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Research Journal of Medicine and Medical Sciences, 4(2): 369-385, 2009
Corresponding Author: Marian Yousry Girgis MD., Neurology Department, Cairo University.
369
Screening for Organic Acid Disorders among Egyptian Children with ClinicallySuspected Neurometabolic Disorders
Laila Abdel Moteleb Selim MD, Sawsan Abdel Hadi Hassan MD, Fadia Ali salem MD, Fayza1 2 2 5
Abdel Hamid Hassan MD, Fatma El Mogy MD, Sahar Abdel Atty MD, Iman Mandour MD, Marian5 5 5 5
Fathy MD, Azza El Orabi amin MD, Iman gamal el din MD, Manal sadek El defrawy MD, Ali el1 3 4 3
ayat MD, Amira El Badawy Msc, Marian yousry MD, Mohammed Abdel Monem MSc, Dina3 1 5 5
Mehaney MSc
Neurology Department, Cairo University Children Hospital, Genetic Department, Cairo University1 2
Children Hospital, Metabolic Unit, Cairo University Children Hospital, Pediatric Hepatology and3 4
Metabolic Unit, Benha Faculty of Medicine and Clinical and Chemical Pathology Department, Faculty5
of medicine, Cairo University
Abs tr ac t: Ba c kground: Organic acid disorders are a group of disorders characterized by the excretion ofnon-amino organic acids in urine. Expanded newborn s c re ening methods by tandem mass spectrometry
(MS/MS) can detect organic acide mias early in infancy with a better outcome when diagnosed in the firs t
ten days of life. Aim: This s tudy aims at re v ie wing the clinical, biochemical and neuroradiological dataof patients diagnosed as organic acidemias and to highlight the importance of including organic acidemias
in Newborn screening programs us ing MS/MS. Methods : Eight hundred p a t ients attending the
neurometabolic clinic at Cairo Un iv e rs ity Children Hospital (CUCH) screened for inborn errors ofmetabolism (IEM) by MS/MS. Organic acid pro file in urine, by gas chromatography mass spectrometry
(GC-MS/MS), was performed for selected cases . Results : Nineteen patie n t s out the 800 cases werediagnosed as organic acidemias (1/42).Three cas e s (15.8%) were diagnosed as methyl malonic acidemias
(MMA), 3 (15.8%) as â-ketothiolase deficiency (BKT), 2 (10.5%) as 3-me t h y lcrotonylglycinuria (MCG),
3 (15.8%%)as biotinidase deficiency , 2 (10.5%) as Canavan disease, one patient (5.3% )for each of thefollowing: glutaric aciduria type I, D-2 hydroxyglutaric a c id u ria ,is o v a le ric a c id u ria (IVA),
asargininosuccinic aciduria (ASA),3-methyl glutaconic aciduria and propionic ac id e mia (PA ).
Developmental delay was a dominant symptom being present in 16/19 (84.2%) followed by metabolicacidos is in 15/19(78.9% ), vomit in g in 12(63.2%), encephalopathy with dis turbed conscious level in 11
(57.8%), seizures in 8 (42%), overwhelming illness [encephalopathy, re s p ira t ory dis tress , seizures ,
septicemia, pers is tent vomitings] in 8 (42%) namely in MMA, PA and BKT and diarrhea in 6(31% )cases .Central nervous sys tem abnormalit ie s in c luding cranial nerve affection in 8(42%) extrapyramidal
ma n ifes tations namely dys tonia in 4 (21%), ataxia in 2(10.5%), long tract s igns in 7(36.8%), h y p o t o n ia
in 11 (57.8%) patients and dysmorphism in 11 cases ( 57.8%). Conclus ion: Screening for organicacidopathies by MS/MS us ing dried blood spot technique is a rapid and efficient method in detecting cases
with suspected organic acidemias , requiring confirmatory tes ts by GC-MS. Including organic acidopathiesin newborn sc re e n in g wo u ld help in rapid and properly timed therapeutic intervention to prevent
devas tating neurological outcomes . However, confirmatory tes ts by GC-MS are mandatory particularly for
clinically suspected cases with normal acyl carnitine profile
Key words: Organic acidemia, methylmalonic acidemia, tandem mass spectrometry.
