Usefulness of Alcohol Septal Ablation in the Left Ventricular Outflow Tract Obstruction in Fabry Disease Cardiomyopathy.

Fabry disease (FD) is an X-linked linked genetic disorder caused by α-galactosidase A deficiency. The typical clinical manifestation is left ventricular hypertrophy, often mimicking hypertrophic cardiomyopathy (HC). In contrast to sarcomeric HC, left ventricular outflow tract obstruction (LVOTO) is less frequent. We describe 6 male patients with genetically confirmed FD and symptomatic LVOTO. All of them underwent a transcatheter alcohol septal ablation with an immediate effect on the obstruction in all cases and without any serious complications. The median LVOT maximal pressure gradient was 85 (60 to 170) mm Hg. The hemodynamic effect persisted during subsequent follow-up (ranging from 6 months to 16 years). Five patients reported substantial symptomatic improvement. Four patients were receiving specific FD therapy before the interventional procedure. In conclusion, alcohol septal ablation appears to be effective in the treatment of LVOTO in patients with FD and appears to be comparable to the limited published experience with surgical septal myectomy. Despite some important differences between FD HC and sarcomeric HC, the recommendation for treating LVOTO should be similar.

Prevalence of Fabry disease in male patients with unexplained left ventricular hypertrophy in primary cardiology practice: prospective Fabry cardiomyopathy screening study (FACSS).

BACKGROUND: A number of studies have already investigated the prevalence of Fabry disease (FD) in adult patients with unexplained left ventricular hypertrophy (LVH) with rates varying from 0 % up to 12 % reflecting referral and gender bias as well as differences in diagnostic methodology. We aimed to perform a prospective screening study evaluating the prevalence of FD in male patients older than 30 years with strictly defined unexplained LVH followed by general cardiologists. METHODS: A predefined number of 100 men with unexplained LVH, defined as maximal wall thickness ≥ 13 mm, were identified during an echocardiographic examination in primary cardiology practice and screened by assessing α-galactosidase A activity in dried blood spots (DBS) or in plasma. RESULTS: Four men (52 ± 4 years, maximal LV wall thickness 18 ± 3 mm) were diagnosed with FD confirmed by enzyme analysis in leukocytes as well as by genetic analysis. Mild extracardiac manifestations of FD were present in two of them. CONCLUSIONS: The prevalence of FD in our cohort of male patients followed in primary cardiology practice with strictly defined otherwise unexplained LVH was 4 %. We recommend systematic screening for FD in all men older than 30 years with LVH of unknown etiology even in the absence of obvious extracardiac manifestations of FD.

Early diastolic mitral annular velocity and color M-mode flow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease.

Fabry disease is an X-linked genetic disorder characterized by progressive intracellular accumulation of neutral glycosphingolipids. Cardiac involvement is frequent and left ventricular (LV) diastolic dysfunction is present in most of the affected subjects. Pulsed-wave tissue Doppler echocardiography (PW-TDE) and color M-mode are new Doppler methods for LV diastolic function evaluation. Their role in the assessment of Fabry disease-related cardiomyopathy remains to be established. In this study we aimed to determine the utility of PW-TDE and color M-mode-derived parameters in the assessment of LV diastolic function in patients with Fabry disease. Eighty-one echocardiographic examinations performed in 35 patients affected by Fabry disease were retrospectively analyzed. Early diastolic lateral mitral annular velocity (E(m)) determined by PW-TDE and color M-mode flow propagation velocity (V(p)) were measured and compared to LV filling patterns obtained using standard Doppler indexes. The receiver operating characteristics (ROC) curves method was used to determine the summary measure of relative accuracy for E(m) and V(p). A comparison of ROC curves showed a significant difference for areas under the curve in favor of E(m) (P < 0.001). Pseudonormal filling pattern, higher LV mass index, higher relative wall thickness, larger left atrial diameter, and older age were more frequent (all P < 0.001) in patients with incorrect diagnosis of normal LV diastolic function based on the measurement of V(p). E(m) appears to be superior to V(p) in the assessment of LV diastolic function in patients with Fabry disease. V(p) fails to detect abnormal LV diastolic function in subjects with pronounced concentric LV remodeling and pseudonormal filling pattern.

Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population.

We have identified 21 different alpha-galactosidase A gene (GLA) mutations in 22 unrelated Czech and Slovak families with Fabry disease. Eleven of these mutations were novel (point mutations D93N, A135V, D155H, G171R, Q280K, G360S, Q330X, splicing errors c.194ins14, c.801ins36 and deletions c.674_732del59, g.3405_6021del2617). Genotyping of family members for family-specific mutations revealed 55 heterozygotes that manifested clinical symptoms of different severity. To examine the contribution of X-inactivation skewing to disease manifestation in Fabry heterozygotes, we have adopted the Mainz severity scoring scheme and compared the score values with the X-inactivation status in 39 carriers in an age-dependent manner. The age-score trendline of Fabry females who had a predominantly inactivated X-chromosome bearing a wild-type GLA allele (10 of 38 females) was markedly steeper than in the rest of the cohort. One female carrier with an inactivated mutated allele had a low score value when compared to the other heterozygotes of the same age. These data suggest that X-inactivation is indeed a major factor determining the severity of clinical involvement in Fabry heterozygotes. There was a statistically significant difference between the severity score values of heterozygotes with random and non-random X-chromosome inactivation at the 5% level of significance. Further studies will show if the degree of the wildtype allele inactivation will be useful as a predictive marker of severity of phenotype in Fabry heterozygotes. Although the correlation between X-inactivation skewing and presentation of the disease in Fabry heterozygotes has previously been suggested in the literature, this report is among the first attempts to examine this relationship systematically.

Fabry disease: percutaneous transluminal septal myocardial ablation markedly improved symptomatic left ventricular hypertrophy and outflow tract obstruction in a classically affected male.

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disease in which left ventricular hypertrophy (LVH) is common, and if severe, may mimic hypertrophic obstructive cardiomyopathy. Alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA) has been used as a safe and effective method to alleviate LVH obstruction in patients with hypertrophic obstructive cardiomyopathy (HCM). We describe a case of a classically affected Fabry 53-year-old male with symptomatic HCM (NYHA class III with exertional angina) who was treated with PTSMA. The procedure safely and effectively alleviated symptomatic left ventricular outflow tract obstruction at long-term follow-up, and the patient's NYHA classification was reduced to NYHA class I to II.

Recurrence of Fabry disease as a result of paternal germline mosaicism for alpha-galactosidase a gene mutation.

We present two sisters with a severe form of Fabry disease, who both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X). Each of the sisters developed renal failure in the third decade of life; the older sibling underwent renal transplantation at 40 years of age. The severe phenotype of the siblings correlates with results of the X-inactivation study: examination of methylation status in human androgene receptor (HUMARA) gene suggests preferential inactivation of the wild-type allele in both patients. Patients' parents had no symptoms of Fabry disease and were tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells. Genotype analysis using DXS7424 marker showed paternal origin of the mutation. The father's sperm was then tested for presence of the mutation to examine the possibility of the germline mosaicism. Both mutant and wild-type alleles were found in DNA isolated from father's sperm. The apparent explanation of these findings is germline mosaicism due to mutation event during the embryonic development of sperm producing cells (spermatogonia). This is the first case of germline mosaicism in Fabry disease reported in the literature.