Table Of ContentEva Morava
Matthias Baumgartner
Marc Patterson
Shamima Rahman
Johannes Zschocke
Verena Peters Editors
JIMD Repor ts
Volume 39
JIMD Reports
Volume 39
Eva Morava
Editor-in-Chief
Matthias Baumgartner Marc Patterson
(cid:129) (cid:129)
Shamima Rahman Johannes Zschocke
(cid:129)
Editors
Verena Peters
Managing Editor
JIMD Reports
Volume 39
Editor-in-Chief Editor
EvaMorava MatthiasBaumgartner
TulaneUniversityMedicalSchool DivisionofMetabolism&Children’sResearch
NewOrleans Centre
Louisiana UniversityChildren’sHospitalZ€urich
USA Z€urich
Switzerland
Editor Editor
Marc Patterson ShamimaRahman
DivisionofChildandAdolescent Neurology ClinicalandMolecular GeneticsUnit
MayoClinic UCLInstituteofChildHealth
Rochester London
Minnesota UK
USA
Editor ManagingEditor
JohannesZschocke VerenaPeters
DivisionofHuman Genetics CenterforChildandAdolescentMedicine
Medical UniversityInnsbruck HeidelbergUniversityHospital
Innsbruck Heidelberg
Austria Germany
ISSN2192-8304 ISSN2192-8312 (electronic)
JIMD Reports
ISBN978-3-662-57576-5 ISBN978-3-662-57577-2 (eBook)
https://doi.org/10.1007/978-3-662-57577-2
#SocietyfortheStudyofInbornErrorsofMetabolism(SSIEM)2018
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Contents
Successful Pregnancy in a Young Woman with Multiple Acyl-CoA
Dehydrogenase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Annalisa Creanza, Mariella Cotugno, Cristina Mazzaccara, Giulia Frisso,
Giancarlo Parenti, and Brunella Capaldo
Role of Intramuscular Levofolinate Administration in the Treatment
of Hereditary Folate Malabsorption: Report of Three Cases.. .. .. .. .. .. .. .. . 7
Emanuela Manea, Paul Gissen, Simon Pope, Simon J. Heales, and Spyros Batzios
The Prevalence of PMM2-CDG in Estonia Based on Population Carrier
Frequencies and Diagnosed Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Mari-Anne Vals, Sander Pajusalu, Mart Kals, Reedik M€agi, and Katrin O˜ unap
Triheptanoin: A Rescue Therapy for Cardiogenic Shock in
Carnitine-acylcarnitine Translocase Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . 19
Sidharth Mahapatra, Amitha Ananth, Nancy Baugh, Mihaela Damian,
and Gregory M. Enns
Glutaric Aciduria Type 1 and Acute Renal Failure: Case Report and
Suggested Pathomechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . 25
Marcel du Moulin, Bastian Thies, Martin Blohm, Jun Oh, Markus J. Kemper,
Rene´ Santer, and Chris Mu€hlhausen
Cardiovascular Histopathology of a 11-Year Old with Mucopolysaccharidosis
VII Demonstrates Fibrosis, Macrophage Infiltration, and Arterial Luminal
Stenosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Valerie Lew, Louis Pena, Robert Edwards, and Raymond Y. Wang
Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset
Niemann-Pick Disease Type C Patients Treated with Miglustat. . . . . . . . . . . . . 39
Elizabeth A. Bowman, Dennis Velakoulis, Patricia Desmond,
and Mark Walterfang
Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After
a Normal Newborn Screen in Two Individuals. . . . . . . . . . . . . . . . . . . . . . . . . . 45
Monica H. Wojcik, Klaas J. Wierenga, Lance H. Rodan, Inderneel Sahai,
Sacha Ferdinandusse, Casie A. Genetti, Meghan C. Towne, Roy W. A. Peake,
Philip M. James, Alan H. Beggs, Catherine A. Brownstein, Gerard T. Berry,
and Pankaj B. Agrawal
v
vi Contents
Rapidly Progressive White Matter Involvement in Early Childhood:
The Expanding Phenotype of Infantile Onset Pompe?. . .. . . .. . .. . .. . . .. . .. 55
A. Broomfield, J. Fletcher, P. Hensman, R. Wright, H. Prunty, J. Pavaine,
and S.A. Jones
Four Years’ Experience in the Diagnosis of Very Long-Chain Acyl-CoA
Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn
Screening Centers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
B. Merinero, P. Alcaide, E. Martı´n-Herna´ndez, A. Morais, M. T. Garcı´a-Silva,
P. Quijada-Fraile, C. Pedro´n-Giner, E. Dulin, R. Yahyaoui, J. M. Egea,
A. Belanger-Quintana, J. Blasco-Alonso, M. L. Fernandez Ruano, B. Besga,
I. Ferrer-Lo´pez, F. Leal, M. Ugarte, P. Ruiz-Sala, B. Pe´rez, and C. Pe´rez-Cerda´
Social Functioning and Behaviour in Mucopolysaccharidosis IH
[Hurlers Syndrome]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Annukka Lehtonen, Stewart Rust, Simon Jones, Richard Brown,
and Dougal Hare
Mitochondrial Encephalopathy and Transient 3-Methylglutaconic Aciduria
in ECHS1 Deficiency: Long-Term Follow-Up. . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Irene C. Huffnagel, Egbert J. W. Redeker, Liesbeth Reneman, Fre´de´ric M. Vaz,
Sacha Ferdinandusse, and Bwee Tien Poll-The
Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different
Routes of Ascertainment. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. 89
Paula J. Waters, Thomas M. Kitzler, Annette Feigenbaum, Michael T. Geraghty,
Osama Al-Dirbashi, Patrick Bherer, Christiane Auray-Blais, Serge Gravel,
Nathan McIntosh, Komudi Siriwardena, Yannis Trakadis,
Catherine Brunel-Guitton, and Walla Al-Hertani
High-Throughput Screen Fails to Identify Compounds That Enhance
Residual Enzyme Activity of Mutant N-Acetyl-a-Glucosaminidase
in Mucopolysaccharidosis Type IIIB. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
O. L. M. Meijer, P. van den Biggelaar, R. Ofman, F. A. Wijburg,
and N. van Vlies
Demographic and Psychosocial Influences on Treatment Adherence
for Children and Adolescents with PKU: A Systematic Review. . . . . . . . . . . . . 107
Emma Medford, Dougal Julian Hare, and Anja Wittkowski
JIMDReports
DOI10.1007/8904_2017_38
RESEARCH REPORT
Successful Pregnancy in a Young Woman with Multiple
Acyl-CoA Dehydrogenase Deficiency
Annalisa Creanza(cid:129)Mariella Cotugno(cid:129)
Cristina Mazzaccara(cid:129)Giulia Frisso(cid:129)
Giancarlo Parenti(cid:129)Brunella Capaldo
Received:07March2017/Revised:08June2017/Accepted:09June2017/Publishedonline:07July2017
#SSIEMandSpringer-VerlagBerlinHeidelberg2017
Abstract Multiple acyl-CoA dehydrogenation deficiency Introduction
(MADD)isaninborndisorderoffattyacidoxidationdueto
a defect in electron transfer to the respiratory chain. We Multiple acyl-CoA dehydrogenase deficiency (MADD),
describe the medical/nutritional management of a success- also known as glutaric aciduria type II, is an autosomal
ful pregnancy in a 19-year-old woman with a known recessivelyinherited disease offattyacid,someaminoacid
diagnosis of MADD. A high-carbohydrate, low-fat, six- and choline oxidation, caused by a defect in the electron
mealdietsupplementedwithproteinwasprescribedtomeet transfer flavoprotein (ETF) or the electron transfer flavo-
the nutritional needs during pregnancy. L-Carnitine supple- protein dehydrogenase (ETFDH), enzymes involved in the
mentationwasalsoprogressivelyincreasedovertheweeks. mitochondrial respiratory chain. This defect results in
Serumacyl-carnitineprofilerevealedraisedlevelsofchain- compromised fatty acid oxidation, with consequent
length C6-C14, which remained substantially unchanged impaired adenosine triphosphate (ATP) synthesis, insuffi-
during pregnancy. Serum amino acid profile was in the cient gluconeogenesis and excessive lipid accumulation in
normal range indicating an adequate nutritional support. different organs.
