Table Of ContentJohannes Zschocke
K. Michael Gibson
Garry Brown
Eva Morava
Verena Peters Editors
JIMD Repor ts
Volume 12
JIMD Reports
Volume 12
.
Johannes Zschocke K. Michael Gibson
(cid:129)
Editors-in-Chief
Garry Brown Eva Morava
(cid:129)
Editors
Verena Peters
Managing Editor
JIMD Reports
Volume 12
Editor-in-Chief Editor
JohannesZschocke EvaMorava
MedizinischeUniversita¨tInnsbruck RadboudUniversityNijmegen
Sektionenfu¨rHumangenetikundKlinische MedicalCenter
Innsbruck DepartmentofPediatrics
Austria IGMD
Nijmegen
Editor-in-Chief Netherlands
K.MichaelGibson
WSUDivisionofHealthSciences ManagingEditor
ClinicalPharmacologyUnit VerenaPeters
Spokane CenterforChildandAdolescent
USA Medicine
HeidelbergUniversityHospital
Editor Heidelberg
GarryBrown Germany
UniversityofOxford
DepartmentofBiochemistry
GeneticsUnit
Oxford
UnitedKingdom
ISSN2192-8304 ISSN2192-8312(electronic)
ISBN978-3-319-03460-7 ISBN978-3-319-03461-4(eBook)
DOI10.1007/978-3-319-03461-4
SpringerChamHeidelbergNewYorkDordrechtLondon
#SSIEMandSpringerInternationalPublishingSwitzerland2014
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Contents
PropionicAcidemiaandOpticNeuropathy:AReportofTwoCases.............. 1
CarolinaArias,ErnaRaimann,PilarPeredo,JuanFranciscoCabello,GabrielaCastro,
AlfValiente,AliciadelaParra,PaulinaBravo,CeciliaOkuma,andVero´nicaCornejo
ChronicKidneyDiseaseinanAdultwithPropionicAcidemia................... 5
H.J.Vernon,S.Bagnasco,A.Hamosh,andC.J.Sperati
TransientMassiveTrimethylaminuriaAssociatedwithFoodProtein–Induced
EnterocolitisSyndrome ................................................ 11
NatalieB.Miller,AvrahamBeigelman,ElizabethUtterson,andMarwanShinawi
IncreasedPrevalenceofHypertensioninYoungAdultswithHighHeteroplasmy
LevelsoftheMELASm.3243A>GMutation ............................... 17
FadyHannah-Shmouni,SandraSirrs,MichelleM.Mezei,PaulaJ.Waters,
andAndreMattman
Niemann-PickDiseaseTypeC:NewAspectsinaLongPublishedFamily–Partial
ManifestationsinHeterozygotes ......................................... 25
KlausHarzer,StefanieBeck-Wo¨dl,andPeterBauer
Chiari1MalformationandHolocordSyringomyeliainHunterSyndrome........ 31
RenzoManara,DanielaConcolino,AngelicaRampazzo,AlessandraZanetti,
RossellaTomanin,RobertoFaggin,andMaurizioScarpa
APatientwithComplexIDeficiencyCausedbyaNovelACAD9MutationNot
RespondingtoRiboflavinTreatment...................................... 37
JessicaNouws,FlemmingWibrand,Marie¨lvandenBrand,HankaVenselaar,
MortenDuno,AllanM.Lund,SimonTrautner,LeoNijtmans,andElsebetØstergard
PulmonaryManifestationsinaPatientwithTransaldolaseDeficiency ........... 47
NadaJassim,MohammedAlGhaihab,SuhailAISaleh,MajidAlfadhel,
MirjamM.C.Wamelink,andWafaaEyaid
BurdenofLysosomalStorageDisordersinIndia:Experienceof387Affected
ChildrenfromaSingleDiagnosticFacility ................................. 51
JayeshSheth,MehulMistri,FrennySheth,RajuShah,AshishBavdekar,
KoumudiGodbole,NidhishNanavaty,ChaitanyaDatar,MaheshKamate,
NrupeshOza,ChitraAnkleshwaria,SanjeevMehta,andMarieJackson
AJapaneseAdultCaseofGuanidinoacetateMethyltransferaseDeficiency........ 65
TomoyukiAkiyama,HitoshiOsaka,HirokoShimbo,TomoshiNakajiri,
