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Journal of Pediatric Neurology, Vol. 2, No. 3, July-Sept, 2004, pp. 145-148


Echocardiographic evaluation in Rett children with cardiac dysautonomia

Francesca Guideri 1, Maurizio Acampa 2, Maria Rosaria Matera 3, Michele Zappella 4, Yusuf Hayek 4

Departments of 1 Internal Medicine and Immunological Sciences, Section of Clinical Immunology, 2 Internal Medicine and Immunological Sciences, Section of Internal Medicine, 3 Pediatrics, 4 Child Neurology and Psychiatry, University of Siena, Siena, Italy
Correspondence: Francesca Guideri, M.D., Dipartimento di Medicina Clinica e Scienze Immunologiche, Sezione di Immunologia Clinica, Policlinico ‘Le Scotte’, viale Bracci, 53100 Siena, Italy. Tel: +39(0)577585741, fax:+39(0)57744114.E-mail:

Received: March 03, 2004. Revised: April 23, 2004. Accepted: May 04, 2004.

Code Number: pn04028


The incidence of sudden death in Rett syndrome is greater than that of the general population. Previous studies suggested cardiac dysautonomia and long QT interval as a prime suspect cause but there are no echocardiographic studies in Rett girls. The aim of this study was the analysis of the cardiac dysautonomia and echocardiographic abnormalities in females affected with Rett syndrome as a possible explanation of the higher risk for sudden death, observed in these subjects. Standard transthoracic echocardiography, heart rate variability and corrected QT interval were studied in 32 Rett girls (4±4.1 years) and in 30 age-matched healthy females (6.8±2.1 years). All Rett girls had cardiac dysautonomia, with loss of physiological heart rate variability but normal cardiac structures, dimensions and function. These results suggest that sudden death in Rett girls may be linked to an electrical instability and not to cardiac structures or valve alterations. (J Pediatr Neurol 2004; 2(3): 145-148). 

Key words: Rett syndrome, echocardiography, cardiac dysautonomia.  


Rett syndrome is a severe neurological disorder, caused by methyl-CpG-binding protein 2 (MECP2) gene mutations (1) and characterized by a profound intellectual and physical disability (2). The prevalence of the disorder in the United Kingdom exceeds 1 in 10,000 of the female population (3). A previous study have shown in almost 80% of cases of classic Rett syndrome the presence of a MECP2 gene mutation (4). The mortality rate in Rett syndrome is 1.2% per annum: of these deaths 26% were sudden, unexpected deaths (3). In comparison the incidence of sudden unexpected death in the general population, between 1 and 22 years of age, was 1.3 per 100,000 patients per year (5).

Sudden death in children may be associated with the diagnosis of hypertrophic or dilated cardiomyopathy, right ventricular cardiomyopathy, coronary artery disease, mitral-valve prolapse, Marfan’s syndrome, or the long-QT syndrome (6). Pathogenesis of sudden death in Rett syndrome is actually unknown but electrical instability is a possible cause and recent studies have shown cardiac arrhythmias in Rett disorder (7,8) supporting this hypothesis. Previous studies (9-11) have shown that in Rett syndrome there is a cardiac dysautonomia, expressed by the loss of physiological heart rate variability (HRV). This alteration is progressive with age and clinical stage (11) and may be relevant to the high risk of sudden death.

Furthermore, cardiac dysautonomia in Rett syndrome is associated with electrocardiographic abnormalities, as flat or inverted T waves and QT interval prolongation (12,13). Actually, there are no echocardiographic studies evaluating the presence of cardiomyopathy or cardiac valves alterations in children with Rett syndrome even if Kearney et al. (14) described an immature configuration of the conduction system in autopsy hearts from six Rett girls, suggesting a possible developmental arrest in this region of the heart.

The aim of this study was the analysis of the heart rate variability and of possible  electrocardiographic and echocardiographic abnormalities in females affected with Rett syndrome as a possible explanation of the higher risk for sudden death, observed in these subjects.


Thirty-two females with Rett syndrome aged 2 to 18 years (4±4.1 years) were recruited from the Department of Child Neurology of the University of Siena. Standard transthoracic echocardiography, HRV and corrected QT interval (QTc) were studied in all patients and in 30 age-matched healthy females (6.8±2.1 years).


Doppler echocardiograms were obtained by using a ESAOTE-Biomedica (advanced ultrasonography) model AU3 Partner. Complete 2-dimensional and conventional color flow imaging and spectral Doppler echocardiography was performed. Ejection fraction was measured in all children by the biplane modified Simpson method. Pulse-wave Doppler parameters and color coded M mode Doppler data were obtained using the 3-7 MHz transducer. The following parameters were evaluated:

a.  Wall thickness, chamber sizes, fractional shortening, wall thickening, cardiac valves opening by means of M-mode and two dimensional echocardiography.

b.  Dopper echocardiography by pulsed Doppler, continuous wave and color-Doppler to study blood flow.

