Table Of ContentJohannes Zschocke
Matthias Baumgartner
Eva Morava
Marc Patterson
Shamima Rahman
Verena Peters Editors
JIMD Repor ts
Volume 22
JIMD Reports
Volume 22
.
Johannes Zschocke
Editor-in-Chief
Matthias Baumgartner Eva Morava
(cid:129) (cid:129)
Marc Patterson Shamima Rahman
(cid:129)
Editors
Verena Peters
Managing Editor
JIMD Reports
Volume 22
Editor-in-Chief Editor
JohannesZschocke MarcPatterson
DivisionofHumanGenetics DivisionofChildandAdolescent
MedicalUniversityInnsbruck Neurology
Innsbruck MayoClinic
Austria Rochester
Minnesota
Editor USA
MatthiasBaumgartner
DivisionofMetabolismandChildren’sResearchCentre Editor
UniversityChildren’sHospitalZurich ShamimaRahman
Zurich ClinicalandMolecularGeneticsUnit
Switzerland UCLInstituteofChildHealth
London
Editor UK
EvaMorava
TulaneUniversityMedicalSchool ManagingEditor
NewOrleans VerenaPeters
Louisiana CenterforChildandAdolescent
USA Medicine
HeidelbergUniversityHospital
Heidelberg
Germany
ISSN2192-8304 ISSN2192-8312 (electronic)
JIMDReports
ISBN978-3-662-47452-5 ISBN978-3-662-47453-2 (eBook)
DOI10.1007/978-3-662-47453-2
SpringerHeidelbergNewYorkDordrechtLondon
#SSIEMandSpringer-VerlagBerlinHeidelberg2015
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Contents
InnateandAdaptiveImmuneResponseinFabryDisease ...................... 1
WladimirMauhin,OlivierLidove,ElisaMasat,FedericoMingozzi,
KuberakaMariampillai,Jean-MarcZiza,andOlivierBenveniste
AsparagineSynthetaseDeficiency:NewInbornErrorsofMetabolism ........... 11
MajidAlfadhel,MuhammadTalalAlrifai,DanielTrujillano,HeshamAlshaalan,
AliAlOthaim,ShathaAlRasheed,HussamAssiri,AbdulrhmanA.Alqahtani,
ManalAlaamery,ArndtRolfs,andWafaaEyaid
OccurrenceofMalignantTumoursintheAcuteHepaticPorphyrias ............ 17
Estefan´ıaLang,MartinScha¨fer,HolgerSchwender,NorbertJ.Neumann,
andJorgeFrank
ImprovementinBoneMineralDensityandArchitectureinaPatientwith
GaucherDiseaseUsingTeriparatide...................................... 23
AnealKhan,DavidA.Hanley,ColleenMcNeil,andStevenBoyd
NetworkingAcrossBordersforIndividualswithOrganicAciduriasand
UreaCycleDisorders:TheE-IMDConsortium ............................. 29
StefanKo¨lker,DriesDobbelaere,JohannesHa¨berle,PeterBurgard,FlorianGleich,
MarshallL.Summar,StevenHannigan,SamanthaParker,AnupamChakrapani,
andMatthiasR.BaumgartneronBehalfoftheE-IMDConsortium
TwoNovelMutationsintheSLC25A4GeneinaPatientwithMitochondrial
Myopathy ........................................................... 39
I.M.L.W.Ko¨rver-Keularts,M.deVisser,H.D.Bakker,R.J.A.Wanders,F.Vansenne,
H.R.Scholte,L.Dorland,G.A.F.Nicolaes,L.M.J.Spaapen,H.J.M.Smeets,
A.T.M.Hendrickx,andB.J.C.vandenBosch
CombinedSepiapterinReductaseandMethylmalonyl-CoAEpimeraseDeficiency
inaSecondPatient:CerebrospinalFluidPolyunsaturatedFattyAcidLeveland
Follow-UpUnderL-DOPA,5-HTPandBH4Trials .......................... 47
MichelMazzuca,Marie-AnneMaubert,Le´naDamaj,FabienneClot,
Maryle`neCadoudal,ChristeleDubourg,SylvieOdent,JeanFranc¸oisBenoit,
NadiaBahi-Buisson,LaurenceChrista,andPascaledeLonlay
AuditoftheUseofRegularHaemArginateInfusionsinPatientswithAcute
PorphyriatoPreventRecurrentSymptoms ................................ 57
JoanneT.Marsden,SimonGuppy,PenelopeStein,TimothyM.Cox,
MichaelBadminton,TriciaGardiner,JulianH.Barth,M.FelicityStewart,
andDavidC.Rees
v
vi Contents
NormalCerebrospinalFluidPyridoxal50-PhosphateLevelinaPNPO-Deficient
PatientwithNeonatal-OnsetEpilepticEncephalopathy ....................... 67
AlinaLevtova,StephaneCamuzeaux,Anne-MarieLaberge,PierreAllard,
CatherineBrunel-Guitton, PaolaDiadori,ElsaRossignol,KeithHyland,
