Europace Advance Access originally published online on November 13, 2006
Europace 2006 8(12):1064-1067; doi:10.1093/europace/eul125
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GENETICS
Isolated ventricular non-compaction: clinical study and genetic review
yna Markiewicz-
oskot1,*oskot1
aw Szydowski1a W
glarz21 Department of Pediatric Cardiology, Medical University of Silesia, Medyków 16, 40-752 Katowice, Poland; 2 Department of Biochemistry, Medical University of Silesia, Narcyzów 1, 41-200 Sosnowiec, Poland
Manuscript submitted 16 March 2006. Accepted after revision 25 August 2006.
* Corresponding author. Tel: +48 32 207 18 55; fax: +48 32 207 18 61. E-mail address: ejaniszewska{at}slam.katowice.pl
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Abstract |
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Isolated non-compaction of the ventricular myocardium (INVM), sometimes referred to as ‘spongy myocardium’, is a congenital and exceedingly rare cardiomyopathy. Isolated ventricular non-compaction occurs in the absence of other structural heart diseases and, hypothetically, it is due to the arrest of myocardial morphogenesis. Isolated non-compaction of the ventricular myocardium may manifest itself from infancy to young adulthood with a high mortality rate. Both sexes are affected. In our study, we present a case of INVM (left and right ventricles) in a 3-year-old girl, diagnosed by two-dimensional echocardiography. The anomaly presented as a restrictive cardiomyopathy. The girl was admitted to our hospital with heart failure, when she was 10 months old. She was treated with dopamine, digoxin, furosemide, spironolactone, and acenocoumarol and her condition improved. Presently, the girl remains asymptomatic and for 3 years of follow-up, her development has been almost normal. We here describe the genetic background of this disorder (based on a literature review).
Key Words: Congenital heart anomaly, Ventricular non-compaction, Restrictive cardiomyopathy, Heart failure, G 4.5 (tafazzin gene), 
-dystrobrevin gene (DTNA), FKBP-12 gene, Lamin A/C gene
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Introduction |
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Isolated non-compaction of the ventricular myocardium (INVM), sometimes referred to as ‘spongy myocardium’, is a congenital and rare cardiomyopathy.1
,2 It appears more often in children than in adults. Isolated non-compaction of the ventricular myocardium may manifest itself from infancy to young adulthood with a high mortality rate. Both sexes are affected.2,3 The disorder may be associated with facial dysmorphism and familial recurrence.3 Isolated non-compaction of the ventricular myocardium occurs in the absence of other structural heart diseases and, hypothetically, it is due to the arrest of myocardial morphogenesis.2
The disorder is characterized by a hypertrophic left ventricle with deep trabeculations and with diminished systolic function, with or without associated left ventricular dilation. In half or more of the cases, the right ventricle is also affected.2,4,5
This disease is accompanied by depressed ventricular function, systemic embolism, and ventricular arrhythmia.3–5 Non-compaction of the ventricular myocardium can present with a variety of symptoms, but these usually include signs of left ventricular systolic dysfunction, even to the point of heart failure.5–7
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Case study |
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We report the case of a 3-year-old girl who was admitted to our hospital with severe heart failure, when she was 10 months old. She had experienced worsening dyspnoea with a respiratory rate of 60 bpm. Clinical examination revealed a low volume pulse with a delayed peak at a rate of 150 bpm and blood pressure of 80/50 mmHg. Cardiac examination detected an increased apical impulse and a systolic murmur. Auscultation over the lung fields revealed basal crepitation. The liver was palpable 4 cm below the costal margin and generalized oedema was present. She had normal facial features. The treatment of patients with INVM targets heart failure and thrombo-embolism. The child was treated with dopamine, digoxin, furosemide, spironolactone, and acenocoumarol and her condition improved.
The infant presented typical clinical and echocardiographic features of Isolated non-compaction of the ventricular myocardium (INVM). The chest X-ray showed an enlarged heart with a cardiothoracic ratio of 0.63. Electrocardiogram demonstrated sinus rhythm and right axis deviation and right ventricular hypertrophy with biatrial enlargement (Figure 1).
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Two-dimensional echocardiograms disclosed numerous prominent trabeculations of both ventricles with deep intertrabecular recesses and thickened endocardium, consistent with restrictive haemodynamics. A markedly thickened endocardium was visible at the apex of both ventricles. The anomaly presented a restrictive cardiomyopathy. The left and right atria were enlarged. (LA-20 mm and Ao-14 mm) (Figure 2). Left ventricular systolic function was depressed, with fractional shortening of only 23% and an ejection fraction of 48–50%.
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During follow-up, the ejection fraction of the left ventricle increased to 60–65%. Doppler echocardiography showed grade 2/6 mitral regurgitation and grade 2–3/6 tricuspid regurgitation and pulmonary hypertension.
There was no familial occurrence of INVM and the patient's parents had no cardiac defects on echocardiographic examination.
The girl has remained asymptomatic for almost 3 years of follow-up and her development has been nearly normal. She has been receiving digoxin, enalapril, furosemide, and acetylsalicylic acid. As far as we know, this is one of the few reported cases with a good recovery.
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Genetics |
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The sporadic type in some patients may be due to chromosomal abnormalities with familial occurrence. Isolated non-compaction of the left ventricular myocardium in the majority of adult patients is an autosomal dominant disorder.8
The familial and X-linked disorders have been described by Chin et al.,3 Hamamichi et al.,9 Bleyl et al.,10 Ritter et al.,11 and Matsuda et al.12
The first gene responsible for INVM, tafazzin (G 4.5), is localized on chromosome Xq28 and expressed at high levels in cardiac and skeletal muscles. It plays a role in the maintenance of mitochondria, is involved in maintaining levels of cardiolipin, promotes differentiation and maturation of osteoblast cells, and prevents adipocytes from maturing.13
Bleyl et al.14 screened the tafazzin gene for mutations in a family with isolated non-compaction of left ventricular myocardium by performing single-stranded conformation polymorphism analysis and direct sequencing. They found a novel glycine-to-arginine substitution at position 197.
