A Rare Presentation of Childhood Pompe Disease: Cardiac Involvement Provoked by Epstein-Barr Virus Infection

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A Rare Presentation of Childhood Pompe Disease: Cardiac Involvement Provoked by Epstein-Barr Virus Infection
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  DOI: 10.1542/peds.109.4.e65 2002;109;e65 Pediatrics NiezenMelle D. Talsma, Marian A. Kroos, Gepke Visser, Jan L.L. Kimpen and Klary E. Provoked by Epstein-Barr Virus InfectionA Rare Presentation of Childhood Pompe Disease: Cardiac Involvement   http://pediatrics.aappublications.org/content/109/4/e65.full.html located on the World Wide Web at: The online version of this article, along with updated information and services, is   of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2002 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly  by guest on June 3, 2013pediatrics.aappublications.orgDownloaded from   A Rare Presentation of Childhood Pompe Disease: Cardiac InvolvementProvoked by Epstein-Barr Virus Infection Melle D. Talsma, MD*; Marian A. Kroos, MSc‡; Gepke Visser, MD, PhD§; Jan L.L. Kimpen, MD, PhD§;and Klary E. Niezen, PhD* ABSTRACT. Myocarditis attributed to Epstein-Barr vi-rus (EBV) as the sole cause is a rare manifestation. Myo-carditis ascribed to EBV infection in combination withother factors has been reported in a few more cases. Wereport a child who experienced active EBV infection andlater, at 19 months of age, received a diagnosis of Pompedisease (acid   -glucosidase deficiency) with predomi-nant cardiac involvement. The cardiac symptoms re-solved at the end of the EBV infection. When the patientwas recently seen, at 8 years of age, she had an increasedleft ventricular wall thickness but normal cardiac func-tion. DNA analysis identified this patient as compoundheterozygote for a mutant Tyr292Cys and a null allele. Inlight of genotype-phenotype correlation, it is notable thata Spanish patient with a functionally similar genotype(Tyr292Cys/Arg854Stop) also had childhood Pompe dis-ease with peripheral muscular involvement.  Pediatrics 2002;109(4). URL: http://www.pediatrics.org/cgi/content/ full/109/4/  e 65;  cardiomyopathy, Pompe disease, Epstein-Barr virus, acid alpha-glucosidase. ABBREVIATIONS. EBV, Epstein-Barr virus; IgM, immunoglobu-lin M; IgG, immunoglobulin G; EBNA, Epstein-Barr B nuclearantigen. M yocarditis is a rare manifestation of Epstein-Barr virus (EBV) infection. To our knowl-edge, only 3 cases of myocarditis in whichEBV infection was thought to be the sole cause have been reported. 1–3 In a few more cases, the myocardi-tis was ascribed to other factors in combination withEBV infection.We present a child who experienced active EBVinfection and later received a diagnosis of Pompedisease (acid   -glucosidase deficiency) with pre-dominant cardiac involvement. When the EBV infec-tion resolved, the heart improved dramatically andthe clinical picture became that of childhood Pompedisease with predominant peripheral muscle in-volvement. 4 Mutation detection of the gene for acid  -glucosidase identified the patient as compoundheterozygote for a mutant Tyr292Cys and a nullallele. CASE REPORT In March 1995, a 19-month-old native Dutch girl was admittedto our hospital because of persistent high serum transaminasesthought to be attributable to infectious mononucleosis. She waswell until September 1994 (13 months of age), when she was seen by a pediatrician, because of splenomegaly, discovered during aroutine examination at a welfare center. At that moment, theimmunoglobulin M (IgM) titer against EBV was 128, the immu-noglobulin G (IgG) titer was 1250, and the IgG anti–Epstein-Barr Bnuclear antigen (EBNA) was  20. During the next 6 months, shetired easily and developed muscular weakness. She had no fever.The serum transaminases were persistently high (aspartate ami-notransferase, 299–384 U/L; alanine aminotransferase, 220–248U/L) with the following EBV titers: IgM,   32; anti-capsid IgG,2500 to 5000; anti-EBV early antigen IgG, 1250; and anti-EBNAIgG, 160 to 320.On admission to our hospital, she had normal heart sounds andno hepatic or splenic enlargement. She had muscular weakness,especially of the shoulder muscles, and weak tendon reflexes. Onpalpation, the muscles were normal. No dysmorphic features,including macroglossia, were found. Creatinine-phosphokinaselevels were repeatedly high (918 and 646 U/L, with a normalmuscle-brain fraction). A thoracic radiograph showed cardiomeg-aly (cardiothoracic ratio 0.6, see Table 1). The electrocardiogramshowed a short P-R interval (0065 seconds at a