PeterT.Clayton,PhilippaB.Mills,andGrantA.Mitchell
BladderandBowelDysfunctionIsCommoninBothMenandWomenwith
MutationoftheABCD1GeneforX-LinkedAdrenoleukodystrophy............. 77
JohannHofereiter,MatthewD.Smith,JaiSeth,KatarinaIvanaTudor,ZoeFox,
AntonEmmanuel,ElaineMurphy,RobinH.Lachmann,andJaleshPanicker
ExtremeContrastofPostprandialRemnant-LikeParticlesFormedin
AbetalipoproteinemiaandHomozygousFamilialHypobetalipoproteinemia....... 85
Masa-akiKawashiri,HayatoTada,MarowaHashimoto,MatsuoTaniyama,
TakamitsuNakano,KatsuyukiNakajima,TakeshiInoue,MikaMori,
ChiakiNakanishi,TetsuoKonno,KenshiHayashi,AtsushiNohara,AkihiroInazu,
JunjiKoizumi,HirotakaIshihara,JunjiKobayashi,TsutomuHirano,HiroshiMabuchi,
andMasakazuYamagishi
GirlswithSeizuresDuetothec.320A>GVariantinALG13DoNotShow
AbnormalGlycosylationPatternonStandardTesting........................ 95
BethannySmith-Packard,ScottM.Myers,andMarcS.Williams
MonitoringofTherapyforMucopolysaccharidosisTypeIUsing
DysmorphometricFacialPhenotypicSignatures............................. 99
StefanieKung,MarkWalters,PeterClaes,PeterLeSouef,JackGoldblatt,
AndrewMartin,ShantiBalasubramaniam,andGarethBaynam
AgeatFirstCardiacSymptomsinFabryDisease:AssociationwithaChinese
HotspotFabryMutation(IVS4+919G>A),ClassicalFabryMutations,andSex
inaTaiwanesePopulationfromtheFabryOutcomeSurvey(FOS) ............. 107
Hao-ChuanLiu,AmandinePerrin,Ting-RongHsu,Chia-FengYang,Hsiang-YuLin,
Wen-ChungYu,andDau-MingNiu
MitochondrialComplexIIIDeficiencyCausedbyTTC19Defects:Report
ofaNovelMutationandReviewofLiterature ............................. 115
AnnaArdissone,TizianaGranata,AndreaLegati,DariaDiodato,LauraMelchionda,
EleonoraLamantea,BarbaraGaravaglia,DanieleGhezzi,andIsabellaMoroni
JIMDReports
DOI10.1007/8904_2014_371
RESEARCH REPORT
Innate and Adaptive Immune Response in Fabry Disease
Wladimir Mauhin(cid:129)Olivier Lidove(cid:129)Elisa Masat(cid:129)
Federico Mingozzi(cid:129)Kuberaka Mariampillai(cid:129)
Jean-Marc Ziza(cid:129)Olivier Benveniste
Received:05May2014/Revised:18September2014/Accepted:30September2014/Publishedonline:18February2015
#SSIEMandSpringer-VerlagBerlinHeidelberg2015
Abstract Fabry disease is an X-linked lysosomal storage immune responses observed in the treatment of naive
disease in which mutations of the gene (GLA) cause a patients and during enzyme replacement therapy with
deficiency of the lysosomal hydrolase a-galactosidase A agalsidase. We propose a comprehensive review of the
(a-Gal). This defect results in an accumulation of glyco- available literature concerning both innate and adaptive
sphingolipids, primarily globotriaosylceramide (Gb3) responses observed in Fabry disease. We particularly
whichcausesamultisystemicvasculopathy.Availablesince highlight the probable role of the toll-like receptor 4
2001 in Europe, enzyme replacement therapy consists in (TLR4) and CD1d pathways triggered by Gb3 accumula-
the administration of agalsidase, a recombinant form of tioninthedevelopmentoflocalandsystemicinflammation
a-galactosidaseA.Enzymereplacementtherapywasshown that could lead to irreversible organ damages. We propose
toimprovetheglobalprognosisbutallowedpartialsuccess an immunological point of view of Fabry disease patho-
in preventing critical events such as strokes and cardiac genesis involving immune cells notably the invariant
arrests. As in most lysosomal storage diseases, frequent natural killer T cells. We finally review anti-agalsidase
immune reactions have been described in naive Fabry antibodies, their development and impact on outcomes.
