Pediatr Cardiol (2008) 29:446–451 DOI 10.1007/s00246-007-9119-6
CASE REPORT
Cardiomyopathy in Multiple Acyl-CoA Dehydrogenase Deficiency A Clinico-Pathological Correlation and Review of Literature Mohit Singla Æ Grace Guzman Æ Andrew J. Griffin Æ Saroja Bharati
Received: 25 May 2007 / Accepted: 24 August 2007 / Published online: 3 October 2007 Springer Science+Business Media, LLC 2007
Abstract Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive defect of the electron transfer flavoprotein or ubiquinone oxidoreductase, resulting in abnormal fatty acid, amino acid, and choline metabolism, leading to metabolic acidosis, hypoglycemia, ‘‘sweaty-feet’’ odor, and early neonatal deaths. This report presents a child diagnosed with this disease at birth by newborn screening using the mass spectrometer, who died suddenly at the age of 6 months. The echocardiogram revealed pericardial effusion, thickened ventricular musculature, and insufficiency of both the atrio-ventricular valves. The autopsy showed immense cardiomegaly, fatty infiltration, and hypertrophy of the ventricles. This is the first detailed case report of clinicopathological correlation of MADD in an infant and brings into light a rare form of cardiomyopathy as a differential diagnosis in critically ill patients.
M. Singla Department of Pediatrics, University of Illinois–College of Medicine, 840 S. Wood St., Chicago, IL 60612, USA G. Guzman S. Bharati Department of Pathology, University of Illinois–College of Medicine, 840 S. Wood St., Chicago, IL 60612, USA A. J. Griffin Division of Pediatric Cardiology, University of Illinois–College of Medicine, 840 S. Wood St., Chicago, IL 60612, USA S. Bharati Maurice Lev Congenital Heart and Conduction System Center, Advocate Hope Children’s Hospital, Advocate Christ Medical Center, Oak Lawn, IL, USA S. Bharati (&) Chicago Medical School and Rush–Presbyterian St. Luke’s Medical Center, Chicago, IL, USA e-mail:
[email protected]
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Keywords Multiple acyl-CoA dehydrogenase deficiency Cardiomyopathy Glutaric acidemia Type II
Multiple acyl-CoA dehydrogenase deficiency (MADD), also known as glutaric acidemia Type II, is a rare autosomal recessive defect of the electron transfer flavoprotein or ubiquinone oxidoreductase, resulting in abnormal fatty acid, amino acid, and choline metabolism [10]. This leads to the impaired metabolism and excretion of glutaric, lactic, ethylmalonic, and other organic acids leading to metabolic acidosis, hypoglycemia, and ‘‘sweaty-feet’’ odor [12]. The affected patients can be detected by neonatal screening done at birth. The patients with the neonatal onset form of MADD usually survive from a few weeks to a few years depending on the severity and management of the disease. Pathologically, MADD is characterized by lipid deposition in the internal organs: hepatic parenchyma, renal tubular epithelium, and myocytes [15]. Fatty acids are the primary source of energy for the cardiac muscles [8], therefore in patients with MADD, large amounts of triglycerides and fatty acids are deposited in the cardiac muscles. We recently encountered a 6-month-old patient diagnosed with MADD who suddenly deteriorated and died of cardiac arrest. This is the first detailed report of an infant with cardiomyopathy in MADD that includes echocardiogram, gross pathology, and microscopy of the heart. Case Report A 6-month-old Hispanic male presented with cough, runny nose, increased frequency of stools, respiratory distress, and decreased intake of his feeds. Over the last month, he
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Fig. 1 Chest X-ray showing markedly enlarged heart. The pulmonary vascularity appears within normal limits
started falling off his growth curve. He had a positive newborn screening test for MADD without congenital anomalies and was then started on a special diet including carnitine and riboflavin. Developmentally, he was slightly delayed for his age and followed up regularly at the
Fig. 2 Echocardiogram of the patient done 24 h before death. (A, B) Apical four-chamber view showing moderate degree of tricuspid and mitral regurgitation, respectively. The left ventricular wall is thickened and echo dense and the interventricular septum bulges into the right ventricular cavity. (C) Paracardial long-axis view of the heart showing the left ventricular inflow and outflow tracts. The left and