cardiac frequencyof 100/min) and massive left ventricular hypertrophy (S in V1 28mm and R in V6 38 mm). Echocardiography revealed an enlarged,diffuse, hypertrophic left ventricle with decreased contractility(see Table 1). Systolic and diastolic left ventricular dimensionswere far above the 95th percentile for normal Dutch children.Both muscle ultrasound and electromyogram were normal.Because of progressive muscular weakness, initially thought to beattributable to polymyositis, a biopsy of the quadriceps musclewas taken. The histologic picture showed predominant lysosomalstorage of glycogen, which is characteristic of Pompe disease. Thisdiagnosis was confirmed by measurement of acid   -glucosidase,which showed enzyme activity below detection level in bothleukocytes and cultured skin fibroblasts using glycogen (respec-tively) glycogen and 4-methylumbelliferyl   - d -glucopyranosideas substrate. 5 DNA analysis was performed to establish the patient’s   -glu-cosidase genotype. DNA analysis in leukocytes from this girl didnot show any of the 3 most common mutations in the Netherlands(IVS1 [  13 G], 525 del T, and del exon 18 allele). 6,7 Full-lengthcDNA sequence analysis by reverse transcriptase–polymerasechain reaction 7 led to detection of a single, apparently homozy-gous, A to T transversion at position 875 in exon 5, resulting inamino acid substitution Tyr292Cys. However, confirmation of thismutation by polymerase chain reaction sequence analysis of genomic DNA indicated that the patient was actually heterozy-gous for 875A 3  T. The combination of both sequence data setsindicates that the seemingly normal 875A allele is not expressed atthe mRNA level. Compound heterozygosity of this type is notunusual in Pompe disease. 6  -Glucosidase cDNA harboring the 875T mutation and wild-type cDNA were cloned in the eukaryotic expression vectorpSHAG5 and expressed in COS cells to study the functional effect.Transfection of the wild-type cDNA to COS cells showed normalactivity of acid   -glucosidase, whereas transfection of the mutatedcDNA to COS cells did not. The Tyr292Cys substitution fullyabolishes the catalytic activity of acid   -glucosidase for the artifi- From *Beatrix Children’s Hospital, Groningen, the Netherlands; ‡Depart-ment of Clinical Genetics, Erasmus University, Rotterdam, the Netherlands;and §Wilhelmina Children’s Hospital, Utrecht, the Netherlands.Received for publication Jul 24, 2001; accepted Dec 5, 2001.Reprint requests to (M.D.T.) Beatrix Children’s Hospital, Hanzeplein 1, 9713GZ Groningen, the Netherlands. E-mail: m.d.talsma@bkk.azg.nlPEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad-emy of Pediatrics. http://www.pediatrics.org/cgi/content/full/109/4/ e 65 PEDIATRICS Vol. 109 No. 4 April 2002  1 of 2  by guest on June 3, 2013pediatrics.aappublications.orgDownloaded from   cial substrate 4-methylumbelliferyl   - d -glucopyranoside, but, in-teresting, approximately 10% of the activity is left with glycogenas the natural substrate.During follow-up of this patient, the peripheral muscularpower diminished further. The girl became wheelchair dependentand has needed ongoing artificial ventilation since April 2001.Initially, the dimensions and the contractility of the left ventricle of the heart returned to normal, as did the cardiothoracic ratio onradiograph (see Table 1). Recent echocardiography revealed anincreased ventricular wall thickness, with still normal contractil-ity. EBV titers stayed high for 1 year but normalized later (IgM,  32; anti-capsid IgG, 256; anti-EBV early antigen,    32; andanti-EBNA, 64). CONCLUSION At the age of 7 years, the patient meets all criteriafor a typical presentation of childhood Pompe dis-ease. 4,8 The transient cardiomegaly is a remarkablefinding. In classic infantile-onset disease, cardiomeg-aly presents at birth and aggravates. In late-onsetdisease, cardiomegaly is absent. Skeletal muscleweakness, by contrast, is a common feature of allclinical subtypes.The acid   -glucosidase activity in leukocytes andfibroblasts of our patient was below detection level, but mutation analysis indicated that some residualactivity for the natural substrate persisted. It mighthave been just enough to prevent cardiomegaly un-der normal circumstances but just too little under thechallenge of an EBV infection. We realize that thistheory for explaining the transient cardiomegaly builds heavily on the value of mutation analysis. Thelatter, however, seems justified in light of a recentreport of a Spanish patient with childhood/juvenilePompe disease. 