INTRODUCTION
Inborn errors of metab o lism (IEMs) are commonthroughout the Middle Eas t, presumably because of the
relatively high rates of consanguinity (38.5%) . Many[1 ,2]
of the IEM carry serious clinical consequences to theaffected neonates , including mild to severe mental
retardation, ph y s ical handicap and even fatality.
Organic acidemias (OA ) caused by mitochondrialenzyme defects in the cata b o lism of branched chain
amino acids and fatty acids oxidation defects cons titutea grou p o f more than 20 disorders . These disorders
include propionic acidemia (PA), me t h y lma lo n ic
acidemia (MMA), isovaleric acidemia (IVA ), biotin-un re s p o n s iv e 3-me t h y lcrotonyl-CoA carboxylase
deficiency, 3-hydroxy-3-me t h y lglutaryl-CoA (HMG-
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
370
CoA) lyase deficiency, â-ke t o t hiolase deficiency andglutaric acidemia type I (GA t ype I), . In these etc...
in th ese disorders acyl-coA esters accumulate in the
mitochondria. Carnitin e plays a key role in removingth e potentially toxic Acyl-coA es ters through the
formation of acylcarnitine es ters an d t h ereby releas ingcoenzyme A and res toring mitochondrial homeos tas is [3 ,4]
This results in increased concentrations of circulating
acylcarnitine, increas ing e xcretion of acylcarnitine inurine and secondary carnitine deficiency [5]
The aim of this descriptive s tudy is to find out the
prevalence of OA disorders detectab le by MS/MSamong all patients attending the Neurome t a bolic Clinic
at Cairo Univers ity Children Hospital (CUCH), located
at the Centre of Social an d Preventive Medicine(CSPM) and to re view the clinical, biochemical and
neuroradio lo g ical data of the Egyptian patientsdiagnosed as organic acidemias and t o highlight the
importance of including organic acidemias in newborn
screening programs with MS/MS.
MATERIALS AND METHODS
Eight hundred pa t ie n t s re fe rre d to the
neurometabolic clin ic , during the period from January
2008 to September 2008, suspected of having inbornerrors of metabolism were subjected to the following:
Clinical evaluation including his tory, general a nd
neu ro lo g ic a l e xa min a t io n a n d family pedigreecons truction
Basic metabolic investigations including completeblood picture (CBC), blood glucose and serum
IVA Case 9 MRI shows no focal cerebral lesion, (normal)
Biotinidase MRI shows generalized demyelination involving both superficial and deep white matter
deficiency Cases
11, 15 &16
#CT brain shows cortical brain atrophy at the frontotemporal regions(case 15&16,partial biotinidase deficiency)
Canavan disease Extensive demyelinating brain disease involving both the deep peri v en t r i cu l ar w h ite matter as well as the subcorticalCases (12 & 14) white matter and involving U fibers,the corpus callosum as well as the internal capsule fig 5.
GA 1 Case 13 prominent cortical brain sulci,basal cisterns and both sylvian fissures with widening of the subdural space at both
frontotemporoparieto-occipitalregions,denoting
severe brain atrophy(fig 3)
D-2 glutaric aciduria M R I s h o w s periventricular ill defined patchy area of abnormal signals, likely related to incomplete myelination process .
Case 17 fig 6.
ASA Case 18 Delayed myelination of dentate nuclei and p o s t er i o r l imbs of internal capsules, colpocephaly,dilatation of the right
lateral ventricle and partial agenesis of the corpus callosum
3 MGA Case 19 Frontotemporal brain atrophy, more on the right side and mild bilateral frontotemporal subdural effusion and right
frontal heamatoma fig 7.
characterized b y in t ra c t a b le metabolic acidos is ,
associated with encephalopathy and dis turbed consciousle v e l. A b d o min a l e xa min a t io n re v e a le d mild
hepatosplenomegaly and there was extens ive exfoliativedermatitis .
Analys is by LC/MS/MS showed an increased C3and ketotic h yperglycinemia and diagnos is was
confirmed by urine organic a c id profile us ing GC-MSfig 1.
