Newborn screening and diagnosis of mucopolysaccharidoses

Abstract

Mucopolysaccharidoses (MPS) are caused by deficiency of lysosomal enzyme activities needed to degrade glycosaminoglycans (GAGs), which are long unbranched polysaccharides consisting of repeating disaccharides. GAGs include: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronan. Their catabolism may be blocked singly or in combination depending on the specific enzyme deficiency. There are 11 known enzyme deficiencies, resulting in seven distinct forms of MPS with a collective incidence of higher than 1 in 25,000 live births. Accumulation of undegraded metabolites in lysosomes gives rise to distinct clinical syndromes. Generally, the clinical conditions progress if untreated, leading to developmental delay, systemic skeletal deformities, and early death. MPS disorders are potentially treatable with enzyme replacement therapy or hematopoietic stem cell transplantation. For maximum benefit of available therapies, early detection and intervention are critical. We recently developed a novel high-throughput multiplex method to assay DS, HS, and KS simultaneously in blood samples by using high performance liquid chromatography/tandem mass spectrometry for MPS. The overall performance metrics of HS and DS values on MPS I, II, and VII patients vs. healthy controls at newborns were as follows using a given set of cut-off values: sensitivity, 100%; specificity, 98.5-99.4%; positive predictive value, 54.5-75%; false positive rate, 0.62-1.54%; and false negative rate, 0%. These findings show that the combined measurements of these three GAGs are sensitive and specific for detecting all types of MPS with acceptable false

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

“…Total KS level in the plasma/serum can be used as a biomarker for MPS IVA (Tomatsu et al , 2010c(Tomatsu et al , 2012b(Tomatsu et al , 2013aHintze et al 2011;Martell et al 2011); however, there are substantial overlaps of KS values between control subjects and MPS IVA patients, especially for patients older than 15 years of age, and consequently total KS alone is not a good biomarker for MPS IVA patients of all ages. GALNS, an enzyme involved in the first step of degradation of polymer KS, hydrolyzes the C (6) sulfate of Gal from di-sulfated KS, Gal(6S)b1 !…”

“…4GlcNAc (6S). Gel permeation chromatography (GPC)-HPLC study showed that 60 % of KS-I was digested with keratanase II (Tomatsu et al 2013a. Di-sulfated KS (L4; 20 mg/ml), polymer KS (20 mg/ml), and chondrosine for internal standard (IS) (1 mg/ml) supplied by Seikagaku Co. were prepared separately in ddH 2 O.…”

“…Patients with a classic (severe) form of MPS IVA have a unique systemic skeletal dysplasia including short-trunk dwarfism, kyphoscoliosis, coxa valga, odontoid hypoplasia, abnormal gait, joint mobility problems, restriction of chest wall movement, and a life span of 20-30 years if an appropriate orthopedic intervention is unavailable. Patients with an attenuated form have a milder skeletal involvement, and most have normal life span (Dũng et al 2013;Yasuda et al 2013;Tomatsu et al 2011Tomatsu et al , 2012aTomatsu et al , 2013aNorthover et al 1996;Montaño et al 2007Montaño et al , 2008Suzuki et al 2001;Hendriksz et al 2013;M€ ollmann et al 2013;Harmatz et al 2013). Patients with MPS IVB show a milder phenotype of skeletal dysplasia than patients with the severe form of MPS IVA.…”

“…KS levels in blood and urine in patients with MPS IVA are associated with age and clinical severity (Tomatsu et al 2010c) and are decreased with enzyme replacement therapy (ERT) on mouse model and bone marrow transplantation (BMT) in a patient with MPS IVA Chinen et al 2014). Thus, KS levels in the blood and/or urine should be a suitable biomarker for early diagnosis, screening, clinical severity, and therapeutic efficacy in MPS IVA (Tomatsu et al , 2010c(Tomatsu et al , 2013a. However, there is significant overlap of KS levels between age-matched controls and patients with MPS IVA, especially in patients older than 10 years of age, suggesting that better biomarkers or methodology for MPS IVA are needed (Tomatsu et al 2010c).…”

Avaliação neurológica e de neuroimagem em pacientes com mucopolissacaridoses

“…Nas MPSs, o depósito intracelular das GAGs ocorre na maioria das células, ocasionando disfunções celulares e teciduais nos diferentes órgãos (Muenzer 2004). O catabolismo das GAGs pode ser bloqueado isoladamente ou em combinações, podendo ocorrer o acumulo das seguintes GAGs: dermatan sulfato (DS), heparan sulfato (HS), queratan sulfato (QS), e o acido hialurônico (Tomatsu et al 2013). …”