Table Of ContentJohannes Zschocke
Matthias Baumgartner
Eva Morava
Marc Patterson
Shamima Rahman
Verena Peters Editors
JIMD Repor ts
Volume 19
JIMD Reports
Volume 19
.
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 19
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
ISBN978-3-662-46189-1 ISBN978-3-662-46190-7 (eBook)
DOI10.1007/978-3-662-46190-7
SpringerHeidelbergNewYorkDordrechtLondon
#SSIEMandSpringer-VerlagBerlinHeidelberg2015
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Contents
ADeNovoVariantinGalactose-1-PUridylyltransferase(GALT)Leading
toClassicGalactosemia ................................................. 1
Thanh-Thanh(Claire)V.Tran,YingLiu,MichaelE.Zwick,DhanyaRamachandran,
DavidJ.Cutler,XiaopingHuang,GerardT.Berry,andJudithL.Fridovich-Keil
RefsumDiseasePresentingwithaLate-OnsetLeukodystrophy.................. 7
FlavieBompaire,Ve´roniqueMarcaud,EmmanuelleLeTrionnaire,Fre´de´ricSedel,
andThierryLevade
MakingtheWhiteMatterMatters:ProgressinUnderstandingCanavan’s
DiseaseandTherapeuticInterventionsThroughEightDecades................. 11
SeeminS.Ahmed,andGuangpingGao
DisorderedEatingandBodyEsteemAmongIndividualswithGlycogen
StorageDisease....................................................... 23
TheresaB.Flanagan,JillA.Sutton,LaurieM.Brown,DavidA.Weinstein,
andLisaJ.Merlo
1
OneYearExperienceofPheburane (SodiumPhenylbutyrate)Treatmentin
aPatientwithArgininosuccinateLyaseDeficiency........................... 31
SemaKalkanUc¸ar,BurcuOzbaran,YaseminAtikAltinok,MelisKose,EbruCanda,
MehtapKagnici,andMahmutCoker
GrowthHormoneDeficiencyandLysinuricProteinIntolerance:CaseReport
andReviewoftheLiterature............................................ 35
MainesEvelina,MorandiGrazia,OlivieriFrancesca,CamilotMarta,CavarzerePaolo,
GaudinoRossella,AntoniazziFranco,andBordugoAndrea
GeographicalandEthnicDistributionofMutationsoftheFumarylacetoacetate
HydrolaseGeneinHereditaryTyrosinemiaType1 .......................... 43
FrancescaAngileri,AnneBergeron,Genevie`veMorrow,FrancineLettre,GeorgeGray,
TimHutchin,SarahBall,andRobertM.Tanguay
PathologicVariantsoftheMitochondrialPhosphateCarrierSLC25A3:TwoNew
PatientsandExpansionoftheCardiomyopathy/SkeletalMyopathyPhenotype
WithandWithoutLacticAcidosis........................................ 59
E.J.Bhoj,M.Li,R.Ahrens-Nicklas,L.C.Pyle,J.Wang,V.W.Zhang,C.Clarke,
L.J.Wong, N.Sondheimer,C.Ficicioglu,andM.Yudkoff
v
vi Contents
BaselineUrinaryGlucoseTetrasaccharideConcentrationsinPatientswith
Infantile-andLate-OnsetPompeDiseaseIdentifiedbyNewbornScreening....... 67
Yin-HsiuChien,JenniferL.Goldstein,Wuh-LiangHwu,P.BrianSmith,Ni-ChungLee,
Shu-ChuanChiang,AdviyeA.Tolun,HaoyueZhang,AmieE.Vaisnins,
DavidS.Millington,PriyaS.Kishnani,andSarahP.Young
DevelopmentalOutcomesofSchool-AgeChildrenwithDuarteGalactosemia:
APilotStudy......................................................... 75
MaryEllenLynch,NancyL.Potter,ClaireD.Coles,andJudithL.Fridovich-Keil
MolecularDiagnosisofHereditaryFructoseIntolerance:FounderMutation
inaCommunityfromIndia............................................. 85
SunitaBijarnia-Mahay,SireeshaMovva,NeerjaGupta,DeepakSharma,RatnaD.Puri,
UdhayaKotecha,RenuSaxena,MadhulikaKabra,NeelamMohan,andIshwarCVerma
LeighSyndromeCausedbytheMT-ND5m.13513G>AMutation:
ACasePresentingwithWPW-LikeConductionDefect,Cardiomyopathy,
HypertensionandHyponatraemia........................................ 95
MarcusBrecht,MalcolmRichardson,AjayTaranath,ScottGrist,DavidThorburn,
andDragoBratkovic
DeepGenotypingoftheIDSGeneinColombianPatientswithHunterSyndrome.... 101
JohannaGalvis,JannetGonza´lez,AlfredoUribe,andHarvyVelasco
ExpandingtheClinicalSpectrumofMitochondrialCitrateCarrier(SLC25A1)
Deficiency:FacialDysmorphisminSiblingswithEpilepticEncephalopathyand
CombinedD,L-2-HydroxyglutaricAciduria ............................... 111
PankajPrasun,SarahYoung,GajjaSalomons,AndreaWerneke,Yong-huiJiang,
