Case report

Electrophysiologic findings in Fabry's disease with a short PR interval

Anderson-Fabry disease (AFD) is an X-linked inherited lysosomal disease caused by a defect in the gene encoding lysosomal enzyme α-galactosidase A (GLA). Atrio-ventricular (AV) nodal conduction defects and sinus node dysfunction are common complications of the disease. It is not fully elucidated how frequently AFD is responsible for acquired AV block or sinus node dysfunction and if some AFD patients could manifest primarily with spontaneous bradycardia in general population. The purpose of study was to evaluate the prevalence of AFD in male patients with implanted permanent pacemaker (PM).

The prospective multicentric screening in consecutive male patients between 35 and 65 years with implanted PM for acquired third- or second- degree type 2 AV block or symptomatic second- degree type 1 AV block or sinus node dysfunction was performed.

A total of 484 patients (mean age 54 ± 12 years at time of PM implantation) were enrolled to the screening in 12 local sites in Czech Republic. Out of all patients, negative result was found in 481 (99%) subjects. In 3 cases, a GLA variant was found, classified as benign: p.Asp313Tyr, p.D313Y). Pathogenic GLA variants (classical or non-classical form) or variants of unclear significance were not detected.

The prevalence of pathogenic variants causing AFD in a general population sample with implanted permanent PM for AV conduction defects or sinus node dysfunction seems to be low. Our findings do not advocate a routine screening for AFD in all adult males with clinically significant bradycardia.

The prevalence of Fabry disease (FD) in male patients with left ventricular hypertrophy (LVH) is about 1%. From the perspective of performing more efficient screening with measurement of α-galactosidase (α-Gal) activity, it is important to raise the pretest probability.

We retrospectively investigated the prevalence of FD in 701 male patients with LVH who already had been screened by measurement of α-Gal activity in eight hospitals. From the viewpoint of enzymatic screening, we validated previously reported clinical features of FD including the electrocardiographic and echocardiographic characteristics with comparing each clinical determinant between patients with FD and non-FD patients. We finally aimed to establish a new screening approach for the detection of patients at high risk of FD.

There were five FD patients (0.7%) in the 701 male patients with LVH. Those five patients with FD all had the cardiac variant type and age at detection of LVH was ≥35 years in all patients. In LVH patients with LV ejection fraction (EF) ≥ 50%, Pend-Q interval < 40 msec, SV1 + RV5 > 4.0 mV, and diffuse LVH were important determinants of FD. In LVH patients with LVEF < 50%, asymmetric septal hypertrophy and posterior wall motion abnormality seemed to be associated with FD.

In our retrospective study, the prevalence of FD in male patients with LVH was found to be 0.7%. We established the efficient combinations of clinical determinants using age at detection of LVH, Pend-Q interval, high voltage, and LVH pattern in an echocardiogram.

Fabry disease (FD) is a rare genetic disorder that leads to left ventricular hypertrophy (LVH), frequently misdiagnosed as hypertrophic cardiomyopathy (HCM). We sought to assess the value of electrocardiography for distinguishing FD from HCM. We retrospectively reviewed and compared standard electrocardiograms and echocardiograms from 26 patients with FD and LVH and 33 sarcomeric patients with HCM, matched for gender, age, and degree of LVH. The mean age of patients with FD was 46 years (interquartile range) (28 to 53) and of HCM 50 (30 to 61) years (p = 0.27). Of them, 16 (61%) and 25 (76%) were male, respectively (p = 0.26). Indexed left ventricular mass was 166 g/m² in FD versus 181 g/m² in HCM (p = 0.88). All patients with FD and 30 (91%) with HCM were in sinus rhythm (p = 0.25). A higher prevalence of right bundle branch block (RBBB) was observed in FD (27%) versus HCM (6%) (p = 0.03). The PR interval was shorter in FD, 140 ms (120-160) versus 160 ms (140 to 180) (p = 0.004). P-wave duration was longer in patients with FD, 100 ms (80 to 120) versus 80 ms (80 to 100) (p = 0.01). The PQ interval (PR interval minus P-wave duration) was shorter in patients with FD, 40 ms (20 to 45) versus 80 ms (40 to 80) (p = 0.001). There were no differences regarding P-wave amplitude, QRS complex duration, corrected QT length, conduction or repolarization abnormalities, Sokolow-Lyon index, and Cornell index. After multivariate adjustments for RBBB, PR interval, P-wave duration, and PQ interval, a PQ interval ≤40 ms and RBBB were significantly associated with FD. In conclusion, there are electrocardiogram characteristics, such as the presence of RBBB or a PQ interval ≤40 ms, that may be helpful for screening and reducing the delay in FD diagnosis.