Pregnancy progressed uneventfulandthepatient gavebirth The clinical expression of MADD is highly heteroge-
to a healthy boy without any complication. neous ranging from severe neonatal-onset form, with or
A careful clinical monitoring associated with an ade- without congenital anomalies, to milder form with a late-
quate medical/nutritional management may improve preg- onset, which is characterized by intermittent episodes of
nancy outcome in women with MADD. lethargy, metabolic acidosis, non-ketotic hypoglycaemia,
muscle weakness, generally triggered by catabolic stress
(Rhead et al. 1987; Turnbull et al. 1988; Mongini et al.
1992).
The clinical diagnosis of MADD is based on the
presence of organic acid and acylglycine derivatives in the
urineandincreasedlevelsofmedium-andlong-chainacyl-
Communicatedby:RobertSteiner carnitines in the blood. Mutations in ETFA, ETFB or
: :
A.Creanza M.Cotugno B.Capaldo(*) ETFDH genes, encoding the alpha and beta subunits of
DepartmentofClinicalMedicineandSurgery,UniversityofNaples electron transfer flavoprotein and the ETF-dehydrogenase,
FedericoII,Naples,Italy confirm the diagnosis.
e-mail:[email protected]
The treatment of MADD consists of a high-carbohy-
:
C.Mazzaccara G.Frisso drate, low-fat, low-protein diet associated with riboflavin
DepartmentofMolecularMedicineandBiotechnologies,CEINGE-
and carnitine supplementation. Prevention offasting and of
BiotecnologieAvanzate,UniversityofNaplesFedericoII,Naples,
other precipitating stresses is also essential. Riboflavin is
Italy
precursor of flavin adenine dinucleotide (FAD), a cofactor
G.Parenti
of several mitochondrial enzymes, such as the acyl-CoA
DepartmentofTranslationalMedicine(G.P.),UniversityofNaples
FedericoII,Naples,Italy dehydrogenases.Thereisevidenceofsymptomsrestoration
2 JIMDReports
after riboflavin treatment particularly in patients with late- biochemical analyses showed remarkable increments in
onset MADD (Olsen et al. 2007). transaminases, lactic dehydrogenase, aldolase and creatine
Advancesinbothnutritionaltherapyandmanagementof kinase. The chromatographic layout of urinary organic
acute attacks have considerably improved the outcome of acids showed a typical dicarboxylic aciduria. MADD
MADD,particularlyinpatientswiththemilderformsofthe diagnosis was confirmed by molecular analysis, performed
disease (Williams et al. 2008; Trakadis et al. 2012). Thus, according to the standardized approach (Scolamiero et al.
an increasing number of women long to have a baby. For 2015), which showed a compound heterozygosity in the
most of the inherited diseases there is a lack of specific ETFDH gene (NM_001281737.1) for the mutations
guidelinesforthemanagementduringpregnancy;therefore, c.1074G>C (p.R358S) and c.1073G>A (p.R358K) in
experience from isolated case reports is particularly exon 9. Her parents were healthy carriers of one of the
valuable. two mutations (Fig. 1).
We present the case of a young woman with MADD Since the diagnosis, the patient was under follow up at
who led to a successful pregnancy and her medical/ the Paediatric Unit of AOU Federico II of Naples; she has
nutritional management during pregnancy and delivery. been treated with a diet restricted in fat and protein
associated with riboflavin,pyridoxine andcarnitinesupple-
mentation. Over the years, the patient required sporadic
Case Description hospitalizations for metabolic decompensations resolved
with intravenous dextrose infusion and hydration.
