Received 14 April 2011Received in revised form 5 May 2011Accepted 6 May 2011Available online 12 May 2011
Keywords:Neonatal carnitine palmitoyltransferase type IIDandy-Walker syndrome
Molecular Genetics and Metabolism 104 (2011) 414416
Contents lists available at ScienceDirect
j ourna l homepage: www.e ls1. Introduction
Carnitine palmitoyltransferase II (CPT II) deciency is an autoso-mal recessive disorder of the mitochondrial beta-oxidation of long-chain fatty acids. CPT II deciency has three distinct phenotypes: alethal neonatal form (MIM #608836), an early-onset infantile form(MIM#600649) and a late-onset adult form (MIM#255110). Both theage of onset and the involvement of organ systems in the diseaseshould be considered for classication .
The lethal neonatal form is a raremultiorgan disease which includeshypoketotic hypoglycemia, severe hepatomuscular symptoms, cardiacabnormalities, seizures and lethargy, as well as dysmorphic features
(microcephaly) and kidney and brain malformations, and is almostuniversally and rapidly fatal [4,5]. The rst case was described in 1989. Until now, only 22 affected families have been described in theliterature .
In this report, we describe the clinical, biochemical and molecularndings in a Moroccan patient with CPT II deciency who wasprenatally diagnosed of fetal hydrocephalus and died suddenly on thethirteenth day of life. The expanded newborn screening resultsobtained using tandem mass spectrometry (MS/MS) were the key toachieve the diagnosis.
2. Case reportAbbreviations: CPT II, Carnitine Palmitoyltransferaspectrometry; CBC, complete blood count; CT, computeacylcarnitine translocase. Corresponding author at: Hospital Materno Infantil,
Avenida Arroyo de los Angeles s/n, 29011, Mlaga, SpaiE-mail address: [email protected] (R. Yahy
1096-7192/$ see front matter 2011 Elsevier Inc. Aldoi:10.1016/j.ymgme.2011.05.003Expanded newborn screeningTandem mass spectrometrydisorder of the mitochondrial beta-oxidation of long-chain fatty acids. It is a rare multiorgan disease whichincludes hypoketotic hypoglycemia, severe hepatomuscular symptoms, cardiac abnormalities, seizures andlethargy, as well as dysmorphic features. Until now, only 22 affected families have been described in theliterature.An increasing number of mutations are being identied in the CPT2 gene, with a distinct genotypephenotypecorrelation in most cases. Herein we report a new case of neonatal CPT II deciency associated with Dandy-Walker syndrome and sudden death at 13 days of life. CPT II deciency was suggested by acylcarnitineanalysis of dried-blood on lter paper in the expanded newborn screening. Genetic analysis of the CPT2 geneidentied the presence of a previously described mutation in homozygosity (c.534_558del25bpinsT).All lethal neonatal CPT II deciency patients previously described presented severe symptoms during the rstweek of life, although this was not the case in our patient, who remained stable and without apparent vitalrisk during the rst 11 days of life.The introduction of tandem mass spectrometry to newborn screening has substantially improved our abilityto detect metabolic diseases in the newborn period. This case illustrates the value of expanded newbornscreening in a neonate with an unusual clinical presentation, combining hydrocephalus and sudden death,that might not commonly lead to the suspicion of an inborn error of metabolism.
2011 Elsevier Inc. All rights reserved.A female infaparents (who wcesarean sectioultrasound evidDandy-Walker mwas fetal hydroc
se II; MS/MS, tandem massd tomography; CACT, carnitine/
Laboratorio de Metabolopatas,n.aoui).
l rights reserved.I (CPT II) deciency is an autosomal recessive, often lethalArticle history: Neonatal onset of carnitine palmitoyltransferase Ia b s t r a c ta r t i c l e i n f oBrief Communication
Neonatal carnitine palmitoyltransferase IIsyndrome and sudden death
Raquel Yahyaoui a,, Mara Gracia Espinosa b, Celia GAna Roldn b, Magdalena Ugarte c, Gonzalo Lastra b,a Clinical Laboratory, Carlos Haya University Hospital, Mlaga, Spainb Neonatology Department, Carlos Haya University Hospital, Mlaga, Spainc Centro de Diagnstico de Enfermedades Moleculares, Centro de Biologa Molecular, Univeeciency associated with Dandy-Walker
ez b, Anita Dayaldasani a, Inmaculada Rueda a,dal Prez a
d Autnoma de Madrid, CIBERER, Madrid, Spain
ev ie r.com/ locate /ymgment was the second child born to Moroccan, unrelatedere not available for study) at 37 weeks gestation vian in Spain. The pregnancy was complicated byence for hydrocephalus with high suspicion ofalformation. The indication for the cesarean sectionephalus with nonreassuring fetal status. Due to the
provided by the ratio C16+C18:1 to C2 . The only conditionknown to present with a similar acylcarnitine prole is carnitine/
symptoms during the rst week of life, although this was not the case
415R. Yahyaoui et al. / Molecular Genetics and Metabolism 104 (2011) 414416ultrasound ndings and prior death of one sibling in the neonatalperiod, the child was transferred to our hospital on the rst day of lifefor diagnosis, work up and potential treatment.
