Left ventricular non-compaction cardiomyopathy: restrictive subtype with MYH7 gene mutation

Abstract

Left ventricular non-compaction is a very rare, still unclassified congenital cardiomyopathy. Nine distinct subtypes of functional and anatomical left ventricular non-compaction have been identified. Studies on the prognosis and mortality of subtypes are ongoing. Our study presented the first restrictive subtype left ventricular non-compaction case with family history and MYH7 gene mutation.

Left ventricular non-compaction, also called hypertrabeculation, spongiform myocardium, persistent myocardial sinusoids, spongiform cardiomyopathy, or zaspopathy, is a rare type of congenital cardiomyopathy. ¹ According to echocardiographic studies, the prevalence in the general population is between 0.014% and 1.3%. ²

The anomaly, first detected by echocardiography in 1984, was classified as primary genetic cardiomyopathy by the American Heart Association in 2006 and is currently in the unclassified cardiomyopathy group by the European Society of Cardiology. ^1,3

Left ventricular non-compaction cardiomyopathy presents clinical findings such as a high risk of malignant arrhythmia, left ventricular dysfunction, and thromboembolic phenomenon. The diagnosis can be made by echocardiography, cardiac MRI, angiography and genetic tests. ^1,4 The subtype of left ventricular non-compaction, genetic mutations, and the presence of family history are the important factors affecting the prognosis. ⁵ We report a rare case of restrictive left ventricular non-compaction associated with an MYH7 gene mutation in a child with a family history.

Case presentation

A 4-year-old male patient was admitted to our emergency department with complaints of sudden onset of palpitations and shortness of breath. He had similar episodes of shortness of breath while at rest (functional class I/II) and a history of frequent lung infections in the last two years.

His heart rate was 168/min, respiratory rate was 32/min, blood pressure was 80/60 mmHg, and crepitant rales were heard in both lungs. The left ventricular activity was increased, and a systolic murmur of 2/6 intensity and S3 was heard on the left sternal border. Hepatomegaly was detected.

The left atrium was enlarged with moderate mitral regurgitation in the echocardiographic examination. Left ventricular ejection fraction was 69%. Non-compaction was detected in the left ventricular apex, the anterior, and lateral wall, with the end-systolic ratio of the non-compact and compact layer >2. Also, blood flow was observed between these trabeculations with the colour Doppler. In Doppler tissue and MRI examinations (from the left ventricular posterior wall and ventricular septum), diastolic functions were in a restrictive pattern (E/A ratio 3.3, E: 0.10 m/sec, A: 0.3 m/sec) (Fig 1 and 2). No arrhythmia was detected in ECG and 24-hour rhythm Holter examination. The mutation in our case was a novel missense mutation located in the exon 14(GCA/GTA) A426V-MYH7 coding region. Segregation analysis within the family revealed that both parents and unaffected brother were homozygous wild genotype (GCA/GCA). Heart failure treatment was done during follow-ups, and arrhythmia was not developed. Our patient, who had been taken to the transplant programme, died at 12 years old due to heart failure.

Fig. 1. Transthoracic echocardiographic images. (a ) Demonstration of characteristically marked enlargement of the left atrium (LA), which is larger than the left ventricle (LV) in 4-chamber view. ( b ) Demonstration of the restrictive pattern by measurement of diastolic functions in the posterior wall of the left ventricle with Tissue Doppler Imaging (E/A ratio 3.3). ( c ) Non-compaction view of the left ventricle in the apical 4-chamber view. ( d ) Myocardial trabeculations on the posterior wall of the left ventricle.

Fig. 2. Cardiac MRI images. (a ) Abnormal trabeculations on the left ventricle, spherical left ventricle. (Ao: Aorta, LV: left ventricle). ( b ) Trabecular view of the left ventricle in the parasternal short axis. (RV: right ventricle, LV: left ventricle).

Discussion

In the aetiopathogenesis of left ventricular non-compaction, pauses in compaction of myocardial fibres during myocardial embryogenesis in foetal life and genetic factors have been held responsible. ⁶ Subtypes of left ventricular non-compaction are as follows: isolated or benign, arrhythmogenic, dilated, hypertrophic, mixed, restrictive, biventricular, normal left ventricle with hypertrabeculated left ventricular non-compaction in the right ventricle, left ventricular non-compaction due to CHD. ⁵ Left ventricular non-compaction is seen most frequently with isolated, dilated, and hypertrophic subtypes. ⁴ In a study done with left ventricular non-compaction patients, the symptoms were congestive heart failure (25%), abnormal cardiac examination (19%), abnormal ECG or chest X-ray film (16%), arrhythmia (10%), chest pain (9%), and syncope (5%). ⁵ In echocardiography, Chin criteria were defined as any one segment with the ratio of trough of trabeculation-to-epicardium (X): peak of trabeculation-to-epicardium (Y) <0.5 at end-diastole, whereas Jenni criteria as any segment with maximum end-systolic non-compacted: compacted thickness ≥2.4. However, Petersen criteria were defined in CMR as end-diastolic non-compacted: compacted thickness ≥2.3. ⁷

Genetics plays an essential role in left ventricular non-compaction, as between 17 and 50% of patients have a family member with cardiomyopathy. ⁸ Left ventricular non-compaction is currently considered a genetically heterogeneous, monogenic disease with autosomal-dominant, autosomal recessive, and X-linked forms reported. ⁹ An autosomal-dominant inheritance pattern in left ventricular non-compaction appears in most families with variable penetration. Left ventricular non-compaction is a heterogeneous disease, and its genetic classification has clinical relevance. In a study, the incidence of mutations in the sarcomere genes was 82%, and the rest were found in non-sarcomere genes. The most frequent mutations in sarcomere genes found in genetic left ventricular non-compaction are MYH7, MYBPC3, and TTN, particularly MYH7. Mutations are more common in children than adults. While TTN was common in adults, it was not seen in children. ⁸ Studies show that the prognosis is worse in patients with mutations and family history. ⁵ Therefore, sequencing patients will help us to better understand and assess the disease prognosis and to identify at-risk family members. ⁴

Here we report the first paediatric case of left ventricular non-compaction subtype restrictive cardiomyopathy secondary to a de novo mutation in the cardiac myosin heavy chain gene MYH7. We present a patient with a family history of MYH7 gene mutation who presented with signs of heart failure at the age of 4 and died at 12. The prognosis was poor, and rapid progression was seen. The importance of this case is that the subtype of left ventricular non-compaction is restrictive. While the cardiac findings of patients with left ventricular non-compaction with MYH7 gene mutation usually have a slow course, our patient was diagnosed at an early age, showed rapid progression, and died. The most important features of our patient’s poor prognosis are the presence of a restrictive pattern and signs of heart failure at an early age, along with his family history.

Treatment for left ventricular non-compaction patients should be directed towards preventing and managing heart failure, ventricular arrhythmias, and thromboembolic events. The long-term prognosis of left ventricular non-compaction is poor. ¹⁰ The patient in our study had heart failure and received anti-aggregant therapy. Anti-arrhythmics were not prescribed because arrhythmia did not develop. However, while waiting for a heart transplant, he died due to rapidly progressing congestive heart failure.

Conclusions

Studies on the clinical course and mortality of the subtypes of left ventricular non-compaction continue today. Our study is the first case of restrictive subtype left ventricular non-compaction with a family history and an MYH7 gene mutation. We think that the presence of restrictive pattern, family history, and early clinical findings in left ventricular non-compaction cause poor prognosis.