9 This Spanish patient, too, was com-pound heterozygote and carrier of the Tyr292Cysallele but combined with the silent Arg854Stop al-lele. 9,10 ACKNOWLEDGMENTS We thank A. J. J. Reuser, PhD, and M. M. P. Hermans, PhD, forvaluable help in preparing the manuscript. In addition, we thankT. Bos and J. Puister for technical assistance. REFERENCES 1. Hebert MM, Yu C, Towbin JA, Rogers BB. Fatal Epstein-Barr virusmyocarditis in a child with repetitive myocarditis.  Pediatr Pathol Lab Med . 1995;15:801–8122. Baykurt C, Caglar K, Ceviz N, Akyuz C, Secmeer G. Successful treat-ment of Epstein-Barr virus infection associated with myocarditis.  PediatrInt . 1999;41:389–3913. Fraisse A, Paut O, Zandotti C, Lagier P, Camboulives J, Pellissier JF.Epstein-Barr virus. An unusual cause of acute myocarditis in children[in French].  Arch Pediatr . 2000;7:752–7554. Hirschhorn R. Glycogen storage disease type II: acid alpha-glucosidase(acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D,eds.  The Metabolic and Molecular Bases of Inherited Disease.  6th ed. 1995:2443–24645. Koster JF, Slee RG, Hulsmann WC. The use of leukocytes as an aid in thediagnosis of a variant of glycogen storage disease type II (Pompe’sdisease).  Eur J Clin Invest . 1972;2:467–4716. Kroos MA, van der Kraan M, van Diggelen OP, et al. Glycogen storagedisease type II: frequency of three common mutant alleles and theirassociated clinical phenotypes studied in 121 patients.  J Med Genet .1995;32:836–8377. Hermans MMP, Van Leenen D, Kroos MA, Reuser AJJ. Mutation de-tection in glycogen storage disease type II by RT-PCR and automatedsequencing.  Biochem Biophys Res Commun . 1997;241:414–4188. Reuser AJJ, Kroos MA, Hermans MMP, et al. Glycogenosis type II (acidmaltase deficiency).  Muscle Nerve . 1995;3:S61–S699. Castro-Cago M, Eiris-Punal J, Rodriguez-Nunez A, Pintos- Martinez E,Benlloch-Marin T, Barros-Angueira F. Severe form of juvenile type IIglycogenosis in a compound-heterozygous boy (Tyr-292 3  Cys/Arg-854 3  Stop) [Forma grave de glucogenosis tipo II juvenil en un nin˜oheterocigoto compuesto (Tyr-292 3  Cys/Arg-854 3  Stop)].  Rev Neurol .1999;29:46–4910. Becker JA, Vlach J, Raben N, et al. The African srcin of the commonmutation of African American patients with glycogen storage diseasetype II.  Am J Hum Genet . 1998;62:991–994 TABLE 1.  Radiographic Cardiothoracic Ratio and Echocardiographic ParametersDate RadiographicCardiothoracicRatioLeft VentricularInner Diameter,Diastolic/Systolic (mm)Posterior WallThickness,Diastolic/Systolic (mm)InterventricularSeptal Diameter,Diastolic/Systolic (mm)FractionalShorteningBodyWeight(kg)March 1995 0.60 37/28 7/10 7.5/10 0.22 10 January 1996 — 32/26 7/10 7.5/9 0.20 12March 1997 — 36/24 8/11 8/9.5 0.33 13October 1998 0.45 36/23 8/13 8/11 0.35 14May 2001 0.48 32/22 8/12 14/15 0.31 19Left ventricular inner diameter, posterior wall thickness, and interventricular septal diameter were measured by echocardiography in theparasternal short axis view. 2 of 2  EPSTEIN-BARR VIRUS AND CARDIAC INVOLVEMENT IN CHILDHOOD POMPE DISEASE  by guest on June 3, 2013pediatrics.aappublications.orgDownloaded from   DOI: 10.1542/peds.109.4.e65 2002;109;e65 Pediatrics NiezenMelle D. Talsma, Marian A. Kroos, Gepke Visser, Jan L.L. Kimpen and Klary E. Provoked by Epstein-Barr Virus InfectionA Rare Presentation of Childhood Pompe Disease: Cardiac Involvement   ServicesUpdated Information &  mlhttp://pediatrics.aappublications.org/content/109/4/e65.full.htincluding high resolution figures, can be found at: References  ml#ref-list-1http://pediatrics.aappublications.org/content/109/4/e65.full.htThis article cites 9 articles, 1 of which can be accessed free at: Citations  ml#related-urlshttp://pediatrics.aappublications.org/content/109/4/e65.full.htThis article has been cited by 2 HighWire-hosted articles: Subspecialty Collections  diseasehttp://pediatrics.aappublications.org/cgi/collection/infectious_ Infectious Disease & Immunity following collection(s):This article, along with others on similar topics, appears in the Permissions & Licensing  mlhttp://pediatrics.aappublications.org/site/misc/Permissions.xhttables) or in its entirety can be found online at: Information about reproducing this article in parts (figures,  Reprints  http://pediatrics.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Village, Illinois, 60007. Copyright © 2002 by the American Academy of Pediatrics. All rightstrademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove andpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly  by guest on June 3, 2013pediatrics.aappublications.orgDownloaded from 
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