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genetics clinics. He had a peculiar ‘‘smelly socks’’-like odor and his chest revealed scattered fine crackles and end expiratory rhonchi. The abdomen was soft and nondistended and his liver was palpable 4 cm below the right costal margin. His heart sounds and the rest of the physical examination was normal for his age. He had no congenital anomalies or dysmorphic facies. On admission, his laboratory results showed serum sodium 135, potassium 4.6, chloride 105, bicarbonate 15, urea 29, creatinine 0.7, white blood count (WBC) 10.8 with 54% neutrophils, 42% lymphocytes, 3.5% monocytes and creatinine kinase 449 IU. Chest X-ray (Fig. 1) showed an enlarged heart and hazy lung fields. He was started on oxygen, albuterol, prednisolone, and intravenous fluids with bicarbonate for metabolic acidosis. Initial blood and urine sepsis screen were negative. An echocardiogram (Figs. 2A– 2D) showed moderate to markedly decreased left and right ventricular function with mild to moderate regurgitation of tricuspid and mitral valves. The left ventricle was moderately dilated and hypertrophied. A pericardial effusion containing approximately 200–300 mL of fluid was seen. After 22 h, he rapidly deteriorated in his respiratory status and developed severe acidosis and went into ventricular fibrillation, followed by cardiac arrest from which he could not be resuscitated. The autopsy included the heart and lungs. On gross examination, the heart was immensely enlarged, weighting 100 g; the normal for this age is 31 g
right ventricular walls are thickened with a moderate pericardial effusion seen surrounding both ventricles. (D) Two-dimensional echocardiogram, subcostal image, showing pericardial effusions measuring 1.83 cm on the right and 1.09 cm on the left. Note the concentrically thickened echo-dense ventricular wall
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Fig. 3 Gross pathology of heart. (A) External view of the heart, note the immense cardiomegaly; (B) left ventricular hypertrophy with marked enlargement; note the pale-looking heart in both A and B
Fig. 4 Microscopy of heart. A Hematoxylin and eosin stain (40·) shows hyperchromasia and slight pleomorphism of cardiomyocyte nuclei and cytoplasmic vacoulation signifying fatty infiltration (arrow). B Trichrome stain (40·) highlighting delicate strands of fibrous tissue (stained blue) interspersed between cardiomyocytes. C, D CD 31 and CD 34 (40·), an endothelial cell marker, showing proliferated microvasculature (stained in brown) intermingled among cardiomyocytes
(Fig. 3A). The entire heart was considerably pale and had a rubbery consistency. All of the cardiac chambers were hypertrophied and enlarged with significant endocardial thickening and whitening of the chambers (Fig. 3B). There was an oblique patent forman ovale. The ventricular septum was hypertrophied and coronary arteries were normal. Microscopy (Fig. 4A–4D) of the heart showed areas of fatty infiltration. There were patches of early fibrosis and apoptosis present in some areas. There was a marked increase in proliferation of microvasculature interspread between the cardiomyocytes.
Discussion and Review of Literature Neonatal-onset MADD is a rare disease, with poor prognosis. The average life expectancy is usually a few months and
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the terminal cause of death in most cases is severe acidosis or cardiorespiratory arrest. Currently, the management of MADD involves low-fat, low-protein, high-carbohydrate diet, avoiding long fasting periods and supplementing with carnitine and riboflavin [12] Carnitine in the diet provides a useful conjugation pathway for the removal of toxic intermediates that accumulate in MADD and enhances their urinary excretion as carnitine esters. Recently sodium-D,L-3hydroxybutyrate has been tried in some cases of severe cardiomyopathy in MADD with some success [21]. Autopsy studies in MADD patients provide welldescribed case reports of brain, kidney and liver pathology, but a lack of areas providing a complete description of the morphology and pathology of the heart. More than half of the autopsy reports of patients with MADD do not describe the heart, and in many of the patients, no cardiac investigations were done (see Table 1). Earlier reports describe
Heart size was not clear
NM
Bennett et al. 1984 [2] Case 1
NM
NM
Colevas et al. 1988 [6]
Wilson et al. 1989 [22]
NM
NM
NM
NM
Galloway et al. 1987 [8]
Normal EKG
Heart enlarged and pale
Pure white appearance
No hypertrophy
Slightly dilated heart
NM
Harkin et al. 1986 [13]
NM
Myocardium appears pure white
NM
EKG: Normal
NM
Case 2
NM
Normal anatomy, nonobstructive cardiomyopathy, decreased left ventricle contractility, thick left ventricular posterior wall and interventricle septum
NM
No malformations seen
Niederwieser et al. 1983 [17]
Normal size heart
NM
NM
NM
Cardiomegaly
Goodman et al.1983 [11]
NM
Bohm et al. 1982 [3]
NM
Small VSD, foramen ovale and PDA
Biventricular hypertrophy
NM
Goodman et al. 1982 [10]
Small VSD
NM
NM
NM
Sweetman et al., 1980 [20],
NM
Case 2
Normal
Goodman et al. 1980 [9]
Heart: Morphology
No cardiac malformation
Heart not described
Przyrembel et al. 1976 [18]
Echocardiography
(II) Case 1:
Chest X-ray
Source
Table 1 Summary of all the MADD case reports describing the heart in infants (arranged chronologically)
NM
Myocytes appear empty. Lipid and glycogen stores seen with electron microscope.