EduardStruys,MikellPaige,MariaLauraAvantaggiati,andMarieMcDonald
AKoreanCaseofb-UreidopropionaseDeficiencyPresentingwithIntractable
Seizure,GlobalDevelopmentalDelay,andMicrocephaly..................... 117
JunHwaLee,Andre´ B.P.vanKuilenburg,N.G.G.M.Abeling,ValeriaVasta,
andSiHounHahn
Erratumto:GrowthHormoneDeficiencyandLysinuricProteinIntolerance:
CaseReportandReviewoftheLiterature ................................ 123
EvelinaMaines,GraziaMorandi,FrancescaOlivieri,MartaCamilot,
PaoloCavarzere,RossellaGaudino,FrancoAntoniazzi,andAndreaBordugo
JIMDReports
DOI10.1007/8904_2014_349
RESEARCH REPORT
A De Novo Variant in Galactose-1-P Uridylyltransferase
GALT
( ) Leading to Classic Galactosemia
Thanh-Thanh (Claire) V. Tran(cid:129)Ying Liu(cid:129)
Michael E. Zwick(cid:129)Dhanya Ramachandran(cid:129)
David J. Cutler(cid:129)Xiaoping Huang(cid:129)Gerard T. Berry(cid:129)
Judith L. Fridovich-Keil
Received:14June2014/Revised:27July2014/Accepted:31July2014/Publishedonline:15February2015
#SSIEMandSpringer-VerlagBerlinHeidelberg2014
Abstract Classic galactosemia (CG) is a potentially that GALT may have a higher new mutation rate than
lethal genetic disease that results from profound previously believed.
impairment of galactose-1-P uridylyltransferase (GALT),
the middle enzyme in the Leloir pathway of galactose
metabolism. Patients with CG carry pathogenic loss-of- Introduction
function mutations in both of their GALT alleles; the
parents of patients are considered obligate carriers. We Classic galactosemia (CG) is a potentially lethal genetic
report here a first exception to that rule – a de novo disorder that affects close to 1/50,000 live births in the
GALT variant in a patient with classic galactosemia. The United States (Pyhtila et al 2014). Patients with CG
new variant, c.563A>C (p.Q188P), which introduces a demonstrateprofoundimpairmentofgalactose-1-phosphate
missense substitution near the active site of the GALT uridylyltransferase (GALT), the second enzyme in the
enzyme, was found in the compound heterozygous state Leloir pathway of galactose metabolism (Fridovich-Keil
in a child with classic galactosemia, but not in either of and Walter 2008). Classic galactosemia is inherited as an
her parents. Extensive genomic studies of DNA from the autosomal recessive trait. Patients carry loss-of-function
child and both parents confirmed the expected degrees of mutations in both of their GALT alleles, and their parents
relationship in the trio as well as inheritance of a are considered obligate heterozygotes for those same
common c.563A>G (p.Q188R) GALT mutation from mutations. The carrier risk for a loss-of-function GALT
the mother. This result demonstrates that not all patho- mutation in the general population is estimated using the
genic GALT mutations are inherited and raises concern Hardy–Weinberg equation at about 1 in 112 people.
Sequencing the GALT alleles in patients with classic
galactosemia reveals striking allelic heterogeneity with
>250 distinct causal or ostensibly causal variants and a
Communicatedby:JohnHWalter,MDFRCPCH
smallnumberofostensiblyneutralpolymorphismsreported
Competinginterests:Nonedeclared
as of January 2013 ((Calderon et al 2007), http://arup.utah.
T.-T.(Claire)V.Tran
edu/database/GALT/GALT_welcome.php). Most variants
BiologyDepartment,EmoryCollege,EmoryUniversity,Atlanta,
are coding missense substitutions, but some are small
GA30322,USA
: : : : insertions, deletions, or indels. Finally, some variants
Y.Liu M.E.Zwick D.Ramachandran D.J.Cutler
J.L.Fridovich-Keil(*) impact only noncoding sequence, and two are large
DepartmentofHumanGenetics,EmoryUniversitySchoolof deletions that remove most or all of the GALT gene (e.g.,
Medicine,Rm.325.2WhiteheadBldg.,615MichaelSt, (Calderon et al 2007; Coffee et al 2006; Gort et al 2006;
Atlanta,GA30322,USA
Papachristoforouetal2014;Tyfieldetal1999),http://arup.
e-mail:jfridov@emory.edu
: utah.edu/database/GALT/GALT_welcome.php).