Although Chace and co workers s tated thatextremely high conce n t rations of C3 (>10 µmol/L)
gen e rally indicate acute PA and Moderate increases inC3 (>6–10 µmol/L) u sually indicate a MMA, this was
not the case in our s tudy as two c a s e s with very highC3 (59.6 and 22.4) were confirmed to be MMA by
GC-MS. This may prove that th is rule is anapproximation, and organic acid analys is and other
confirmatory tes ts are required to accurately diagnoseany of these disorders .[9]
2- Beta Ketothiolase: Three case s o u t of 800 (0.375%)
attending the outpatient clinic showed elevated wholeblood C5OH were detected b y M S/MS and further
confirmed as BKT by GC- MS. All 3 cases suffered from severe metabolic acidos is
triggered by an a t t a ck of gas troenteritis and fever and
c u lminating into dis turbed conscious level a n d
admiss ion in ICU. All patients exhibited minordysmorphic facial features in the fo rm of synophyris ,
and high arched palate,2/3 developed hypotonia,1/3developped shock and required artificial ventilation
(case no. 2),and case 3 re q uired peritoneal dialys is forcorrection of intractable metabolic acidos is .
3- Is ovaleric Acidemia: W e have recorded only one
patient out of 800 patients (0.125%) seen a t theneurometabolic clinic who was diagnosed as isov a leric
acidemia, showing an elevated C5= 6.7umol/l (fig 2).C5 is the primary marker fo r IVA and the flag was set
at 0.7umol/L. Because C5 acylcarn it ine represents amixt u re o f is o me r s ( is o v a le ry lc a rn it in e , 2-
methylbutyrylcarnitine, and pivaloylcarnitine) a nd theclinical picture overlaps other o rganic acidemias and
urea cycle defects further diagnos tic evaluation byperforming urine organic acid p rofile by GC-MS was
performed to confirm diagnos is .
The patient presented with several ep is odes ofmetabolic acidos is and encephalopathy with dis turbed
consc io u s level with repeated attacks of vomiting,dehydration and refusal o f feeding necess itatingfreque n t hospital admiss ions . Examination revealed
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
375
Fig. 1: 1a showing the photography of case no6 wit h me thyl malonic academia(MMA);1b, a serial of TW I&TW 2
brain MRI showing moderate atrophic brain changes mos tly apparent in fronto t e mp o ral regions ;1c,theLC-MS/MS curve of the same case showing increas e d C3(the marker component of MMA/PA), and 1d,
urinary acylcarnitine profile by lC-MS/MS showing high methylmalonyl carnit in e m/ z 374.5 (case No 6).
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
376
Fig. 2a: photography of case9 with Isovaleric academia(IVA)
Fig. 2b: Lc-MS/MS curve of case 9 showing high C5 (Isovaleryl Carnitine)
Fig. 3: 3a,photography of case 13 with glutaric aciduria type 1showing severe dys tonic pos turing
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
377
Fig. 3b: Lc-MS/Ms & GC-MS results of dried blood s p o t a n d urine organic acid profile of Case No13 with
Glutaric Aciduria Type I.
Fig. 3c: TW I Brain MRI showing prominent cortical brain sulci, basal cis terns and both s y lv ian fis sures with
widening of the subdural space at both frontotemporoparieto-occip it a lre gions denoting severe brainatrophy(case 13, Glutaric Aciduria type1).
mic ro c e p h a ly with generalized hypot o n ia a n d
hyporeflexia, dysmorphism in the form of everted earlobules and synophyris , fig 2 mild normocytic anemia
and thrombocytopenia pancytopenia, as well as isolatedneutropenia and th ro mbocytopenia may occur in IVA
and is a ttributed to bone marrow suppress ion [10]
Hyperammonemia was also observed in the patient and
is presume d to be due to inhibition of N_acetylglutama t e synthetase by isovaleryl CO-A(leading to
reduced N ac e t y l glutamate and impairement of urea
cycle . Similar clinical presentations were previous ly[11]
reported by others [12 ,13 ,14 ,15 ,16 ,17]
4- 3 Methyl Glutaconic Aciduria: 3-Methylglutac o n ic
aciduria is a rare hereditary metabolic d isorderch a ra cterized by increased urinary excretion of 3-
methylglutaconic and 3-methylglutaric acids . Fourclinical forms are recognized .[18]
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
378
Fig. 4: 4a, case no7 with methylcrotonyl glycinuria(MCG)
Fig. 4b: Lc-MS/MS curve demons trating high C5OH in case 7(MCG)
Fig. 4c: TW I brain MRI from case 7 showing both cortical & central atrophic brain changes
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
379
Fig. 5: fig 5a , urine GCMS profile from case 12 with canavan disease showing increased N-acetyl aspartate
Fig. 5b: T2W brain MRI from case 12 with canavan disease showing extens ive demyelination in v o lv in g both
the deep periventricular & the subcortical white matter, U fibers , and corpus callosum .