Initial physical exploration revealed macrocephalus with a cranialperimeter of 44.5 cm (N97 percentile) and dysmorphic facial featureswithout other visible abnormalities. Laboratory evaluation includingCBC, coagulation and measurement of serum ions, glucose, creatinineand urea was normal. Diagnosis of Dandy-Walker syndrome wasconrmed with cranial sonography and CT scan. She remainedassymptomatic the rst 10 days of life, then a ventricularperitonealshunting was performed without complications during the operationor immediate postoperative period. At 12 days of life, the patient had asudden episode of ventricular tachyarrhythmia which requiredresuscitation with intubation and adrenaline. Initial serum analysisshowed metabolic acidosis secondary to cardiorrespiratory failure,with subsequent normalization. Both the electrocardiogram andechocardiogram results were normal. The patient remained stableduring 24 h. She developed prolonged bradycardia and died ofunexplained cause on the thirteenth day of life. The autopsy couldnot be performed because the parents' consent could not be obtained.
The expanded newborn screening results showed normal levels ofamino acids related to hepatic function (Phe, Tyr, Met), markedlydecreased free carnitine (3.32 mol/L; reference values 7.0048.43 mol/L) and elevated long-chain species of acylcarnitines, espe-cially C16 and C18, in association with a low acetyl signal (Table 1). Theratio C0/C16+C18 was low (0.31; reference values 230) and the ratioC16+C18:1/C2wasvery high (15.59; reference values 0.070.49). Fromthe newborn screening results we calculated the risk of CPT II deciencyusing the Region 4 Collaborative Project CACT/CPT-2 post-analyticalinterpretation tool , which generated a score of 143 (interpretationguidelines: a score N50 indicates a most likely biochemical diagnosis ofCACT/CPT-2 deciency; cited with permission).
Mutation analysis of the CPT2 gene was performed on dried wholeblood on lter paper. The patient was identied as homozygous for apreviously described mutation: c.534_558del25bpinsT (p.Leu178_Ile186delinsPhe) [3,5,19,20,25,26].
In addition to dysmorphia, the clinical features of neonatal CPT IIdeciency include nonketotic hypoglycemia, metabolic acidosis,seizures, arrhythmias, nephromegaly, hepatomegaly, and cardiome-
Table 1Acylcarnitine prole in newborn screening sample (dried blood spot).
Species Acyl group Patient's result(mol/L)
C2 Acetyl 0.81 5.3445.09C16 Palmitoyl 8.18 0.384.47C16:1 Hexadecenoyl 0.55 b0.33C18 Stearoyl 2.43 0.181.19C18:1 Oleyl 4.45 b3.653-OH-C16:1 3-OH-hexadecenoyl 0.10 b0.068galy with cardiomyopathy [10,14,15]. Central nervous system anom-alies include ventriculomegaly, subarachnoid and subependymalhemorrhages, calcications, periventricular cysts and polymicrogyria,which are thought to result from abnormal neuronal migration  ordestructive lesions occurring during the rst half of the pregnancy. The patients are usually symptomatic at birth or within the rst4 days of life  and die during the rst week of life.
Lethal CPT II deciency is associated with an accumulation ofarrhythmogenic long-chain acylcarnitines in tissues  such as thatwhich occurred in our patient and other children described in theliterature [4,5,15,18]. Acylcarnitine analysis using tandem massspectrometry may show elevated long chain acylcarnitines (C16,in our patient, who remained stable and without apparent vital riskduring the rst 11 days. The surgical intervention on her tenth day oflife may have been the cause which triggered the sudden death.Dandy-Walker syndrome has been previously associated withneonatal CPT II deciency in a patient very similar to ours who alsoshowed no alteration in renal function or cardiac disease, and whoshared the same mutation in compound heterozygosity .
The cloning of the CPT2 gene (assigned to chromosome 1p32) hasenabled the identication and analysis of mutations in CPT II patients,as well as the correlation of mutant genotypes to clinical phenotypes[2,3]. More than 60 pathogenic mutations have been identied inpatients with CPT II deciency, establishing the genetic heterogeneityof the disease. To date, only eight individual mutations, all located inthe CPT2 gene, have been found in patients with the neonatal form ofCPT II deciency [3,19,22]. Truncating CPT2 mutations in homozy-gosity or compound heterozygosity are associated with the severeneonatal form of the disease, while homozygous and/or compoundheterozygous mild missense mutations are o