Ann Thorac Surg 2001;72:1391-1392
© 2001 The Society of Thoracic Surgeons
Case report
Ventricular septal defect closure in a neonate with combined methylmalonic aciduria/homocystinuria
Markus K. Heinemann, MDa,
Maren Tomaske, MDb,
Friedrich K. Trefz, MDd,
Axel Bosk, MDb,
Winfried Baden, MDc,
Gerhard Ziemer, MDa
a Department of Thoracic, Cardiac, and Vascular Surgery, Tübingen University Hospital, Tübingen, Germany
b Pediatric Intensive Care Unit, Tübingen University Hospital, Tübingen, Germany
c Department of Pediatric Cardiology, Tübingen University Hospital, Tübingen, Germany
d Zentrum für Stoffwechseldiagnostik, Reutlingen, Germany
Accepted for publication October 30, 2000.
Address reprint requests to Dr Heinemann, Department of Pediatric Cardiac Surgery, University Hospital, Langenbeckstr 1, D-55131 Mainz, Germany
e-mail: heinemann{at}uni-mainz.de
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Abstract
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Methylmalonic acidemia with associated homocystinuria is a rare inborn error of amino acid metabolism affecting energy supply on the cellular level. Its effects on recovery from surgically induced organ ischemia are largely unknown. We report the successful closure of a nonrestrictive ventricular septal defect by following a normothermic strategy combined with ample metabolic substrate supply.
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Introduction
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Methylmalonic acidemia with associated homocystinuria is a rare inborn error of amino acid metabolism, genetically transmitted in an autosomal recessive way. It results from a combined deficiency of methylmalonyl-CoA-mutase and methylene-H4-folate-homocysteine-methyltransferase. Defective synthesis of adenosyl-cobalamin and methylcobalamin, two cofactors in a cobalamin-dependent reaction, leads to impaired conversion both of methylmalonyl-CoA to succinyl-CoA, and of homocysteine to methionine [1]. Thus, some forms of the disease respond to treatment with cobalamin [2]. In the severe form of newborn-onset disease, failure to thrive, lethargy, and seizures occur within the first weeks of life [3].
Our female patient (2.8 kg, 38 cm) was admitted at the age of 19 days as an emergency with cardiac and hepatic failure. A history of feeding difficulties, muscular hypotonia, and progressive pancytopenia eventually led to selective screening for inborn errors of metabolism and the diagnosis of the enzyme defect by both urine and serum analysis [4, 5]. Organic acids in urine showed highly increased methylmalonic acid (1940 mmol/mol creatinine). Urinary amino acid analysis revealed homocystinuria. Enzyme measurements with complementary studies indicated cobalamin-C,D-deficiency. The patient responded to high doses of hydroxo-cobalamin (1 mg intravenously per day) and betaine treatment (750 mg/day) [2, 4]. Intensive care therapy, including mechanical ventilation and peritoneal dialysis, for prolonged secondary renal failure had also become necessary. As the child was found to have a nonrestrictive ventricular septal defect (VSD), there was general agreement that this needed urgent surgical closure after recompensation.
To furnish the maximum amount of substrate, 1 mg of hydroxo-cobalamin was given once daily during the week preceding surgery. The operation was then performed under normothermia (36°C), using bicaval cannulation with a flow rate of 200 to 250 mL/kg/min. The bypass system was primed with blood and albumin, and 1 mg of hydroxo-cobalamin was added. Cold blood cardioplegia was administered into the aortic root by hand injection for cardiac arrest. The large perimembranous VSD was exposed through a right atriotomy and the tricuspid valve. It measured 1 cm in diameter, reaching the aortic valve. Closure was achieved by implanting a Dacron (C. R. Bard, Haverhill, MA) patch with a running 5.0 polypropylene suture. The aortic cross-clamping time amounted to 34 minutes. Upon release of the aortic cross-clamp, the heart defibrillated spontaneously and started beating in a ventricular escape rhythm, soon converting into regular sinus rhythm. After reperfusion, weaning from cardiopulmonary bypass (total bypass time 72 minutes) was uneventful under administration of dopamine (8 µg/kg/min) and nitroglycerine (10 µg/kg/min). Lactate levels reached a maximum of 3.4 mmol/L and fell constantly after cessation of bypass. After 50 ml of preexisting ascites had been drained through a small incision in the diaphragm, the chest was closed with absorbable sutures, and the child was transferred to the intensive care unit in stable condition.
The postoperative course was complicated by an atrioventricular-junctional tachycardia that was treated with sotalol for 4 days. Hemodynamically, the child was stable with the dopamine being reduced over the first 72 hours. Recurrent pleural effusions and ascites required drainage. Hydroxo-cobalamin treatment (1 mg twice a week) was continued, supported by administration of vitamin B6 (100 mg/d), folic acid (5 mg/d), and betaine (3 x 250 mg/d). Cholestasis in conjunction with a choledochal cyst and a thickened gall bladder led to laparatomy 2 weeks postoperatively. A cholecystectomy and cystojejunostomy were performed, and cholestasis resolved. The child could be transferred to the normal ward after 10 days and was finally dismissed 3 months after the original admission.
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Comment
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Inborn errors of organic acid metabolism often impair energy substrate storage on the cellular level. Dietary measures or supply of deficient metabolites usually suffice as therapy under normal circumstances. The combination of such a metabolic defect with congenital heart disease seems to be exceedingly rare. When confronted with the necessity to close a nonrestrictive VSD in the presence of methylmalonic acidemia with associated homocystinuria, extensive literature searches and personal communications with leading centers of pediatrics and pediatric cardiac surgery did not reveal any helpful advice on how to manage extracorporeal circulation. Nothing seemed to be known about how surgically inflicted organ ischemia would be affected by the enzyme defect. As the metabolic disorder afflicts enzymes within the mitochondria responsible for cellular energy supply, there was concern if energy stores depleted by ischemia could be refilled appropriately enough to ensure organ function after reperfusion. It was finally decided not to pursue the routine institutional surgical protocol for neonatal cardiac surgery, ie, deep hypothermia and circulatory arrest or low-flow perfusion. Conversely, to limit possible organ malfunction to the heart, normothermic bypass with blood-cardioplegic arrest was to be employed with hydroxo-cobalamin added to the pump prime to further supply the missing substrate. The parents were informed about the uncertainties and possibilities regarding the effects of cardiac surgery, and consent was given. Fortunately, the operation was successful and lactate levels as a measure for energy depletion never reached problematic levels.
From this anecdotal experience, we conclude that normothermic cardiopulmonary bypass can be recommended as being relatively safe in the setting of inborn errors of metabolism influencing cellular energy supply.
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References
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Fenton W.A., Rosenberg L.E. Inherited disorders of cobalamin transport and metabolism. In: Scriver C.R., Beaudet A.L., Sly W.S., Valle D., eds. The metabolic and molecular bases of inherited disease, 7th ed. New York: McGraw-Hill, 1995:3129-3150.
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Henriquez H., el Din A., Ozand P.T., Subramanyam S.B., al Gain S.I. Emergency presentations of patients with methylmalonic acidemia, propionic acidemia and branched chain amino acidemia (MSUD). Brain Dev 1994;16(Suppl):86.
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Ogier de Baulny H., Gérard M., Saudubray J.M., Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment. Eur J Pediatr 1998;157(Suppl 2):S77.
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Thompson G.N., Walter J.H., Bresson J.L., et al. Substrate disposal in metabolic disease: a comparison between rates of in vivo propionate oxidation and urinary metabolite excretion in children with methylmalonic acidemia. J Pediatr 1989;115:735-739.[Medline]
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Abstract
Introduction
