Fabry disease

ECG 1: This electrocardiogram is characteristic of Fabry disease with nascent cardiac involvement ; sinus rhythm, P wave of very short duration with short PQ interval (< 120 ms); narrow QRS with left ventricular hypertrophy (positive Sokolow index); inferior and lateral repolarization disorders (negative T waves); prolonged QT interval (QTc of 446 ms);

Comments: The diagnosis of Fabry disease was confirmed in this patient by molecular analysis of the GLA gene. Fabry disease is a hereditary disease of lysosomal overload linked to the X chromosome, due to an alpha-galactosidase A deficiency, with multisystemic involvement (possible dermatological, renal, cardiac, gastrointestinal, cochlear and neurological manifestations). Cardiac involvement is secondary to myocardial intracellular accumulation (in lysosomes) of Gb3 and alters the prognosis with increased mortality from heart failure or sudden death. A generally concentric left ventricular hypertrophy typically only appears after several decades (around 30 to 40 years of age) and reflects the progression of the disease. An MRI allows highlighting wall thickening as well as the fibrotic plaques associated with segmental contraction disorders. Right ventricular hypertrophy is also relatively common. The electrocardiographic signs evolve in parallel with macroscopic myocardial changes (increase in voltages, repolarization disorders, prolongation of the PQ interval, prolongation of the duration of the P wave). Providing that an enzymatic replacement therapy is available, early diagnosis is necessary to prevent progression toward irreversible anatomical lesions. Certain electrocardiographic signs have been described in the early phase often before detection of ultrasound morphological abnormalities. The electrocardiogram can therefore orient the diagnosis to the initial phase and can show:

• A shortening of the PQ interval is one of the signs that can appear in the initial phase before any ultrasound abnormality; the mechanisms involved in reducing the time between activation of the first atrial cell and that of the first ventricular cell are subject to debate; various electrophysiological studies have eliminated the hypothesis of an accessory route; this reduction of the PQ interval appears to be related to the presence of a P wave of shortened duration indicative of an increase in the rates of atrial conduction; the concomitant observation of very narrow QRS is also in favor of an improved myocardial conductivity; a shortened PQ interval is an early sign and therefore must systematically evoke the diagnosis of Fabry disease especially in a family context or suspected compatible symptoms; the progression of the disease may be marked by a prolongation of the PQ interval (in parallel with the prolongation of the duration of the QRS complex) indicative of the evolution of the degenerative process;
• At the early stage, it is common to observe a P wave of short duration with progressive increase during the course of the disease;
• Electrical left ventricular hypertrophy (positive Sokolow index) is observed in 50% of men and 30% of women; this incidence increases significantly with the progression of the disease;
• Repolarization abnormalities (moderate ST segment depression and negative T waves) are frequently observed in the lateral region in the absence of coronary artery disease; these changes generally correspond to the delayed enhancement detected during an MRI (localized myocardial fibrosis); prolongation of the QT interval is relatively rare;
• The occurrence of supraventricular rhythm disorders (atrial fibrillation observed in 18% of patients or ventricular fibrillation (non-sustained VT in approximately 8%) justifies regular follow-up; in addition, evidence of sinus node dysfunction or a high grade atrioventricular block is an indication for pacemaker implantation;

Take-home message: The detection of a short PR interval, without pre-excitation, in the presence or absence of left ventricular hypertrophy should evoke the diagnosis of Fabry disease.