The patient is a 19-year-old woman who was diagnosed Attheageof18,thepatientwashospitalizedforasevere
with MADD at the age of 3 years, due to occurrence of episode of rhabdomyolysis (serum creatine kinase level:
lethargy and asthenia associated with anorexia. Routine 69960UI/L), which resolved with intravenous infusion of
Fig.1 PedigreesofthefamilywithMADDdefect.Theelectropherogramshowingthemutationinthenucleotidesequenceisundereachsymbol
JIMDReports 3
Dextrose solution (initially 33%, then 10%), hydration and points showed amino acid levels within or slightly below
increased oral L-carnitine supplementation (100 mg/kg/ the normal range (Table 2).
day). Few months later, the patient unexpectedly became Periodic glucose home monitoring evidenced blood
pregnant. She was not blood related to her partner. The glucose levels within the normal range and no value was
geneticanalysisof the partner didnot reveal any mutations below 70 mg/dL throughout the gestation. Periodic obstet-
of ETFA/ETFB/ETFDH genes. At 8 week of gestation, the ricultrasoundexaminationevidencednormalfoetalgrowth.
patientwasingoodclinicalconditionsandtheresultsofher At the 39th, the patient underwent an elective cesarean
biochemical routine tests were normal. Echocardiographic section to reduce the risk of metabolic decompensation.
examination evidenced a normal cardiac function. The During deliveryandin the immediate postoperativeperiod,
medicalandnutritionalmanagementforthewholegestation she received intravenous carnitine (3,000 mg/day) and
is reported in Table 1. A normocaloric (1,700 kcal) diet isotonic solution (with 10% dextrose) at variable rate to
moderately restricted in fat and protein was recommended; maintainnormoglycaemia.Shegavebirthtoa3.1kghealthy
anadequateintakeofcarbohydrate(>50%oftotalcalories) boy without any complication. The baby was breastfed for
wasprovidedsinceitisthemainenergysubstrateforfoetal 2 months during which the patient continued the medical/
metabolism. The diet was divided into three main meals nutritionaltherapyfollowedduringpregnancy.Atbreastfeed-
and three snacks in order to avoid prolonged fasting and to ing discontinuation,shereturnedto her usual dietary protein
prevent the risk of hypoglycaemia. In addition, the patient restriction and carnitine was reduced to the pre-gestation
was recommended to have a glucose supply (25–50 g) dose while continuing riboflavin and pyridoxine.
every2hincaseofdiscomfortorepisodicvomitingandto
contact the hospital in case of persistence of symptoms,
fever or acute illness. Discussion
Inthesecond andthirdtrimester,aproteinsupplementa-
tion was added to meet the increased protein requirement Patients with MADD generate less energy from fatty acids
(Table 1). Riboflavin, pyridoxine and L-carnitine dosages andaminoacidsbecauseofadefectivetransferofelectrons
were maintained constant. Folic acid, multivitamin and from flavoproteins to the mitochondrial respiratory chain.
mineral supplements were started in the first trimester. At The reduced supply of energy is responsible for a number
the beginning of the third trimester, L-carnitine was of clinical manifestations involving particularly those
increased to 4,000 mg/day because of an increased sense organs that have a high flux of beta-oxidation: the skeletal
of fatigue. muscle, with consequent hypotonia, weakness and exercise
At the 22nd and the 36th week of pregnancy, the acyl- intolerance; the heart with cardiomyopathy and arrhyth-
carnitine profile was analysed through spot extraction of mias; the liver with hepatomegaly and liver dysfunction;
blood on filter paper with chromatography liquid-mass the brain with encephalopathy.
