Molecular Genetics and Metabolism 104 (2011) 414–416
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Molecular Genetics and Metabolism
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Brief Communication
Neonatal carnitine palmitoyltransferase II deficiency associated with Dandy-Walkersyndrome and sudden death
Raquel Yahyaoui a,⁎, María Gracia Espinosa b, Celia Gómez b, Anita Dayaldasani a, Inmaculada Rueda a,Ana Roldán b, Magdalena Ugarte c, Gonzalo Lastra b, Vidal Pérez a
a Clinical Laboratory, Carlos Haya University Hospital, Málaga, Spainb Neonatology Department, Carlos Haya University Hospital, Málaga, Spainc Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular, Univesidad Autónoma de Madrid, CIBERER, Madrid, Spain
Abbreviations: 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, Málaga, SpaiE-mail address: [email protected] (R. Yahy
1096-7192/$ – see front matter © 2011 Elsevier Inc. Aldoi:10.1016/j.ymgme.2011.05.003
a b s t r a c t
a r t i c l e i n f oArticle history:Received 14 April 2011Received in revised form 5 May 2011Accepted 6 May 2011Available online 12 May 2011
Keywords:Neonatal carnitine palmitoyltransferase type IIDandy-Walker syndromeExpanded newborn screeningTandem mass spectrometry
Neonatal onset of carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive, often lethaldisorder 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 identified in the CPT2 gene, with a distinct genotype–phenotypecorrelation in most cases. Herein we report a new case of neonatal CPT II deficiency associated with Dandy-Walker syndrome and sudden death at 13 days of life. CPT II deficiency was suggested by acylcarnitineanalysis of dried-blood on filter paper in the expanded newborn screening. Genetic analysis of the CPT2 geneidentified the presence of a previously described mutation in homozygosity (c.534_558del25bpinsT).All lethal neonatal CPT II deficiency patients previously described presented severe symptoms during the firstweek of life, although this was not the case in our patient, who remained stable and without apparent vitalrisk during the first 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.
se II; MS/MS, tandem massd tomography; CACT, carnitine/
Laboratorio de Metabolopatías,n.aoui).
l rights reserved.
© 2011 Elsevier Inc. All rights reserved.
1. Introduction
Carnitine palmitoyltransferase II (CPT II) deficiency is an autoso-mal recessive disorder of the mitochondrial beta-oxidation of long-chain fatty acids. CPT II deficiency 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 classification [1–3].
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 first case was described in 1989[6]. Until now, only 22 affected families have been described in theliterature [3–23].
In this report, we describe the clinical, biochemical and molecularfindings in a Moroccan patient with CPT II deficiency 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 report
A female infant was the second child born to Moroccan, unrelatedparents (who were not available for study) at 37 weeks gestation viacesarean section in Spain. The pregnancy was complicated byultrasound evidence for hydrocephalus with high suspicion ofDandy-Walker malformation. The indication for the cesarean sectionwas fetal hydrocephalus with nonreassuring fetal status. Due to the
Table 1Acylcarnitine profile in newborn screening sample (dried blood spot).
Species Acyl group Patient's result(μmol/L)
Normal range(μmol/L)
C2 Acetyl 0.81 5.34–45.09C16 Palmitoyl 8.18 0.38–4.47C16:1 Hexadecenoyl 0.55 b0.33C18 Stearoyl 2.43 0.18–1.19C18:1 Oleyl 4.45 b3.653-OH-C16:1 3-OH-hexadecenoyl 0.10 b0.068
415R. Yahyaoui et al. / Molecular Genetics and Metabolism 104 (2011) 414–416
ultrasound findings and prior death of one sibling in the neonatalperiod, the child was transferred to our hospital on the first 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 wasconfirmed with cranial sonography and CT scan. She remainedassymptomatic the first 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 μmol/L; reference values 7.00–48.43 μmol/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 2–30) and the ratioC16+C18:1/C2wasvery high (15.59; reference values 0.07–0.49). Fromthe newborn screening results we calculated the risk of CPT II deficiencyusing the Region 4 Collaborative Project CACT/CPT-2 post-analyticalinterpretation tool [24], which generated a score of 143 (interpretationguidelines: a score N50 indicates a most likely biochemical diagnosis ofCACT/CPT-2 deficiency; cited with permission).