One female patient (0.125%) was diagnosed as 3methylglutaconic aciduria. The patient p resented
initia lly with delayed mental and motor developmentalmiles tones and recurrent ches t infections . Examination
rev e a led obes ity, generalized hypotonia and moderatehepatos p lenomegaly, mild cardiomegaly with left to
right shunt demons trable on echocardiography. Patientexhibited one attack of metabolic decompensation wit h
metabolic acidos is and dis turbed conscious level. Theclinical presentations of this c a s e are cons is tent with
those of 3 methylglutaconic aciduria type II (BarthSynd ro me ). MS/MS revealed an elevated C5OH[19 ,20]
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
380
Fig. 6: Urine organic acid profile from case no 17 by GC-MS showing marked increased of d 2 is o me r o fglutaric aciduria .
Fig. 7: TW 1 brain MRI from Case 19 showin g ma rked frontotemporoparietal atrophic brain changes , bilateralfrontoparietal subdural effus ion and right frontal hematoma.
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
381
and GC-MS analy s is showed increased 3-methylglutaconic acid and 3 methyl glutaric acid.
B- Cerebral Organic Acidurias: Cerebral organic
acidurias are a group of disorders in which neurologicalmanifes tations can be the leading presenting feature,sometimes in the absence o f metabolic derangement.
Characteris tic clinical findings are ataxia, myoclonus ,e xt ra p y ramidal symptoms, metabolic s tro ke a n d
megalencephaly. As a group these "cerebral" organic[21]
acid disorders are often undiagnosed and their true
incidence is much less well-known than that of the"class ical" organic acid disorders .
1- Methyl Cr otonyl Glycinuria: Two male s iblings
(descendant of consanguineous parents) were diagnosedas methyl crotonyl glycin uria. Extremely high C5OH
on MS/MS analys is (60 umol/l, Cut off value = 1.0umol/L) (fig 4b). Highly ele v ated 3 hydroxyisovaleric
and 3 methyl crotonyl glycinuria were the biochemicalmarkers found on urine o rg a n ic acid analys is by GC-
MS result in g from deficiency of 3 methyl Co-Ac a rb o xy la se deficiency (MCCD). Both p a t ie n t s
presented with glo bal developmental delay, profoundmental retardation, growth retard a t ion, involuntary
movements , squint, microcephaly, hypertonia a n dspas tic gait. Cerebral palsy-like symptoms accompanied
by extrapyramidal s igns called for extens ive me tabolicevaluation including the determination of urinary 3-
methyl crotonyl glycin u ria fig 4. There was no his toryof metabolic decompensation or encephalo pathy.Controvers ial clinical presentations were reported in the
literature. The main clinical features of p a tients[22 ,23 ,24]
with MCCD reported in the literature included
muscular hypotonia and atrophy , failure to thrive,[25]
seizures and pro fo und irrevers ible metabolic acidos is
, i n v o l u n t a ry mo v e me n t s , me t a b o l i c[ 2 6 , 2 7 ]
decompensation , quadriplegia, hemipares is and focal[28]
seizures Brain MRI results in the 2 p a t ients with MCG
showed both cortical and central a trophic brainchanges . Marked atrophic brain c h a nges and multiple
loci of leukodys trophy on brain MRI were also foundby Murayama et al., 1997 and De Kremer et al.,[29 ,30]
2 - D2 Hy dr o x y G l u t a r i c Ac i dur i a: D2-
Hydroxyglutaric aciduria is a neurometabolic diseasecharacterized by the accumulation of abnormal amounts
of D-2-hydroxyglutarate in cerebrospinal fluid, bloodand urine firs t described by Chalmers et al.,[31]
A 5 months old female patient presented withintractable seizures as th e leading symptom.. She also
had - mild ps y c h omotor retardation and compensatedmetabolic acidos is , with no dysmorphic fa cial features ,
a picture s imilar t o t h a t reported by Van der Knaap eta l . , The brain MRI of our patient showed[3 2 ]
periventricular ill defined patchy area of abnormals ignals , likely related to incomple t e myelination
process . Comparab le findings were reported by W ajneret al[33]
MS/ M S screening showed an elevated C3, whichwa s not remarkable. Urine organic acid profile sho we dhighly elevated D 2-hydroxyglutaric acid, s u c cinic acid
and lactic acid with low 2- o xo g lutaric acid. Furtherc o nfirmation and id e n t ific a t io n o f t h e e xa c t
configuration of 2-hydroxyglutaric acid was performedand data were cons is te n t with D 2-hydroxyglutaric
aciduria (fig 6).