tandem spectrometry (LC-MS-MS). Blood acyl-carnitine The severity of the clinical phenotype of MADD is
profile revealed raised levels of chain-length C6-C14, explained by the type of mutation in the ETFA/ETFB/
which remained substantially stable during pregnancy. ETFDH genes, which results in different levels of residual
Blood amino acid analysis performed at the same time enzyme activity (Olsen et al. 2003). Nonsense mutations
Table1 Medicalandnutritionalmanagementduringthecourseofpregnancy
Week Weight(kg) Energyintake(kcal/day) CHOg(%) Pg(%) Lg(%) Proteinsupplement(g/day) Therapy(mg/day)
8 63.8 1,700 257(53) 80(18) 59(29) 0 L-Carnitine3,000
Riboflavin100
Pyridoxine300
12 65.0 1,900 260(53) 90(19) 57(28) 10 L-Carnitine3,000
Riboflavin100
Pyridoxine300
24 70.0 2,100 263(49) 110(21) 60(30) 30 L-Carnitine4,000
Riboflavin100
Pyridoxine300
34 79.5 2,100 263(49) 110(21) 60(30) 30 L-Carnitine4,000
Riboflavin100
Pyridoxine300
CHOcarbohydrate,Pprotein,Llipid
4 JIMDReports
Table2 Bloodacyl-carnitineandaminoacidprofilesduringthecourseofpregnancy
Bloodacyl-carnitinelevels(mmol/L) Bloodaminoacidlevels(mmol/L)
Metabolite Week22 Week36 Normalrange Metabolite Week22 Week36 Normalrange
C2 5 4.9 3.5–15.4 Asparticacid 15 94 24–102
C3 0.28 0.32 0.07–0.65 Glutamicacid 73 298 67–223
C4 0.76 0.35 0.12–0.42 Serine 73 232 111–297
C5 1.35 0.65 0.05–0.24 Glutamine 429 401 432–871
C6 1.12 1.00 0.04–0.18 Alanine 298 554 193–597
C8 3.67 2.74 0.07–0.25 Glycine 145 401 240–460
C10 5.38 5.49 0.09–0.43 Threonine 133 195 109–268
C12 1.21 1.32 0.04–0.21 Arginine 23 76 36–172
C14 0.56 0.53 0.03–0.23 Histidine 87 119 72–131
C16 0.40 0.32 0.01–0.23 Taurine 78 212 50–270
C18 0.19 0.15 0.01–0.18 Tyrosine 46 69 45–107
Phenylalanine 62 163 59–112
Methionine 21 32 21–44
Leucine 98 144 82–258
Valine 190 237 187–411
Isoleucine 57 62 42–111
Lysine 147 195 150–286
Proline 168 191 50–350
Ornithine 46 75 63–133
are associated with fatal disease while missense mutations, Althoughthemutationidentifiedinourpatientcannotbe
particularly in the ETFDH gene, leaving a detectable linked with certainty to mild/late-onset MADD, she is
residual enzyme activity, may account for the milder forms likelytohaveamildformofthediseaseinconsiderationof
of the disease (Olsen et al. 2003; Goodman et al. 2002; some important characteristics, i.e., the absence of congen-
Schiff et al. 2006; Yotsumoto et al. 2008). In the latter ital abnormalities, age at diagnosis and the relatively mild
forms, symptomsareusually elicited byillnessorcatabolic clinical course of the disease. Throughout the years, the
stress, as physical exercise, prolonged fasting, irregular patient suffered from sporadic episodes of vomiting,
diet, although additional factors, not yet identified, such as hypoglycaemiaandmuscleweakness,whichweretriggered
cellular temperature, have been reported to modulate the by catabolic stress. Although pregnancy cannot be consid-
enzymatic activity (Olsen et al. 2003). ered a strictly catabolic condition, it may precipitate
OurpatienthadbiallelicmutationsinETFDHgene,both metabolic decompensation in women with inherited disor-
in exon 9: c.1074G>C (p.R358S) and c.1073G>A (p. ders of energy metabolism. Nausea, recurrent vomiting or
R358K). The former, already described in the homozygous fasting may cause a shift of maternal metabolism towards
stateinthreePalestiniansiblings,wasassociatedwithearly ketosis and reduce glucose availability at a time of
onset and milder forms of MADD (Olsen et al. 2005). The increased metabolic demand. Thus, the gestation in a
c.1073G>A (p.R358K) mutation was submitted just once woman with MADD may represent a high-risk condition
toClinVardatabase(rs796051959 inhttps://www.ncbi.nlm. both for the mother’s health and for foetal growth. Hence,
nih.gov/clinvar/)aspathogenicallele,althoughlackinglink strict nutritional/medical surveillance is of paramount
to a specific clinical condition. However, familial segrega- importance in pregnant women with MADD. At present,
tionstudyandinsilicoanalysis,performedbybioinformat- no guidelines are available for the care of pregnant women
ics tools, confirmed that this substitution is likely with this condition. Likewise, a clear management plan for
pathogenetic. deliveryiswarranted,aslabourisassociatedwithincreased