KatsuhiroKobayashi,MakioOka,FumikaEndoh,andHarumiYoshinaga
v
vi Contents
AccumulationofOrderedCeramide-CholesterolDomainsinFarber
DiseaseFibroblasts.................................................... 71
NataliaSantosFerreira,MichalGoldschmidt-Arzi,HelenaSabanay,JudithStorch,
ThierryLevade,MariaGilRibeiro,LiaAddadi,andAnthonyH.Futerman
InfantileSialicAcidStorageDisease:TwoUnrelatedInuitCasesHomozygous
foraCommonNovelSLC17A5Mutation .................................. 79
MatthewA.Lines,C.AnthonyRupar,JackW.Rip,BerivanBaskin,PeterN.Ray,
RobertA.Hegele,DavidGrynspan,JeanMichaud,andMichaelT.Geraghty
MotorDevelopmentSkillsof1-to4-Year-OldIranianChildrenwithEarly
TreatedPhenylketonuria ............................................... 85
SepidehNazi,FarzanehRohani,FiroozehSajedi,AkbarBiglarian,andAryaSetoodeh
ANovelLargeDeletionEncompassingtheWholeoftheGalactose-1-Phosphate
Uridyltransferase(GALT)GeneandExtendingintotheAdjacentInterleukin11
ReceptorAlpha(IL11RA)GeneCausesClassicGalactosemiaAssociated
withAdditionalPhenotypicAbnormalities ................................. 91
RenaPapachristoforou,PetrosP.Petrou,HilarySawyer,MaggieWilliams,
andAnthiDrousiotou
SuccessfulDesensitisationinaPatientwithCRIM-PositiveInfantile-OnsetPompe
Disease.............................................................. 99
J.Baruteau,A.Broomfield,V.Crook,N.Finnegan,K.Harvey,D.Burke,
M.Burch,G.Shepherd,andA.Vellodi
HeterozygousMutationsintheADCK3GeneinSiblingswithCerebellarAtrophy
andExtremePhenotypicVariability ..................................... 103
LubovBlumkin,EstherLeshinsky-Silver,AyeletZerem,KerenYosovich,
TallyLerman-Sagie,andDoritLev
ClinicalPresentationandPositiveOutcomeofTwoSiblingswithHolocarboxylase
SynthetaseDeficiencyCausedbyaHomozygousL216RMutation.............. 109
T.P.Slavin,S.J.Zaidi,C.Neal,B.Nishikawa,andL.H.Seaver
NoMutationintheSLC2A3GeneinCohortsofGLUT1DeficiencySyndrome–Like
PatientsNegativeforSLC2A1andinPatientswithAHCNegativeforATP1A3... 115
C.LeBizec,S.Nicole,E.Panagiotakaki,N.Seta,andS.Vuillaumier-Barrot
NovelAssociationofEarlyOnsetHepatocellularCarcinomawithTransaldolase
Deficiency .......................................................... 121
CharlesA.LeDuc,ElizabethE.Crouch,AshleyWilson,JayLefkowitch,
MirjamM.C.Wamelink,CornelisJakobs,GajjaS.Salomons,XiaoyunSun,
YufengShen,andWendyK.Chung
Lathosterolosis:ADisorderofCholesterolBiosynthesisResembling
Smith-Lemli-OpitzSyndrome .......................................... 129
A.C.C.Ho,C.W.Fung,T.S.Siu,O.C.K.Ma,C.W.Lam,S.Tam,andV.C.N.Wong
JIMDReports
DOI10.1007/8904_2013_234
CASE REPORT
Propionic Acidemia and Optic Neuropathy:
A Report of Two Cases
Carolina Arias(cid:129)Erna Raimann(cid:129)Pilar Peredo(cid:129)
Juan Francisco Cabello(cid:129)Gabriela Castro(cid:129)
Alf Valiente(cid:129)Alicia de la Parra(cid:129)Paulina Bravo(cid:129)
Cecilia Okuma(cid:129)Verónica Cornejo
Received:26February2013/Revised:13April2013/Accepted:17April2013/Publishedonline:2July2013
#SSIEMandSpringer-VerlagBerlinHeidelberg2013
Abstract Introduction: Propionic acidemia is a metabolic and also by neuroimaging (MRI of optic pathway).