3- Glutaric Aciduria: One p a tient was diagnosed withglutaric aciduria by a typical increase in the C5DC,
which is a dic a rb oxylic acylcarnitine that was detectedat m/z 388 by a Pre 85 scan. Increased C5DC is
indicative of GA-I. Although relatively rare in t h egeneral popu la t io n , it o ccurs more frequently in
populations that are more commonly consanguineous .[34]
The reported p atient presented at the age of 6
months with tonic clonic se izu res , opis thotonicdys tonia. neck retroflexion, progress ive macrocephaly,
and a compensated metabolic acidos is , with sparse hair,ves icular eruption on the back, dysmo rphic facial
features in the form of upturned n o s e , and frontalb o ss ing(fig 3a). Subtle early findings , such as tru n c a l
hypotonia and relative macrocephaly as seen in thispatien t , are often present but eas ily overlooked. Many
are misdiagnosed as cerebral pals y or infectiousencephalopathy. Comparable findings are also[3 5 , 36 ,37]
described by M orton et al., . Brain MRI shows[38]
prominent cortical brain sulci, basal cis terns a nd bothsylvian fis sures with widening of the subdural space at
both frontotemporoparieto-occipital regions , a picture ofsevere cortical brain atrophy(fig 3c). These findings are
s imilar to reported literature. [39]
4 - Canavan Disease: Canavan disease is one of themost common cereb ral degenerative diseases of
infancy . It is one of a group of genetic disordersknown as leukodys trophies . In this disorder the white[40]
matter of the brain degenerates into spongy tissue. It iscaused by a mutation in the g e n e fo r aspartoacylase
enzyme (ASPA).[41]
Two patients (0.250%) were diagnosed as canavandisease (4 & 12months respectively). The salient
clinical features were atonia of neck muscles ,truncalhypotonia, upper a nd lower limb hypotonia in the
young infant while the older presented with hypertonia,o c u la r ma n ifes tations in the form o f v is u a l
inattentiveness and oculoclonia, severe mental defectand megalancephaly. The ne u rologic findings are due
to demyelination a nd leukodys trophy as reported byMatalon et al., and Matalon et al.,[42 ,43]
Res. J. Medicine & Med. Sci., 4(2): 369-385, 2009
382
Both patients had a normal metabolic screeningu s in g M S/ M S, h o we v er, organic acid profile
demons trated marked increase in N acetyl aspartic acid(NAA) in urine(fig5a). This is in a c c o rd ance with
Matalon et al., who d emons trated excess ive urinary[44]
NAA e xc retion almos t 200 times the amounts found innormal age-matched individuals . Neither enzymatic
assay nor brain biopsy was performed in our cases . Exte n s ive demyelination involving both superficial
and deep white matter as well as u fibres and internalcapsule were shown on brain MRI in both cases (fig5b).
Molecular diagnos is was carried out on one patient bygene sequencin g o f t he 6 exons and of intron –exon
junction of t h e A SPA for the proband case as well ashis s is ter, and both parents . Results proved that the
p a t ient is homozygous for the protein sequenc evariant of ASPA gene located on chromosome 17:
p.Arg233fs / p.Arg233fs while the s is ter as well a s bothparents was heterozygous for the protein sequ e n c ing
variants of the ASPA gene.