disease patients. Humoral immune responses following
enzyme replacement therapy have also been described,
with unclear consequences on the progression of the
disease. While cost-effectiveness of enzyme replacement
therapy in Fabry disease begins to be questioned and new Introduction
therapeutic strategies arise such as chaperone or gene
therapy, it appears necessary to better understand the First described in 1898, Fabry disease (FD) is the second
most common lysosomal storage disease (LSD) after
Gaucher disease, with a worldwide incidence estimated
between 1/40,000 and 1/117,000 live births (Meikle et al.
Communicatedby:VerenaPeters 1999; Fuller et al. 2006). This figure is probably under-
estimated since late-onset variants have been described,
Competinginterests:Declared
:
with an expected incidence of late-onset disease as high as
W.Mauhin O.Benveniste
InternalMedicineDepartment,LaPitié-SalpêtrièreHospital,47-83 1/3,100 births (Spada et al. 2006). FD is a lysosomal
boulevarddel'hôpital,75013Paris,France storage disease caused by the reduction or absence of
:
O.Lidove(*) J.-M.Ziza hydrolase a-galactosidase A (a-GalA) activity in lyso-
InternalMedicineandRheumatologyDepartment,LaCroixSaint somes, causing a systemic intracellular accumulation of
SimonHospital,125rued'Avron,75020Paris,France
neutral glycosphingolipids (GSL), most notably of globo-
e-mail:[email protected]
: : : : : triaosylceramide (Gb3). More than 600 mutations have
W.Mauhin O.Lidove E.Masat F.Mingozzi K.Mariampillai
been identified in the galactosidase alpha (GLA) gene
O.Benveniste
(Xq21.3-q22) (http://www.ncbi.nlm.nih.gov/omim; Sakur-
InsermUMRS974,UniversityPierreandMarieCurie,47-83
boulevarddel'hôpital,75013Paris,France aba database http://fabry-database.org/mutants). A wide
2 JIMDReports
spectrum of clinical symptoms usually begins in the early tion in vitro (Thomaidis et al. 2009). Evidence-based
childhood of FD patients and progressively enriches all management of FD is therefore limited by the lack of
alongtheevolutionofthedisease.Thesesymptomsinclude standardized and reliable biomarkers.
®
acroparaesthesia, gastrointestinal disorders, angiokerato- Concerning the treatment, agalsidase alfa (Replagal ,
®
mas, heat intolerance, hearing impairment, ophthalmologic Shire HGT Inc.) and agalsidase beta (Fabrazyme ,
abnormalities but also proteinuria and glomerulosclerosis Genzyme Corp.), two recombinant a-GalA, bimonthly
leading to end-stage renal disease (ESRD), cardiac hyper- infused, have been shown to reduce Gb3 plasma levels
trophy and arrhythmia and cerebrovascular disease includ- (Schiffmann et al. 2001; Eng et al. 2001). Results on
ing transient ischemic attacks and strokes (Mehta et al. urinary Gb3 levels were less prominent (Schiffmann et al.
2010). Although X-linked, FD also affects females due to 2001; Eng et al. 2001). Overall under these enzyme
thelyonizationprocessthatinactivatesoneX-chromosome. replacement therapies (ERT) and in the short term (from
Affected women present mild to severe phenotype which 20 to 25 weeks of treatment), sustained clinical benefits
usually appears around 5 years later than in males (Beck were observed such as reduction of left ventricle mass,
2006). Before enzyme replacement therapy (ERT), life stabilization of renal functionand reductionof pain with in
expectancy in FD patients was 58.2 years in males and parallel a reduction of Gb3 contents in kidney, heart and
75.4 years in females (Waldek et al. 2009). Death was skin (Schiffmann et al. 2001; Eng et al. 2001). Neverthe-
mostly caused by cardiovasculardisease(MacDermotetal. less, long-term effects (median follow-up of 6.0 years)
2001a,b;Waldeketal.2009).Inmales,FDisdiagnosedby appear more unobvious with the description of a persistent
demonstrating a deficiency of a-GalA in plasma or progression of cardiac fibrosis and renal failure and no
leukocytes (Winchester and Young 2006). In heterozygous significant benefit on cardiac death, renal death and stroke
females, the gold standard is the genetic analysis since (Weidemannetal.2013).Tworecentreviewsevenreported
enzymatic assays fail to detect one third of the patients no evidence for the use of ERT (El Dib et al. 2013) and
because of the residual enzyme activity (Linthorst et al. only benefits in reducing left ventricular mass but limited
2010; Wang et al. 2007; Wilcox et al. 2012). Whereas renal effects (Rombach et al. 2014). Both reviews only
“classical FD” consists in a multi-organ pathology, single considered six studies. One mechanism suspected in the
organ variants are more and more evoked, following incomplete long-term response to ERT is the development
systematic investigations in specific medical conditions of immune responses against agalsidase. Actually, immune
suchashypertrophiccardiomyopathies,cryptogenicstrokes reactions are described in both treatment-naive and agalsi-
orisolatedrenaldisease(Nakaoetal.2003;Chimentietal. dase-treated FD patients (Rozenfeld et al. 2009; De
2004; Rolfs et al. 2005). Such screenings with molecular Francesco et al. 2013). Antibodies against agalsidase are
testing are thus limited by the existence of variants of notably well described, but their role remains unclear
unknown significance in terms of pathogenicity and (Linthorst et al. 2004; Bénichou et al. 2009; Wilcox et al.
