Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood.

BACKGROUND: FLNC is one of the few genes associated with all types of cardiomyopathies, but it also underlies neuromuscular phenotype. The combination of concomitant neuromuscular and cardiac involvement is not often observed in filaminopathies and the impact of this on the disease prognosis has hitherto not been analyzed. RESULTS: Here we provide a detailed clinical, genetic, and structural prediction analysis of distinct FLNC-associated phenotypes based on twelve pediatric cases. They include early-onset restrictive cardiomyopathy (RCM) in association with congenital myopathy. In all patients the initial diagnosis was established during the first year of life and in five out of twelve (41.7%) patients the first symptoms were observed at birth. RCM was present in all patients, often in combination with septal defects. No ventricular arrhythmias were noted in any of the patients presented here. Myopathy was confirmed by neurological examination, electromyography, and morphological studies. Arthrogryposes was diagnosed in six patients and remained clinically meaningful with increasing age in three of them. One patient underwent successful heart transplantation at the age of 18 years and two patients are currently included in the waiting list for heart transplantation. Two died due to congestive heart failure. One patient had ICD instally as primary prevention of SCD. In ten out of twelve patients the disease was associated with missense variants and only in two cases loss of function variants were detected. In half of the described cases, an amino acid substitution A1186V, altering the structure of IgFLNc10, was found. CONCLUSIONS: The present description of twelve cases of early-onset restrictive cardiomyopathy with congenital myopathy and FLNC mutation, underlines a distinct unique phenotype that can be suggested as a separate clinical form of filaminopathies. Amino acid substitution A1186V, which was observed in half of the cases, defines a mutational hotspot for the reported combination of myopathy and cardiomyopathy. Several independent molecular mechanisms of FLNC mutations linked to filamin structure and function can explain the broad spectrum of FLNC-associated phenotypes. Early disease presentation and unfavorable prognosis of heart failure demanding heart transplantation make awareness of this clinical form of filaminopathy of great clinical importance.

Peculiarities of Histological Structure of Pulmonary Veins in Patients with Total Anomalous Pulmonary Venous Drainage as Morphological Substrates Relating to Formation of Postoperative Pulmonary Venous Obstruction.

The histological and immunohistochemical methods were employed to examine the peculiarities of histological structure of pulmonary veins and left atrium of the heart in norm and in various types of total anomalous drainage of pulmonary veins. In contrast to normal pulmonary vein covered with external multiple muscle layers (myocardial sleeve), such sleeve is absent in veins that have no connection with the left atrium irrespective of the type of the defect. In patients with total anomalous pulmonary venous drainage, the structure of left atrium was heterogeneous featuring either the presence or absence of inner angiomural lining in this atrium. The structural peculiarities are important for insight into etiology of the development of postoperative pulmonary venous obstruction in patients with total anomalous pulmonary venous drainage.

[Asymptomatic ventricular pre-excitation in children: a 17 year follow-up study].

Results of long term clinic-electrophysiological follow-up of a large group of children with Wolf-Parkinson-White (WPW) phenomenon are present. From 1993 to 2011 we examined 176 children - 117 boys (66,5%) and 59 girls (33,5%) - with manifesting type of WPW. Age at first examination was 12.5+/-3.2 ( 0.1 18 ). In 66.5% of children WPW phenomenon was present in the age from 10 to 18 . Hundred fifty nine children (104 [65.4%] boys and 55 [34.6%] girls) were followed up for 0.5-17 years (mean 7.4+/-4.5 years). During follow-up spontaneous attacs of atrioventricular reciprocal tachycardia appeared in 13 children (8.2%, 95% confidence interval [CI] 4.4-13.6%). Spontaneous disappearance of signs of ventricular pre-excitation on electrocardiogram and transition to intermittent form of WPW were registered in 14(8.8%, 95%CI 4.9-14.3%) and 12 children (7.5%, 95% CI 3.9-12.8%). Short lasting syncopal states were observed in 15 children (8.4%). In 3 of them atrial fibrillation with high rate of venricular rhytm was induced during transesophageal electrophysiological study. Two (1.3%) children had history of clinical death. In one of them WPW phenomenon was combined with hypertrophic cardiomyopathy and polymorphic ventricular tachycardia. This child died at the age of 11 years. One (0.6%) boy with WPW phenomenon died suddenly in 3 years after initial examination. Thus, children with WPW phenomenon are at risk of development of life threatening states and sudden cardiac death. Stratification of risk of sudden death is necessary at examination of such children.