Ichida et al.15 identified a cys118-to-arg (C118R) missense mutation in the exon 4 of the tafazzin gene in a 5-month-old male with INVM associated with a dilated, mildly hypertrophic heart, poor systolic function on echocardiogram and clinical heart failure. The mother was healthy but was found to be heterozygous for the same mutation along with a splice donor mutation (IVS10+2T
A) in intron 10.15
Chen et al.16 identified a novel splice acceptor site mutation in intron 8 of G 4.5 in a family with severe infantile X-linked left ventricular non-compaction, resulting in the deletion of exon 9 from the mRNA; it is predicted significantly to disrupt the protein product. Kenton et al.17 identified a splice site acceptor mutation in intron 10 of tafazzin gene, resulting in the deletion of exon 10 from the mRNA. Thirteen mutations affiliated with this gene have so far been reported.18
The second gene responsible for INVM encodes -dystrobrevin (DTNA), a cytoskeletal protein found in the dystrophin-associated glycoprotein complex.15 It was localized in 18q12.1–q12.2 by in situ hybridization.19
Ichida et al.15 screened the -dystrobrevin gene in a Japanese family in which members of four generations were affected: five of them with left ventricular non-compaction associated with congenital heart defects and one with isolated non-compaction of the left ventricular myocardium. A missense mutation in the dystrobrevin gene, P121L, was found.
A 362C>T mutation was also identified in this gene in a family with non-isolated left ventricular non-compaction (LVNC).20
Furthermore, isolated non-compaction of the left ventricular myocardium is observed among the FK506-binding protein 1A gene (FKBP1A) mutants where the gene has been ‘knocked out’ by embryonic stem cell technology. The FKBP1A gene maps to 20p13.21
The fourth gene associated with left ventricular non-compaction encodes lamin A/C (LMNA)-related sequence mapped to human chromosomes 1q12.1–q23 and 10.22 Lamin A/C mutations have also been associated with familial or sporadic dilated cardiomyopathy (DC), with or without conduction system disease.23,24
Hermida-Prieto et al.24 studied the LMNA gene in 67 consecutive patients with DC. Two disease-causing mutations were found in two families. In family A, a novel R349L mutation was present in the mother and her identical twin daughters. In family B, the R190W mutation was present in two cousins with DC and without conduction system disease and in two of their sons. One of the carriers fulfilled diagnostic criteria for isolated left ventricular non-compaction.24
In 2004, Sasse-Klaassen et al.25 discovered a novel gene locus for autosomal dominant left ventricular non-compaction. They mapped a locus for autosomal dominant left ventricular non-compaction to a 6.8 Mb region on human chromosome 11p15.25
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Discussion |
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Isolated non-compaction of the ventricular myocardium is a rare congenital cardiomyopathy. This disorder is characterized by the presence of numerous prominent trabeculations and deep intertrabecular recesses that communicate with the left ventricular cavity. Isolated non-compaction of the ventricular myocardium may be isolated or associated with congenital heart anomalies such as ventricular septal defect, pulmonary stenosis, and atrial septal defect.15
Similar myocardial pattern of persisting sinusoids was reported in association with severe aortic stenosis or pulmonary atresia with an intact interventricular septum.26,27 The typical symptoms of INVM have also been described in a patient with Becker muscular dystrophy, and INVM was suggested to be a part of this systemic myopathy.28 The familial as well as the sporadic form of INVM may coexist with a dysmorphic facial appearance such as a prominent forehead, strabismus, gothic palate, or micrognatia.3 Isolated non-compaction of the ventricular myocardium occurs in the absence of other structural heart diseases and it is considered to be due to the arrest of myocardial morphogenesis.2
The largest study performed on an adult population with isolated non-compaction of the left ventricle was described by Oechslin et al.27 Non-compacted myocardium was classically seen in the apical region in more than 80% of the cases.27 These characteristic clinical and echocardiographic features were also present in our case. Patients with non-compaction have a high incidence of heart failure, arrhythmias, thrombo-embolism, and sudden cardiac death.4,5,27
Chin et al.3 collected eight cases of children and young adults (11 months to 22 years), with a follow-up as long as 5 years. Echocardiographic images were diagnostic and corresponded to the morphological appearances at necropsy. Clinical manifestations of the non-compacted myocardium included depressed left ventricular systolic function in five patients, ventricular arrhythmias in five, systemic embolization in three, and familial occurrence in four patients.3 Our patient had no arrhythmias, but she sustained cerebral embolism and receives sodium valproate for treatment of seizures.
The endomyocardial morphology of left ventricular non-compaction lends itself to the development of mural thrombi within the deep intertrabecular recesses. Anticoagulants are warranted when thrombi are seen on echocardiography.3 Hook et al.4 reported a case of non-compacted myocardium involving the left and right ventricles with endocardial fibrosis, which presented as a restrictive cardiomyopathy. These features are similar to the ones seen in our patient, in whom endocardial fibrosis may have been responsible for the restrictive physiology.
Isolated non-compaction of the ventricular myocardium should be included in the differential diagnosis of young patients presenting with a restrictive cardiomyopathy.
Left ventricular non-compaction does not have an invariably fatal course when diagnosed in the neonatal period. A significant number of patients have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an ‘undulating’ phenotype.
Genotype–phenotype correlation of gene mutations, in all cases reported in the literature up to date, revealed no correlation between location or type of mutation and cardiac phenotype or disease severity.
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References |
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