disease produced by a deficiency of the enzyme propionyl- Conclusions: Pathophysiology of optic neuropathy is not
CoA carboxylase. It can lead to coma, with severe completely understood. There is evidence that the damage
neurologic encephalopathy or present later in life with isduetoanaccumulationofneurotoxiccompoundssecondary
vomiting, hypotonia, and seizures. An early diagnosis with to the metabolic block increasing the oxidative stress. We
adequate treatment helps to prevent the sequelae. Among suggest an annual ophthalmologic evaluation in the long-
the described complications is optic neuropathy, although term follow-up of organic acidurias with visual loss, in
not commonlyreported, it isvery disabling. Objectives: To order to detect this disabling sequela at an earlier stage.
describe two patients with propionic acidemia and optic
neuropathy. Patients and Methods: Patient 1: 16 years old,
male, parents without consanguinity. He was diagnosed at Introduction
5 months of age because of hypotonia and seizures. Until
the age of 9 years, he evolved satisfactorily; therefore, he Propionic acidemia (PA) (OMIM 606054) is an organic
stopped treatment. At 13 years, he presented bilateral optic aciduria (OA) due to propionyl CoA carboxylase enzyme
neuropathy. Patient 2: 20 years, female, parents without deficit, composed by two subunits: a (PCCA, OMIM
consanguinity.Shewas diagnosedwith PAat11months of 232000), chromosome 13q32 and b (PCCB, OMIM
age because of hypotonia and seizures. She evolved 232050), chromosome 6p21. The incidence is 1:100.000
satisfactorily until the age of 9 years when she presented newborns.
a metabolic decompensation followed by a bad metabolic There are two clinical presentations: an acute neonatal
control. At 18 years, she presented bilateral progressive form, characterized by severe metabolic decompensation
optic neuropathy. Results: Both patients have psychometric and a late chronic progressive form with hypotonia, failure
scores with borderline IQ 84–75 (WISC-R) beside optic to thrive, and developmental delay. The diagnosis is
neuropathy. They were evaluated by an ophthalmologist confirmed by enzyme or molecular analysis (Cornejo and
Raimann 2010; Ogier de Baulny and Saudubray 2002).
The accumulation of organic acids, either transported
Communicatedby:DanielaKarall throughtheblood-brainbarrier(BBB)orsynthesizedinthe
central nervous system, leads to secondary metabolic
Competinginterests:Nonedeclared
: : : : :
C.Arias(*:) E.Raimann:P.Peredo: J.F.Cabello G.Castro alterationsduetotheirtoxicity(Schreiberetal.2012).This
A.Valiente A.delaParra P.Bravo V.Cornejo causes brain damage and inhibition of mitochondrial
LaboratoryofGeneticsandMetabolicDiseases,InstituteofNutrition metabolism explaining acidosis, hypoglycemia, and hyper-
andFoodTechnology,(INTA)UniversityofChile,ElLíbano5524,
ammonemia. It has been suggested that there is an
Santiago7830490,Chile
imbalance of amino acids transport through the BBB
e-mail:[email protected]
leading to a low protein synthesis and secondary carnitine
C.Okuma
deficit, which can generate less energy (Wajner and
DivisionofNeuroradiology,InstituteofNeurosurgery(INCA)
Dr.AlfonsoAsenjo,Santiago,Chile Goodman 2011). Recently, oxidative stress has been
2 JIMDReports
a b c
Fig. 1 MRI brain and orbits: Case 1 at 15 years old. (a) T2W- increased signal of optic chiasm (chiasmal atrophy). (c) Coronal
weightedaxialimage,redarrowshowsdiscretehyperintensesignalin T2-weightedSTIR,redarrowshowsdecreasedvolumeandincreased
putaminal nucleus, there is also signs of brain atrophy. (b) T2W- signal in intraorbital portions of both optic nerves (severe bilateral
weighted coronal image, red arrow shows decreased volume and opticatrophy)
reported in OA due to decreased antioxidant capacity optic neuropathy. Magnetic resonance imaging (MRI) of
(Ianchulev et al. 2003; Wajner and Goodman 2011). the brain and optic pathway was performed, demonstrating
These pathophysiological effects explain the multisystemic severe bilateral optic neuropathy (Fig. 1).
