JIMD Short Report #008 (2006) Online DOI 10.1007/s10545-006-0335-7
S H O RT R E P O RT
Pericardial effusion in primary systemic carnitine deficiency Duangrurdee Wattanasirichaigoon · Pongsak Khowsathit · Anannit Visudtibhan · Umaporn Suthutvoravut · Dussadee Charoenpipop · Sook Z. Kim · Harvey L. Levy · Vivian E. Shih
Received: 23 January 2006 / Accepted: 7 March 2006 C SSIEM and Springer 2006
Summary A patient with pericardial effusion and a complicated presentation of primary systemic carnitine deficiency (PSCD) is described. This is the first case of PSCD reported to have pericardial effusion. Compound heterozygosity for two mutations in the SLC22A5 gene, T440M and F23del, and four SLC22A5 polymorphisms (c.IVS3+6A>G, c.−77G>A, c.−78C>T, and p.S95S) were identified in the patient. Abbreviations LDH lactic acid dehydrogenase MCT medium-chain triglycerides PSCD primary systemic carnitine deficiency VLCADD very long-chain acyl-CoA dehydrogenase deficiency
Communicating editor: Michael Bennett Competing interests: None declared D. Wattanasirichaigoon () · P. Khowsathit · A. Visudtibhan · U. Suthutvoravut Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand e-mail:
[email protected] D. Charoenpipop Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand S. Z. Kim Korea Genetic Research Center, Cheong Ju City, Chung Buk, Republic of Korea H. L. Levy Children’s Hospital Boston, Boston, Massachusetts, USA V. E. Shih Massachusetts General Hospital, Boston, Massachusetts, USA
Primary systemic carnitine deficiency (PSCD) (McKusick 212140) is an autosomal recessive disorder characterized by early-onset hypoketotic hypoglycaemic encephalopathy, Reye-like syndrome, sudden infant death, hepatopathy, and late-onset skeletal myopathy and/or cardiomyopathy (Spiekerkoetter et al 2003a). Carnitine transport across the plasma membrane is reduced, most severely affecting kidney, heart, skeletal muscle and small intestine (Tein 2003). It results from mutations in the SLC22A5 gene, which encodes a solute carrier protein OCTN2. This protein regulates carnitine/organic cation transport. We report here a patient with this disorder confirmed by DNA and mRNA analysis. A previously healthy 8-month-old Thai girl presented with a one-day history of head dropping, episodic loss of consciousness, and tonic-clonic seizures following 3 days’ history of diarrhoea. On evaluation she had massive hepatomegaly, elevated liver enzymes, metabolic acidosis (anion gap 23), hyperammonaemia (122 μmol/L; normal 21–50), hyperuricaemia (9.3 mg/dl; normal 2.6–6.0), normal blood glucose, and trace urinary ketones. Carnitine levels were not initially measured owing to unavailability. A previously healthy 7-year-old brother had died of rapidly progressive encephalopathy and sudden cardiac arrest following acute gastroenteritis. He had marked hepatomegaly. Her 3-year-old sister had isolated cleft lip/palate but was otherwise normal. Her parents were normal. The patient was treated with a protein-restricted diet (0.5– 0.75 gm/kg per day) on the assumption that she had a urea cycle disorder and she regained consciousness on day 2. However, mild hyperammonaemia persisted and her liver size was increased. Liver biopsy revealed severe panlobular fatty change with micro- and macro-vesicular fat vacuoles as well as hepatic fibrosis. On day 16, the patient became lethargic with tachypnoea and pulsus paradoxus. Investigations revealed cardiomegaly Springer
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JIMD Short Report #008 (2006) Online
Fig. 1 Four-chamber echocardiogram. Note massive pericardial effusion (PE), 16 mm, hypertrophy of interventricular septum and left ventricle (LV) with interventricular septal thickness (diastolic) 11.4 mm (normal range for age 2.6–5.6) and left ventricular posterior wall thickness (diastolic) 8.6 mm (normal range 2.9–5.5). RV, right ventricle; RA, right atrium; LA, left atrium
with normal ECG. Laboratory data included hypoglycaemia (47 mg/dl; normal 60–110), normal level of total creatine kinase (CK) (160 IU/L; normal 0–190) and elevated CK-MB fraction (41% of total CK; normal T missense mutation in exon 8 (p.T440M) and a paternally inherited in-frame three base deletion, TTC, at position 67–69, resulting in a phenylalanine deletion at codon 23 (F23del) without affecting splicing of the
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adjacent exons, 1 and 2 (data not shown; primers used for PCR and sequencing of mRNA were exonic primers Ex1: 5 -TGCCTGGCTTGCCTGGTCGG-3 (forward) and Ex2: 5 -GTCTGACAGCTGCCCTGAAA-3 (reverse); GenBank reference sequences NT 034772 and NM 003060). We also identified three new single-nucleotide polymorphisms (SNPs): c.IVS3+6A>G; c.−77G>A; and c.−78C>T in the 5 untranslated fragment of exon 1, and a reported SNP, p.S95S (data not shown). Analysis of carnitine transport in fibroblast was not available in the country. The case represents a complicated diagnostic presentation of PSCD and the first description of pericardial effusion in the disorder. The hyperammonaemia with normoglycaemia initially led to the differential diagnoses of hyperammonaemic conditions such as urea cycle disorders, lysinuric protein intolerance, the hyperinsulinaemia and hyperammonaemia syndrome (Stanley et al 1998). Retrospectively, the deceased brother probably also had PSCD, though no material was available for genetic confirmation. At present the patient is 4 years old and healthy with normal neuropsychological development. Her ventricular hypertrophy resolved completely within one year after the treatment compared to the 1–12 months described elsewhere (Kinali et al 2004; Lamhonwah et al 2002). These data suggest that despite her more severe phenotype and the recommended therapeutic dose of carnitine we used, 100 mg/kg per day compared to 200–400 mg/kg per day in other reports (Kinali et al 2004; Lamhonwah et al 2002; Pierpont et al 2000), an excellent outcome resulted. However, serum level should be checked and the dosage adjusted accordingly.
JIMD Short Report #008 (2006) Online
The T440M mutation was previously identified in Turkish, Croatian and caucasian patients and the F23del mutation has been reported in those of East Indian descent (Lamhonwah et al 2002). The present mRNA data indicates that the TTC deletion does not disrupt normal splicing of the adjacent exons. The 3-methyglutaconic aciduria that has been associated with T440M homozygosity (Lamhonwah et al 2002) was not observed in our case. However, as in our case, all of the reported patients with a T440M mutation have had hypertrophic cardiomyopathy. The occurrence of T440M and F23del in various populations suggests SLC22A5 mutational hot spots. With regard to IVS3+6A>G polymorphism, the wildtype (A-allele) donor score is 0.62, whereas the SNP (Gallele) donor score is slightly different at 0.63 (splice prediction tool, http://www.fruitfly.org/cgi-bin/seq tools/). This SNP has high potential for being an activated cryptic splice site in case of a nearby splice site mutation. Acknowledgements We thank Supranee Thongpradit and Dr Thomas Zytkovicz for technical assistance, Dr Pim Suwannarat for editing the manuscript, and the Faculty of Medicine, Ramathibodi Hospital for its funding for Research Career Development to D.W. This work was support by grants from Mahidol University and from the Thai Research Fund.
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