X.Huang G.T.Berry SomeGALTmutationsarecommon,especiallyincertain
TheMantonCenterforOrphanDiseaseResearch,Divisionof
GeneticsandGenomics,DepartmentofPediatrics,BostonChildren’s populations. For example, c.563A>G (p.Q188R) accounts
Hospital,HarvardMedicalSchool,Boston,MA,USA for the vast majority of CG patient alleles in Northern
2 JIMDReports
Europeand>60%ofCGpatientallelesintheUnitedStates
(Tyfield et al 1999). The mutation c.855G>T (p.K285N)
accounts for a majority of CG patient alleles in Eastern
Europe (Lukac-Bajalo et al 2007). Finally, c.404C>T
(p.S135L) accounts for a majority of CG patient alleles in
parts of Africa (Henderson et al 2002). Other mutations,
suchasc.584T>C(p.L195P),arelesscommon,accounting
for only a small percentage of reported patient alleles, and
yet others are “private” – reported only in one affected
patient or family. The heterogeneity of CG patient alleles Fig. 1 The family described in this study. The child, FKT118, has
identifiedtodaystandsasastrikingrecordofthemanynew biochemically confirmed classic galactosemia and a GALT genotype
of c.563A>G (p.Q188R)/c.563A>C (p.Q188P). The mother,
GALT variants that have arisen over the course of human FKT118P1, is a heterozygous carrier of the c.563A>G (p.Q188R)
history,butuntilnowtherehavebeennoreportedexamples mutation.Thefather,FKT118P2,doesnotshowanyGALTmutations
of de novo GALT variants identified in a living patient or inhisDNA.Thebiologicalrelationshipsillustratedwereconfirmedby
family. We report here the first such case. extensive marker analysis. The couple also has another unaffected
biologicalchild(notillustrated)whohasnotbeengenotyped
Methods GALT Genotyping of DNA from Both Parents
Study Volunteers DNAs from parental saliva samples collected using Ora-
gene kits were also genotyped by dideoxy sequencing of
The volunteers in this study were a child with classic the relevant GALT locus using the following primers:
galactosemia and both of her parents (Fig. 1). All three hGALT-F4(2): 50-AAGCTTTGGTTCTGGGGAGT-30 and
participated following appropriate informed consent/assent hGALT-R3: 50-GTGTCTGGTAGGGCCATGTT-30. Initial
in Emory IRB Protocol # 00024933 (PI: JL Fridovich- studies revealed that the mother, designated FKT118P1,
Keil). The child was also a consented volunteer in a was a carrier of the c.563A>G (p.Q188R) missense
research study of galactosemia conducted out of Boston mutationand that thefather,designated FKT118P2,carried
Children’sHospital(IRBProtocol#NS09-07-0369(PI:GT neithermutation.Concernedthattheremayhavebeensome
Berry)). mistake, we collected an independent saliva sample from
FKT118P2 and repeated the test; again we found neither
GALT Genotyping of DNA from the Child GALT mutation.
DNA samples isolated from independent blood draws from Affymetrix6.0MicroarrayAnalysisofGenomicMarkersin
the child were assessed by dideoxy sequencing of the the Trio
full GALT locus first in a clinical genetics laboratory (at
Boston Children’sHospital) andsubsequentlyinaresearch To confirm the biological relationships among the three
laboratory(atEmoryUniversity).Intheresearchlaboratory study volunteers, we subjected each DNA sample to
the GALT gene was PCR amplified as a single ~6 kb genotyping using the Affymetrix Genome-Wide Human
amplicon using the primers 50-AGTACCAGGGGAG- SNP Array 6.0 that tests more than 900,000 single
GAATTAATTTGAATTTT-30 and 50-ATTCAGT- nucleotide polymorphisms (SNPs) scattered across the
CACTGTCCAGCCTTAGTGTGATTT-30 as described genome (http://www.affymetrix.com/catalog/131533/
previously (Boutron et al 2012), and the relevant region AFFY/Genome-Wide-Human-SNP-Array-6.0#1_1).
