsohn et al., ), despite having a relatively high allele frequency reported in the Genome Aggregation Database (gnomAD; gnomad.broadinstitute.org, accessed October 26, 2017), a large population database. Both individuals had a non‐classical form of the disease (Gottwald et al., ; Mendelsohn et al., ).…”

Section: Variantsmentioning

confidence: 99%

“…Interestingly, this allele has only been reported in a homozygous state twice (Gottwald et al., ; Mendelsohn et al., ), despite having a relatively high allele frequency reported in the Genome Aggregation Database (gnomAD; gnomad.broadinstitute.org, accessed October 26, 2017), a large population database. Both individuals had a non‐classical form of the disease (Gottwald et al., ; Mendelsohn et al., ).…”

Section: Variantsmentioning

confidence: 99%

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Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in theARSBgene

et al. 2018

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Maroteaux–Lamy syndrome (MPS VI) is an autosomal recessive lysosomal storage disorder caused by pathogenic ARSB gene variants, commonly diagnosed through clinical findings and deficiency of the arylsulfatase B (ASB) enzyme. Detection of ARSB pathogenic variants can independently confirm diagnosis and render genetic counseling possible. In this review, we collect and summarize 908 alleles (201 distinct variants, including 3 polymorphisms previously considered as disease‐causing variants) from 478 individuals diagnosed with MPS VI, identified from literature and public databases. Each variant is further analyzed for clinical classification according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results highlight the heterogeneity of ARSB alleles, with most unique variants (59.5%) identified as missense and 31.7% of unique alleles appearing once. Only 18% of distinct variants were previously recorded in public databases with supporting evidence and clinical significance. ACMG recommends publishing clinical and biochemical data that accurately characterize pathogenicity of new variants in association with reporting specific alleles. Variants analyzed were sent to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and MPS VI locus‐specific database (http://mps6-database.org) where they will be available. High clinical suspicion coupled with diagnostic testing for deficient ASB activity and timely submission and classification of ARSB variants with biochemical and clinical data in public databases is essential for timely diagnosis of MPS VI.

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Spondyloepiphyseal Dysplasias and Bilateral Legg-Calvé-Perthes Disease: Diagnostic Considerations for Mucopolysaccharidoses

Abstract: Mucopolysaccharidosis type VI

Cited by 23 publications

References 30 publications

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

Overcoming the barriers to diagnosis of Morquio A syndrome

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in theARSBgene

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