penetrance (Lukas et al. 2013; Thomas and Mehta 2013). 2012). In this review we present the spectrum of the
AnotherdifficultyinthemanagementofFDcomesfrom immunological reactions, both innate and adaptive,
the lack of reliable biomarkers. Historically, Gb3 levels in observedinthenaturalhistoryofFDanddevelopedagainst
plasma, urine and organs, especially increased in Fabry agalsidase therapy, and their impact on outcome in FD.
males, have been used as potential biomarkers of the
disease(Schiffmannetal.2010).ButGb3plasmalevelsare Proinflammatory Pattern in Naive-Treatment FD Patients
normal in the majority of Fabry females; therefore, clinical
correlation appears difficult (Vedder et al. 2007). Most of 1. Innate immunity response: the role of invariant natural
the therapeutic trials have been monitored with Gb3 levels. killer Tcells, CD1d/TLR4 pathway and Gb3 deposit.
Lyso(Gb3), the deacylated form of Gb3, is taking over this Fabry disease is characterized by a lack of a-GalA
roleofbiomarkerasitwasshowntobehighlyincreasedin causing an accumulation of GSL in the late endocytic
the plasma ofbothmaleand femalepatients witha relative and lysosomal compartments. Self-GSL is recognized
elevation exceeding markedly that of Gb3 (Aerts et al. as an antigen by the invariant natural killer T cells
2008). Moreover plasma lyso(Gb3) was shown to be an (iNKTs).Indeed,iNKTscharacterizedbytheirVa24-Ja
independent risk factor for white-matter lesions in males T-cell receptor(TCR)-alphachain rearrangementrepre-
andleftventricular hypertrophy infemales (Rombachetal. sent a subset of natural killer T cells. The iNKTs
2010a). Another technique was attempted using flow recognize as an antigen self-GSL presented by the
cytometry: as the membrane antigen CD77 corresponds to major histocompatibility complex (MHC) class I-like
Gb3, the quantification of CD77 expression on peripheral molecule CD1d of antigen-presenting cells (APCs)
blood mononuclear cells (PBMCs) was shown to be (Spada et al. 1998). Human iNKTs are divided into
correlatedwithGb3accumulationanda-GalAdownregula- threesubsetsaccordingtotheCD4andCD8expression
JIMDReports 3
with a different inflammatory profile: positive only for patients revealed a trend towards higher basal levels of
CD4 (CD4 iNKTs), positive only for CD8 (CD8 IL-1b (p ¼ 0.095) and TNF-a (p ¼ 0.049) secretion
iNKTs) and double negative for CD4 and CD8 (DN than controls. This production was abolished in vitro
iNKTs) (Gumperz et al. 2002). Numerous quantitative when using a toll-like receptor 4 (TLR4) blocking
and qualitative defects have been implicated in antibody. TLRs are innate immune receptors that
antimicrobial response defects, antitumor immunity recognize pathogen-associated molecular patterns
and autoimmunity (Sugita et al. 2004; Chuang et al. (PAMPs) of microorganisms. Via TLRs, DCs link
2012; Hunn and Hermans 2013). The recognition of innate and adaptive immunity (Iwasaki and Medzhitov
GSL induces the release of various proinflammatory 2004). TLR4 enhances DC maturation in a proinflam-
cytokines such as interferon-gamma (IFN-g) and matory way inducing the secretion of IL-12 and IFN-g
tumor necrosis factor alpha (TNF-a), interleukin 4 but the inhibition of IL-4 (Caielli et al. 2010). It also
(IL-4), IL-5, IL-9, IL-10, IL-13 and IL-17 (Gumperz triggers iNKT activation by inducing presentation of
et al. 2002). It also upregulates CD40l inducing IL-10 endogenous GSL by CD1d molecules. (Caielli et al.