Heart rate variability

Twelwe-lead electrocardiogram was continuously monitored and recorded for up to 10 minutes, in supine position, during spontaneous breathing. Commercially available imaging system (Cardioline ECT WS 2000, Remco Italia) was used. QRS detection and R-R interval measurement were automatically performed, looking for the R wave peak as a reference point. Premature beats, missed beats and artifacts were visually identified using an interactive graphic interface and corrected by the operator. In this way, an RR tachogram was obtained, that is, a discrete series of successive RR intervals as a function of the number of recognized QRS complexes. Algorithm, used for the analysis of the tachogram, was a spectral method (fast Fourier Transformation). Three main spectral components were distinguished in a spectrum calculated from short-term recordings of five minutes:

a. A very low frequency component (VLF): <0.04 Hz;
b. A low frequency component (LF): range 0.04-0.15 Hz;
c. A high frequency component (HF): range 0.15-0.4 Hz.

The measurement of VLF, LF, and HF power components and of total power was made in absolute values of power (millisecond squared).

QTc interval

Twelwe-lead electrocardiogram were recorded simultaneously. Standard criteria were applied for the QT measurement (15). QT intervals were measured from the onset of Q wave or the onset of the QRS to the end of T-wave, defined as return to the T-P baseline. When U waves were present, the QT was measured to the nadir of the curve between the T and U waves. The QT interval, determined by the longest hand-measured QT interval in any lead, was corrected for the heart rate by the Bazett method to yield the QTc value (QTc was calculated by dividing the QT interval by the square root of the R-R interval, excluding those intervals shorter than 521 msec and longer than 1111 msec; Bazett’s formula considers values exceeding this range as unreliable (16). The QTc was considered abnormal if greater than 0.44 second.



All the Rett girls and control subjects had normal cardiac structures, dimensions and function (Table 1). The Doppler study showed only paraphysiological alterations in both groups (Table 2).

Heart rate variability

The R-R interval in Rett children was significantly lower in comparison with the control group (531±66 vs 677±78 msec, P <0.001). The total power spectrum of heart rate variability (from 0.03 to 0.4 Hz) was significantly lower in children with Rett syndrome, compared with healthy children (1125±675 ms2 vs 6243±4179 ms2, P <0.001). As far as the VLF, LF and HF contents were concerned, children with Rett syndrome had significantly lower power spectrum values compared to control subjects (343±271 ms2 vs 984±715 ms2, P=0.002; 438±337 ms2 vs 1586±938 ms2, P <0.001; 230±266 ms2 vs 2351±2080 ms2, P <0.001).

The sympathovagal balance expressed by the ratio of LF to HF showed statistically significant differences between the groups considered: in fact, in females with Rett syndrome the ratio was higher than in control subjects (3.8±2.9 vs 1±0.5, P <0.001), reflecting the higher prevalence of sympathetic activity in classical Rett syndrome.

QTc interval.

In patients with Rett syndrome the QTc interval was significantly longer than in the control group (0.44±0.02 vs 0.40±0.01 sec., P <0.001). 


According to previous studies (10-12), we showed the presence of a cardiac dysautonomia (low HRV and sympathetic hyperactivity) and of a prolongation of QTc interval in Rett girls. No hypertrophic or dilated cardiomyopathy, right ventricular cardiomyopathy or mitral-valve prolapse were detected in these girls. Reduced HRV is a powerful and independent predictor of an adverse prognosis in patients with heart disease and in the general population (17).

Furthermore, it is well known the proarrhythmic role exerted by transient or persistent alterations in sympathetic and vagal control mechanisms (18). Specifically, sympathetic hyperactivity favors the onset of life-threatening cardiac arrhythmias, whereas vagal activation usually exerts relatively protective and antifibrillatory effects. In animals, augmentation of the cardiac vagal control by nerve stimulation of by drugs is associated with a reduction of sudden death in susceptible models; in humans a number of drugs which have been shown to reduce mortality and sudden death in large randomized trials can also be demonstrated to increase heart rate variability. So, it is still unclear whether the relationship between measures of cardiac vagal control and mortality is causative or mere association (17).

The QT interval is an indirect measure of the time between ventricular depolarization and repolarization. Its prolongation is thought to be associated with the occurrence of malignant ventricular arrhythmias (19). Actually, it is not known if QTc prolongation observed in Rett disorder is related to an alteration in cardiac ionic channels as for congenital and acquired long QT syndromes. Our previous study suggested a role for nerve growth factor in the alteration in ventricular repolarization: in fact evidence exsists that low nerve growth factor plasma levels may be associated with prolonged QT interval and this may be explained by the retarded pattern of both nexal and desmosomal junction formation resulting in the dispersion in action potential duration (20). As a consequence those drugs prolonging QT interval or increasing sympathetic activity should be avoided. Our results suggest that sudden death in Rett girls may be linked to an electrical instability and not to cardiac structures or valve alterations.


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Copyright 2004 - the Society of Pediatric Science, Yüzüncü Yil University, Faculty of Medicine, Department of Pediatric Neurology, Van, Turkey

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