complications in OA, most frequently neurologic (symmet- The second case: Female, 20 years old, parents without
rical necrosis of globus pallidus), renal, dermatologic, consanguinity, and a family history of three brothers who
pancreatic, and cardiac. Optic nerve atrophy has been died in the neonatal period of undetermined cause. She
reported in organic acidemias, mainly, propionic acidemia presented at 11 months of age with focal seizures and
and methylmalonic acidemia (Ianchulev et al. 2003; hypotonia leading to the diagnosis of PA. After nutritional
Williams et al. 2009; Patton et al. 2000; Gerth et al. 2008; treatment was started with natural protein restriction
Gr€unert et al. 2013); however, it is very disabling. (0.7 g/kg/day), L-carnitine (100 mg/kg/day), and biotin
(10 mg/day) she progressively improved her psychomotor
Case Reports development. At age 9, she had a severe metabolic
decompensation, subsequently metabolic control was irreg-
The first case: Male, 16 years old, parents without ularwithelevationofC3,highammoniaanddecreasedfree
consanguinity. His brother died at 27 weeks of gestational carnitine. The amino acids supplementation was poor. In
age(GA) of undeterminedcause. He was bornat34 weeks the cognitive evaluation (WISC-R) at age 12, total IQ was
GA, birth weight 2,160 g, length 46 cm, Apgar 9–9. 81 (low normal range).
Diagnosis was suspected at 5 months of age by Atage18,shepresentedprogressivevisualloss.Ophthal-
developmental delay, hypotonic syndrome and focal seiz- mologic evaluation found a decreased visual acuity in both
ures. Increased glycine and propionylcarnitine were found. eyes at 20 cm 20/800, color vision 0/10, visual field and
Nutritional treatment was started with natural protein ocular motility was preserved. The fundus showed a pale
restriction (1.2 g/kg/day), L-carnitine (100 mg/kg/day), papillae whit small central excavation and an unaltered
and biotin (10 mg) for improving seizure control and retina and macula, consistent with bilateral optic nerve
psychomotor development. From age 9, he showed poor atrophy. Brain and optic path MRI revealed bilateral optic
adherence to nutritional therapy with elevated levels of neuropathy (Fig. 2).
propionylcarnitine(C3)andammoniaanddecreasedlevels
of free carnitine (C0). Plasma levels of amino acids Discussion
involved in the metabolic pathway were below the
recommended range, with the exception of methionine The pathophysiology of optic nerve atrophy in OA is still
and threonine. Total IQ assessed by WISC-R was 78 at unknown, but the accumulation of neurotoxic substrates
12 years of age (borderline). due to the metabolic block can produce the damage
He presented a bilateral visual loss at age 13. The (Williams et al. 2009). This compromise can usually affect
ophthalmologic evaluation detected visual field contraction several organs as liver, bone marrow, kidney, pancreas,
of all isopters in both eyes (remaining at 10 (cid:1)). Visual heart, and brain. The central nervous system and optic
acuity was 0.05 to 1 meter in both eyes. The fundus nerve are particularly susceptible to damage because of
revealed pale papillae and dystrophic retina speckled with the high concentration of polyunsaturated fatty acids
pigment migration, consistent with bilateral progressive in mitochondrial membranes (Schreiber et al. 2012).
JIMDReports 3
a b c
Fig.2 MRIbrainandorbits:Case2at17yearsold.Coronalimages (c)T1FS-weightedcontrast,redarrowshowsdiscreteimpregnationof
(a)T2-weightedSTIRand(b)STIR-FLAIR,redarrowsdemonstrate opticnerves,leftmoreevident
hyperintense signal in intraorbital portions of both optic nerves.
Moreover,theaccumulationofpropionyl-CoAinmitochon- Synopsis
driainducesultrastructuralchanges,producinginhibitionof
pyruvate dehydrogenase, alpha-ketoglutarate dehydroge- Optic neuropathy complication organic acidemia.
nase, complexes of the respiratory chain and glutathione
synthetase. This favors the hypothesis of mitochondrial References
dysfunction induced by the accumulation of enzymatic
block–derived compounds (Schwab et al. 2006). The
CornejoV,RaimannE(2010)Erroresinnatosdelmetabolismodelos
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