Eur J Pediatr (2002) 161: 524–527 DOI 10.1007/s00431-002-1029-2
O R I GI N A L P A P E R
Thorsten Marquardt Æ Georg Hu¨lskamp Josef Gehrmann Æ Volker Debus Æ Erik Harms Hans Gerd Kehl
Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia Received: 15 March 2002 / Revised: 23 June 2002 / Accepted: 24 June 2002 / Published online: 22 August 2002 Ó Springer-Verlag 2002
Abstract Severely affected children with congenital disorder of glycosylation type Ia (CDG-Ia; MIM 212065) may develop hypertrophic cardiomyopathy. In this report we describe the near-death of a 10-month-old girl with CDG-Ia due to acute left-ventricular outlet obstruction caused by hypertrophic cardiomyopathy and acute dehydration. The girl had multi-organ failure and signs of severe myocardial damage mimicking myocardial infarction. Conclusion: hypertrophic cardiomyopathy contributes to the high mortality of young children with congenital disorder of glycosylation type Ia. Even if cardiomyopathy in this disease is non-obstructive, acute fluid-loss might cause left ventricular outflow tract obstruction and life-threatening myocardial ischaemia. Patients with congenital disorder of glycosylation type Ia are at risk for cardiac complications and should be monitored regularly by echocardiography. Keywords Carbohydrate-deficient glycoprotein syndrome Æ Congenital disorder of glycosylation Æ Hypertrophic cardiomyopathy Æ Myocardial ischaemia Abbreviations CDG congenital disorder of glycosylation Æ HCM hypertrophic cardiomyopathy Æ PMM2 phosphomannomutase 2
Introduction Congenital disorder of glycosylation type Ia(CDGIa) is the most frequent form of the known disorders of Nglycosylation. It is caused by a deficiency of phosphomannomutase 2 (PMM2; gene locus 16p13.3–13–2), an enzyme that converts mannose-6-phosphate to T. Marquardt (&) Æ G. Hu¨lskamp Æ J. Gehrmann Æ V. Debus E. Harms Æ H.G. Kehl Klinik und Poliklinik fu¨r Kinderheilkunde, Albert-Schweitzer-Strasse 33, 48149 Mu¨nster, Germany E-mail:
[email protected] Tel.: +49-251-8358519 Fax: +49-251-8356085
mannose-1-phosphate [3,10]. Consequently, the GDPmannose pool is decreased in CDG-Ia cells [8] leading to the formation of truncated lipid-linked oligosaccharides and a hypoglycosylation of glycoproteins. Typical clinical features consist of psychomotor retardation, cerebellar atrophy, hepatopathy, coagulation abnormalities, convergent strabismus, inverted nipples and abnormal fat distribution. Cardiomyopathy and pericardial effusions are facultative symptoms. The most frequent mutation, R141H, has a carrier frequency of 1/70 in the general population but has never been found in a homozygous state in CDG-Ia patients [9]. It is generally assumed that the homozygous form is lethal and that some residual acitivity of PMM2 is needed for survival. Of all children with CDG-Ia, about 20% die in the first years of life. This most likely represents the more severely affected group of children. In this report we describe the near-death of a 10-monthold girl with CDG-Ia due to acute left-ventricular outlet obstruction.
Case report The girl was born at term with normal weight, length and head circumference. Muscular hypotonia and inverted nipples were noted early so that the presence of CDG-Ia was suspected. Internal strabismus, another typical symptom of CDG-Ia, was not present during the first 2 months of life but developed later. In the first 8 weeks of life, three septic-like events occurred. No bacteria could be isolated from repeated blood samples. During these episodes, serum transaminase concentrations increased to several hundred units per litre and AT III activity decreased below the detection level. Hypoalbuminaemia and low cholinesterase levels were constantly present. Cerebellar hypoplasia and generalised brain atrophy were revealed by ultrasound investigations and MRI in the first weeks of life. Pericardial effusion was present from the age of 2 months and persisted thereafter. There was no evidence of structural heart disease. An extended abdomen with loose and frequent stools and inappropriate weight gain led to parenteral nutrition until 6 months of age. Septum hypertrophy of the left ventricle without outlet obstruction was first noted at 6 months of age and had remained unchanged 2 months later. Repeated blood pressure measurements were within the normal range so that hypertensive cardiomyopathy
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Fig. 1. The patient at 10.5 months of age. She had internal strabismus, severe dystrophy (body weight 5 kg), and ascites. Due to frequent watery stools, the perianal skin was inflamed and ulcerated could be excluded. Echocardiography revealed no signs of pulmonary hypertension. At the same time, weight and body length were already below the 3rd percentile and weight gain continued to be insufficient even though feeding by gastric tube and caloric intake was increased to more than 150 kcal/kg body weight per day
Fig. 2. A Echocardiography showing hypertrophy of the interventricular septum (arrow) and severe outlet obstruction (LA left atrium, RA right atrium, LV left ventricle, RV right ventricle, OT outlet tract). B The outlet obstruction caused an increased blood flow velocity of more than 4.5 m/s corresponding to an estimated pressure gradient of more than 100 mm Hg. Doppler examination showed a typical dynamic outlet obstruction due to an increasing gradient during the systolic contraction of the heart (seen by the initial slow velocity increase, see arrow)
(Fig. 1). Recurrent severe ascites was the major clinical problem for the next few months and diuretic therapy was initiated with furosemide, spironolactone and, later, in combination with hydrochlorothiazide. Laboratory investigations for CDG at the end of the 1st week of life revealed a transferrin pattern consistent with type Ia. In the patient’s leucocytes, PMM activity was undetectable and was lower than in 15 other CDG-Ia patients previously diagnosed with some residual activity under equivalent assay conditions (method [10], modified as described in [5]). Two mutations were found in the PMM2 gene: the maternally inherited deletion of 24delC in exon 1 leading to a frame shift and the paternally inherited missense mutation 691G>A in exon 8 leading to amino acid exchange V231M. At 10 months of age, hypertonic dehydration with a weight loss of more than 7% of body weight occurred within a few days and was caused by diarrhoea and ongoing diuretic therapy. Upon arrival in hospital, the child had asevere metabolic acidosis (venous pH 6.6, pCO2 39 mm Hg, BE –33.1 mmol/l). Serum sodium was 157 mmol/l, creatinine had increased to 1.1 mg/dl and leucocytosis with 61,400 cells/ll was noted. C-reactive protein was below the detection level and IL-8 levels were in the normal range. Body temperature was 39.2°C. Echocardiography revealed hypertrophic cardiomyopathy (HCM) with acute severe left-ventricular outflow tract obstruction (pressure gradient more than 100 mm Hg) (Fig. 2). Diameters of the left ventricular walls were as follows: asymmetric thickening of the interventricular septum with diameters between 5.1 and 10 mm (normal value 4–5.5 mm), posterior wall 6.2 mm (normal value 4–5 mm). One day later, the electrocardiogram showed significant ST elevations as high as 2.5 mV comparable to acute myocardial infarction. ECG changes within the next few days were similar to those seen after myocardial infarction but normalised much faster (Fig. 3). Troponin levels peaked at 9.5 ng/ml (normal