and IL-12 secretion by dendritic cells (O’Reilly et al. 2010).PathologicalinvolvementsofTLR4pathwayare
2011). A quantitative reduction of iNKTs has been reported throughan endogenous ligand-mediated signal
reported in murine models of different LSDs including inanantibody-inducedarthritis(Kimetal.2012).TLRs
FD (Gadola et al. 2006; Macedo et al. 2012). In Fabry also recognize endogenous ligands. Accumulated gan-
knockout(KO)mice,anage-associatedincreaseinGb3 gliosides in GM1 and GM2 gangliosidosis were
storage was reported (Macedo et al. 2012). Concomi- reported to act as an endogenous ligand for TLR4
tantly, a progressive decrease in iNKT rates was (Jou etal.2006).Hence,Gb3isquestionedtoactasan
observed, which differs depending on the organs with endogenousligandtoTLR4(DeFrancescoetal.2013).
amoresignificantreductioninthespleen(around75%) Infact,theGb3accumulationappearstobethestarting
andaffectingprimarilytheCD4iNKTssubset.ERTwas point of an innate immunity reaction, involving CD1d
shown to prevent the progression of this splenic iNKT and TLR4 pathways which would induce a dysregula-
deficiency in mouse (Macedo et al. 2012). In FD tion of one of the iNKT subsets and DCs, source of a
patients, under ERT for most of them, the quantitative pathological proinflammatory state with secretion of
reduction in the iNKT pool was not found in PBMCs specific proinflammatory cytokines. We tried to sum-
(Balreiraetal.2008).ThisabsenceofdisorderiniNKTs marize in Fig. 1 the interrelations between Gb3
has been thought to result from the differences in accumulation, innate immunity cells and cytokines.
intracellular trafficking of mouse and human CD1d As previously mentioned, ERT could have a benefi-
molecules or the role of ERT. More recently, Pereira cialimpactoninnateimmuneresponseinFDintermsof
etal.reported a decrease inCD4 iNKTs, an increase of iNKT cell counts (Macedo et al. 2012; Pereira et al.
DN iNKTs and a reduction in the IL-4 production, 2013).Butnodedicatedprospectiveandcontrolledstudy
without significant difference between ERT-treated and has been done to evaluate the impact of ERTon innate
untreated patients (Pereira et al. 2013). Of note, only 4 immune response as an endpoint in human. Besides,
patients were treated among the 15 included, limiting other therapeutic keyscould arise fromspecific research
theimpactofERT.Interestingly,RozenfeldandBalreira on innate immunity. For example, lysosomal phospholi-
showedalowlevelofCD1dthatcouldcorrespondtoan paseA2was reportedtoplaya roleinthe generationof
increase of internalization and an increase in the CD1dcomplexesandcouldthereforebecomeapossible
expression of MHC class II in monocytes from Fabry target like in coronary diseases (Paduraru et al. 2013;
patients (Balreira et al. 2008; Rozenfeld et al. 2009). The STABILITY Investigators 2014).
Therefore it seems that the GSL accumulation in FD But TLRs are not only expressed by immune cells.
induces disturbances in iNKT distribution and plays a Endothelial cells, podocytes and kidney tubular epithe-
proinflammatory role via CD1d pathway. lial cells also expressed TLR4 (Anders et al. 2004;
TheproinflammatorypatterninFDiswelldescribed Banas et al. 2008). Interestingly, Ma et al. recently
with an increase of inflammatory cytokines (De reported the role of TLR4 activation in diabetic
Francesco et al. 2013). Urinary Gb3 levels were found nephropathy (Ma et al. 2014). TLR4(cid:2)/(cid:2) diabetic mice
to be highly correlated with increased IL-6 plasma had significantly attenuated albuminuria, reduced kid-
levels (r ¼ 0.971, p < 0.01) in 14 FD patients (Bian- ney hypertrophy and glomerular injury. They were also
cini et al. 2012). The supernatant of PBMC samples protected from fibrosis and tubular injury. First
from 29 Fabry patientsshowed a significantincreasein observed in hepatic fibrosis, TLR4 seems to drive a
secreted IL-6 and IL-1b compared to 15 healthy fibrogenic response through the TGF-b signalling
controls,anddendriticcells(DCs)fromthesameFabry pathwayindiabeticnephropathy(Sekietal.2007;Qian
