Abstract
Glycogen storage disease type II (also known as Pompe disease (PD)) is an autosomal recessive disorder caused by defects in α-glucosidase (AαGlu), resulting in lysosomal glycogen accumulation in skeletal and heart muscles. Accumulation and tissue damage rates depend on residual enzyme activity. Enzyme replacement therapy (ERT) should be started before symptoms are apparent in order to achieve optimal outcomes. Early initiation of ERT in infantile-onset PD improves survival, reduces the need for ventilation, results in earlier independent walking, and enhances patient quality of life. Newborn screening (NBS) is the optimal approach for early diagnosis and treatment of PD. In NBS for PD, measurement of AαGlu enzyme activity in dried blood spots (DBSs) is conducted using fluorometry, tandem mass spectrometry, or digital microfluidic fluorometry. The presence of pseudodeficiency alleles, which are frequent in Asian populations, interferes with NBS for PD, and current NBS systems cannot discriminate between pseudodeficiency and cases with PD or potential PD. The combination of GAA gene analysis with NBS is essential for definitive diagnoses of PD. In this review, we introduce our experiences and discuss NBS programs for PD implemented in various countries.
Highlights
Glycogen storage disease type II (OMIM 232300), known as Pompe disease (PD), is an autosomal recessive disorder caused by a defect in α-glucosidase (AαGlu; EC 3.2.1.20/3), resulting in the accumulation of lysosomal glycogen in skeletal and heart muscles [1]
A pseudodeficiency allele is a change in the GAA gene sequence that results in AαGlu enzyme activity reduction, but is not enough to cause PD [21,22]
A full-population pilot study of 43,701 newborns using dried blood spots (DBSs) in a multiplex fluorometric enzymatic assay for detecting PD, FD, GD, and MPSI was performed in Missouri on January 11, 2013 [41]
Summary
Glycogen storage disease type II (OMIM 232300), known as Pompe disease (PD), is an autosomal recessive disorder caused by a defect in α-glucosidase (AαGlu; EC 3.2.1.20/3), resulting in the accumulation of lysosomal glycogen in skeletal and heart muscles [1]. Newborn screening (NBS) is an optimal approach for early diagnosis and treatment of IOPD. We describe NBS programs for PD, the diagnostic algorithm for PD, AαGlu enzyme assays using dried blood spots (DBSs) and fibroblasts, GAA gene analysis, and pseudodeficiency in GAA. N2.BNS BPSroPgrroagmrafmorfPoDr PD NBNS BfoSrfPoDr PiDs ciusrcruenrrtelyntplyerpfoerrmfoermd eind TinaiTwaaiwn,aJna,pJaanp,aann, dansdevseervaelrsatlatsetastiens tihnethUenUitenditeSdtaStetastoefs of AmAemriceari(cUa S(UAS).AC)u. A definitive diagnosis of PD is achieved in patients harboring two known pathogenic GAA variants with decreased AαGlu activity in the blood (leukocytes, DBSs, isolated lymphocytes) or. PPaattiieennttss wwiitthh LLOOPPDD ddeeffiinniittiivveellyy ddiiaaggnnoosseedd bbyy GGAAAA ggeennee aannaallyyssiiss wwiillll nneeeedd ttoo bbee rreegguullaarrllyy ffoolllloowweedd uupp ffoorr tthhee ddeevveellooppmmeenntt ooff ssiiggnnss oorr ssyymmppttoommss rreellaatteedd ttoo PPDD,, eevveenn iiff tthheeiirr GGAAAA ggeennee vvaarriiaannttss aarree kknnoowwnn,, bbeeccaauusseetthheerreeisisccoonnsisdiderearbalbelevavraiaritaiotinoinnihnohwowanadnwdhwenhepnatpieanttisenwtsillwpirlel spernetsseynmt spytommpst.oPmasti.ePntastiwenitths wonitehoornne oorknnoowknnowvanrivaanrtisanetxsheibxhitiibnigtindgecdreecarseeadseedneznyzmyamtiactiaccaticvtiitvyityshsohuoludldrerceecieviveeaadddditiitoionnaalltteessttss,, iinncclluuddiinngg pphhyyssiiccaall eexxaammiinnaattiioonnss,, ccaarrddiiaacc eevvaalluuaattiioonnss,, AAααGGlluu aaccttiivviittyy aassssaayyss iinn fifibbrroobbllaassttss,, uurriinnaarryy gglluuccootteettrraassaacccchhaarriiddee ((HHEEXX44)) aanndd bblloooodd ccrreeaattiinnee kkiinnaassee((CCKK))aannaallyysseess,,aanndd//oorrppaarreennttaallDDNNAAaannaallyysseess.
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