Large amount of fat deposition in heart
NM
Fat in myocardial fibers and interstitium
Fatty deposition in heart
No autopsy done
Fatty degeneration of heart
Myocardial cells stuffed with tiny sudanophlic droplets (fatty degeneration of heart)
Broad heart muscles with large nuclei. Intrasarcoplasmic fat droplets seen with Sudan red
Diffuse fatty infiltration of myocardium
NM
Severe fatty change in cardiac muscle cells
First case
Histopathology: Heart
TE: Ventricular fibrillation
Grade III/VI holosystolic murmur
TE: Cardiac arrest
TE: Sudden of cardiac failure
Pansystolic murmur present
TE: Ventricular fibrillations, cardiac arrest
Cardiomyopathy TE: Ventricular tachycardia
TE: Cardiac arrest
Systolic murmur present
Sudden death
Other Comments
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NM
NM
NM
Moderate cardiomegaly
Cardiomegaly
Cardiomegaly
NM
NM
Kamiya et al. 1990 [15]
Medlock et al. 1991 [16]
Hockey et al. 1993 [14]
Al-Essa et al. 2000 [1] Case 1
Case 2
Case 3
Slukvin et al. 2002 [19]
Domizio et al. 2005 [7]
Cardiomegaly
NM
Hypotension
Hypotension
Moderate cardiomegaly with poor ventricle function and hypertrophic septum
NM
Right Ventricular Hypertrophy, VSD tricuspid regurgitation
NM
Echocardiography
NM
Vascular connection normal, widely open PDA, heart valves normal
NM
Regurgitation in all four valves
Patient living when study published
NM
NM: Not mentioned; TE: Terminal event
Cardiac vacuolization: lipid storage myopathy
Vacuolar degeneration, lipid accumulation not seen on oil red O staining
NM
NM
NM
Microvesicular fatty changes
-Derangement and loss of myofibrils with severe fatty change
- No cardiac anomalies
Heart weight: 54 g, biventricular hypertrophy, patent forman ovale and PDA
-Atrophic cardiac muscles with obscured intracytoplasmic striations
Histopathology: Heart
-Heart weight:31.8 g, with pale myocardium
Heart: Morphology
Note: It is important to point out that none of the cases cited in the table have detailed cardiac pathology
Chest X-ray
Source
Table 1 continued
TE: Cardio-respiratory failure
S2 abnormal, holosystolic low-pitched murmur
TE: Resistant acidosis, respiratory failure
TE: Respiratory failure with a large pneumothorax
TE: Ventricular fibrillation
Grade III/VI holosystolic murmur
Heart failure
Other Comments
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fatty infiltration of the heart in MADD. It is of interest to point out that MADD has been implicated as one of the causes of sudden infant death syndrome [4]. There are several important features that might give a clue and alert the pediatric cardiologist to include MADD as one of the differential diagnosis of cardiomyopathy in critically ill neonates (e.g., polycystic kidneys with facial dysmorphism and steatotic liver). The composition of amniotic fluid and cultured amniocytes can confirm the diagnosis in a suspected pregnancy. The diagnosis of cardiomyopathy in the early neonatal period could include using tandem mass spectrometry to detect elevated acylcarnitine levels. Individuals with MADD show an unusual level of decanoylcarnitine relative to octanoylcarnitine C8 and higher levels of long- and short-chain acylcarnitines [5]. Our patient had a metabolic acidosis (pH 7.32, bicarbonate 14) with a high anion gap of 17. At the time of admission to the hospital, per the family, the patient had not been feeding well. He also had an upper respiratory infection. This patient’s renal function was also compromised; which might have resulted in diminished excretion of the toxic acids. The immense cardiomegaly, upper respiratory infection, poor feeding, and compromised renal function might have resulted in decompensation of this patient, which led to the metabolic acidosis. In addition, it is known that excess amounts of organic acids produced in MADD are directly toxic to tissues and are arrythmogenic. Acknowledgments We express our sincere thanks to Sunita J. Ferns and Kristina Borgen for helping us in the echocardiogram and microscopy of the heart, respectively. We also thank the family of the patient for consenting to publish this report.
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