Mutation analysis of the CPT2 gene was performed on dried wholeblood on filter paper. The patient was identified as homozygous for apreviously described mutation: c.534_558del25bpinsT (p.Leu178_Ile186delinsPhe) [3,5,19,20,25,26].
3. Discussion
In addition to dysmorphia, the clinical features of neonatal CPT IIdeficiency include nonketotic hypoglycemia, metabolic acidosis,seizures, arrhythmias, nephromegaly, hepatomegaly, and cardiome-galy with cardiomyopathy [10,14,15]. Central nervous system anom-alies include ventriculomegaly, subarachnoid and subependymalhemorrhages, calcifications, periventricular cysts and polymicrogyria,which are thought to result from abnormal neuronal migration [5] ordestructive lesions occurring during the first half of the pregnancy[10]. The patients are usually symptomatic at birth or within the first4 days of life [5] and die during the first week of life.
Lethal CPT II deficiency is associated with an accumulation ofarrhythmogenic long-chain acylcarnitines in tissues [4] 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,
C18 and C18:1) with low C2 and C0 signals [16]. The most sensitiveindicator to describe the reduction in long-chain fatty acid oxidation isprovided by the ratio C16+C18:1 to C2 [16]. The only conditionknown to present with a similar acylcarnitine profile is carnitine/acylcarnitine translocase (CACT) deficiency, a very rare disorder thatcan be distinguished from CPT II deficiency by its clinical presentation[27].
Patients with lethal neonatal CPT II deficiency present severesymptoms during the first week of life, although this was not the casein our patient, who remained stable and without apparent vital riskduring the first 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 deficiency 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 [5].
The cloning of the CPT2 gene (assigned to chromosome 1p32) hasenabled the identification 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 identified inpatients with CPT II deficiency, 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 deficiency [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 often associated with theadult form [3,19,28].
The case we report was homozygous for a 534T insertion followedby a 25-bp deletion (p.Leu178_Ile186delinsPhe), this known muta-tion was previously described in compound heterozygosity in threefamilies with the lethal neonatal phenotype [5,19,20]. However, thepresence of this mutation in compound heterozygosity is not enoughto present the neonatal form, as shown by reports of at least four casesof the adult form [25,26,29]. This may be another example of thephenotypic heterogeneity that has been frequently reported for thisdisease and the possibility of other genetic factors being involved. Ourpatient represents the first homozygous phenotype described in theliterature of this mutation, thus confirming the presumable severity ofthe said mutation in homozygosity as predicted by Isackson [3].
The introduction of MS/MS to newborn screening has substantiallyimproved our ability to detect metabolic diseases in the newbornperiod. The first neonatal case of CPT II deficiency to be detected byexpanded newborn screening was reported in 2001 [11]. It is thoughtthat this method is highly sensitive and specific for the neonatal form[30]. To our knowledge, this is the first report of neonatal CPT IIdeficiency detected by expanded newborn screening in Europe. Thecase illustrates the value of expanded newborn screening in a neonatewith an unusual clinical presentation, combining hydrocephalus andsudden death, that might not lead to the suspicion of an inborn errorof metabolism. Although this disease is invariably fatal, earlydetection is still useful to enable genetic counseling in the parentsand future prenatal diagnosis. Deficiency of CPT II should be includedin newborn screening programs as well as in the differential diagnosisof patients with central nervous system malformations and earlydeath.
Financial disclosure
This work received no external financial support.
Conflict of interest
None of the authors had a personal or financial conflict of interest.
416 R. Yahyaoui et al. / Molecular Genetics and Metabolism 104 (2011) 414–416
Acknowledgments
Dr. Piero Rinaldo MD, PhD, Mayo Clinic, Rochester, MN, and themembers of the R4S Collaborative Project, for their assistancewith theCACT/CPT-2 post-analytical interpretation tool.
Dr. Celia Pérez-Cerdá, PhD, CEDEM, Universidad Autónoma deMadrid, Spain, for helping with the revision of the manuscript.
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