To elaborate an ECG-based nomogram estimating the probability to detect cardiac involvement by cardiac magnetic resonance (CMR) in Fabry Disease (FD).

119 FD patients and 26 healthy controls underwent ECG and CMR. Test (n = 88, 60%) and validation cohorts (n = 57, 40%) were randomly derived. Cardiac involvement was defined as the presence of low myocardial T1 value, a CMR-surrogate of myocardial glycosphingolipid storage. ECG changes associated with low T1 value were identified in the test cohort, included in the nomogram and then tested in the validation cohort.

Sokolow-Lyon index (AUC = 0.769), ratio between P-wave and PR-segment durations (Pwave/PRsegment) (AUC = 0.778), QRS duration (AUC = 0.703), QT (AUC = 0.769) duration were independently associated with the presence of low T1 on CMR at multivariate analysis. An ECG-based nomogram including these four parameters was accurate in identifying patients with CMR evidence of glycosphingolipid storage (c-index of the derived-nomogram = 0.90 in the test group; 0.81 in the validation group).

We propose a practical ECG-based nomogram accurately estimating the probability to detect low T1 values by CMR in FD patients. The application of this tool in clinical practice could improve early detection of FD cardiac involvement.

Idiopathic cardiomyopathies are divided into three forms: primary restrictive, infiltrative, and storage disorders. Primary restrictive cardiomyopathies are usually genetically inherited. They are characterized by bi-atrial enlargement with non-dilated ventricles in addition to a characteristic histopathological morphology. Cardiac transplantation is the ideal treatment. Cardiac amyloidosis is the major form of infiltrative restrictive cardiomyopathies. Its prognosis is poor, but several therapies are being investigated and implemented. Storage cardiomyopathies are the consequence of accumulation of substances due to genetic defects affecting metabolic pathways; we review Fabry disease, glycogen storage diseases and hemochromatosis.

The prevalence of Fabry disease (FD) in Japanese patients presenting with unexplained left ventricular hypertrophy (LVH) has remained unclear.

We measured plasma α-galactosidase A activity in 177 men with a diagnosis of hypertrophic cardiomyopathy (HCM) (maximum LV wall thickness ≥15 mm).

Two patients (1.1%) showed very low α-galactosidase A activity [0.0 and 0.3 nmol/hr/ml (normal range: 3.6–17.6 nmol/hr/ml)], and a clinical diagnosis of cardiac variant of FD was finally made. One patient was a 55-year-old man who came to our hospital because of abnormal results of electrocardiography and showed concentric LVH in echocardiography. A missense mutation, R112L, was identified. The other was a 74-year-old man who had been diagnosed with HCM at the age of 60 years in another hospital and was referred for evaluation of repeated hospitalization for heart failure. Although echocardiography revealed asymmetric septal hypertrophy (ASH) with interventricular septal wall thickness of 16 mm and posterior wall thickness of 11 mm and reduced LV ejection fraction with hypokinetic posterior wall motion, his echocardiographic findings at the initial diagnosis of HCM were not ASH but concentric LVH with normal LV systolic function. A splicing mutation, IVS4+919G>A, was identified.

The prevalence of FD in Japanese male patients with a clinical diagnosis of HCM was found to be 1.1%. These patients showed late onset and concentric LVH at initial presentation.