5 - Biotinidase Deficiency: Three patients in this s tud ywere diagnosed with biotinidase deficiency. Their
MS/ M S scan was normal. MS/MS can be normal in upto 20% of patients with biotinidase deficien c y a n d
therefo re t h e b e s t method of screening is asemiquantitative co lo rimetric assessment of biotinidase
act iv ity that can be performed on whole blood spotted
on filter paper.[45]
Marked deficiency in the activity of biotinid aseenzyme (<10%) was re p o rt ed in one patient (case 11)and 2 cases (s iblings) with partial biot in id a s e
deficiency (10- 30%).The case with marked enzyme deficiency presented
with lack of head support and in t ractable seizures .Patient had extens ive seborrheic dermatitis , with total
a lo p e c ia , c o n ju n c t iv it is with periorb it a l s kininflammation and very sparse eye brows , hypotonia and
deve lo p me n t a l delay. Similar presentations wereprevious ly reported by others . Other features cited[46 ,47]
in the literature by W o lf e t al., and W olf et al., ,[48 ,49]
included ataxia , s ensory neural hearing loss were
encountered in the two s iblings with partial biotinidased e ficiency and in addition they had bilateral pyramid a l
tract affe c tion with very rough and sparse hair. Theformer case showed extens ive demyelination including
subco rtical and periventricular white matter while thela t t e r two cases showed cortical atrophic changes on
MRI.Although many previous sc reening programs
emphasized only o n t h e value of amino acidabnormalities , this s tudy h ig hlights the importance of
screening high risk group s fo r organic acidopathies ,which are evidently highly prevalent fro m this s tudy
among our cons a n guineous community. It also drawsattention to the importance of implementing expanded
metabolic screening to avert serious co n sequences ofeither mental retardation or even death. The availability
of second further c o n firmatory tes ts provided by theGC-MS is of utmo s t importance for differentiating
subgroups of abnormal acylcarnitne profiles detected inNBS by MS/MS.
Conclus ion: Organic acidemias are not rare aspre v ious ly thought especially in countries with high
rates of consanguin e o u s ma rriages like Egypt.Expanded screening fo r organic acidopathies by
MS/MS us ing dried blood spot technique is a rapid andeffic ie nt method in detecting cases with poss ible
organic acid emias requiring confirmatory tes ts by GC-MS. Including organic acidopathies in newborn
s c reening programs would be of tremendous help inearly detection of pos itive cases , t hus a rapid and
properly timed therapeutic inte rv e n t io n can beundertaken to prevent devas tating neurological outcome.
Advances in n ewborn screening technology, coupledwith recent advances in the diagnos is and treatment of
rare but serious congen it a l conditions that affectnewb o rn infants , provide increased opportunities for
pos itively affectin g t he lives of children and theirfamilies . These ad v a n tages , however, also pose new
challenges in response to the management of affectedinfants
ACKNOWLEDGMENT
W e express our de epes t gratitude to Prof. Dr.Mohammed Abdel Hamid, Faculty of Pharmacy Kuwait
Univers it y ; Prof. Dr. Mohamed Rashed, King FaisalHospital, Riyadh; for their continuous support and help
for urinary GC/MS analys is , throughout our work byoffering their experie n ces and collaboration. W e also
would like to thank Catherine Sabane,hospital neckerDe s e nfants malades …. for s incere help with genetic
s tudies performed.
Footnotes: Nonstandard abbreviations : MS/MS, tandemmass spectrometry; C3 , p ro p io n y lc a rnitine; C5,
isovalerylcarnitine ; C5OH, 3-hydroxydecanoylcarnitine;PA, propionic acidemia; MM A , me t h y lma lo n ic
a c id e mia ; GC-MS, g a s c h ro ma t o g ra p h y / ma s ss p e c t r o me t r y ; ES I / M S / M S , e l e c t r o s p r a y
io nization/tandem mass spectrometry; PICU, pediatricintens ive care unit; IEM, inborn errors of metabolism;
CUCH, Cairo Univers ity Children Hospital.
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