was sequenced using the following custom primers: Briefly, to be considered for downstream analyses, each
hGALT-F4(2): 50-AAGCTTTGGTTCTGGGGAGT-30 (30 array was required to pass the Affymetrix recommended
end anneals to position 1324), hGALT-F03(1): 50- quality control (QC) parameters – namely >86% call rate,
CCCTGGTCGG ATGTAACG-30 (30 end anneals to posi- >0.4 contrast QC, and gender concordance. Genotype
tion 1164), and hGALT-R3: 50-GTGTCTGGTAGGGC- calling was performed using Birdseed algorithm (version
CATGTT-30 (30 end anneals to position 2111). Both the 2),asimplementedintheAffymetrixPowerToolssoftware
clinical and research labs identified the same two muta- (APT 1.12.0). Estimations of alleles that are identical by
tions: the common c.563A>G (p.Q188R) missense muta- state(IBS)fromgenotypecallswereperformedusinganin-
tion and also a novel c.563A>C (p.Q188P) missense house script (D.J.C). In comparison with the parents, the
mutation, each found in the patient in the compound proband had approximately 73% of genotypes that were
heterozygous state. IBSatbothalleles(IBS2),27%atoneallele(IBS1)and0%
JIMDReports 3
Table1 Percentageof>900,000markerlociinthetriointerrogatedusingtheAffymetrixGenome-WideHumanSNPArray6.0showing0,1,or
2alleleswithidentitybystate(IBS)
LevelofIBS 0of2alleleswithIBS 1of2alleleswithIBS 2of2alleleswithIBS
Expectedforparentandoffspring 0.0010 0.2692 0.7307
ObservedforFKT118P1andFKT118 0.0002 0.2665 0.7333
ObservedforFKT118P2andFKT118 0.0002 0.2686 0.7311
with IBS0 value, thus confirming the familial relationship Dideoxy Sequencing Reveals a Novel GALT Variant in a
(see Table 1). Child with Classic Galactosemia
Initial GALT genotyping was performed in 2008 in a
Results clinical genetics lab (Emory Genetics Laboratory) using
allele-specific primer extension (Luminex; http://www.
Case Report premierbiosoft.com/primerplex/allele-specific-primer-
extension.html)todetectthepresenceorabsenceofapanel
Theproband(FKT118,Fig.1)isa6-year-oldgirlwhowas ofcommon mutations.Theresultdemonstrated presenceof
bornatgestationalage34weeksanddiagnosedwithclassic c.563A>G (p.Q188R) and absence of the wild-type allele
galactosemia as an infant in follow-up to an abnormal atthatlocus;noothermutationsincludedinthepanelwere
newborn screening result. On day 1 of life, she was detected. The genotype was therefore reported, to the
supplementedwithaproprietaryformulacontaininglactose sensitivity of the assay, as c.563A>G (p.Q188R)/
because of a poor sucking reflex. In the first week of life, c.563A>G (p.Q188R). Of note, c.563A>C (p.Q188P)
she manifested poor feeding, emesis, loose stools, and was not one of the common GALT mutations included in
jaundice. The serum total bilirubin concentration was the panel.
23 mg%. The newborn screening test for galactosemia Yearslaterafreshbloodsamplewascollected(atBoston
was positive and the infant was switched to a soy-based Children’sHospital)andsubjectedtoGALTgenotypingvia
formula on day 5 of life. Seizures occurred at 3 years of full gene dideoxy sequencing. Two mutations were
age, including grand mal seizures. There is a history of detected, c.563A>G (p.Q188R) and c.563A>C
language delay and a speech defect. Magnetic resonance (p.Q188P), each in the compound heterozygous state. With
imaging (MRI) of the brain conducted at 5 years of age permission, this result was shared with our research lab at
revealed areas of patchy subcortical white matter signal Emory University that repeated the dideoxy sequencing on
increases possibly related to non-suppressed perivascular an archived DNA sample from the child; the c.563A>G
spaces. On physical examination at age five, the proband (p.Q188R)/c.563A>C (p.Q188P) result was confirmed
had scars on her face due to a seizure-induced fall. There (Fig. 2). A search of the galactosemia literature and GALT
was diffuse hypotonia. There were no discernible peaks of mutation database (http://arup.utah.edu/database/GALT/
galactitol on magnetic resonance spectroscopy (MRS). The GALT_welcome.php) revealed no prior reports of the
erythrocyte GALT enzyme activity was undetectable, and c.563A>C (p.Q188P) mutation.
the galactose-1-phosphate level was 3.67 mg% while on a
lactose-restricted diet (reference range <1 mg%). The Dideoxy Sequencing of Parental GALT Loci Coupled with
urinary galactitol excretion was 178 mmol/mmol creatinine ComprehensiveGenomicSNPAnalysisoftheTrioReveals
(reference range 2–36). By early childhood the serum that c.563A>C (p.Q188P) is a De Novo Variant in this
follicle stimulating hormone (FSH) level was elevated and Family
the anti-M€ullerian hormone level was undetectable. A
DEXA scan of bone density did not reveal any region with In response to a parental request for GALT genotyping to
a Z score that was below two standard deviations of the determine which side of the family was at risk for carrying
reference mean. which GALT mutation, parental saliva samples were
