Natural history of the respiratory involvement in Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked disorder caused by deficient activity of enzyme alpha-galactosidase A, resulting in the accumulation of glycosphingolipids within lysosomes. Pulmonary involvement in AFD has previously been documented, but until now has been studied only in a few series of patients without any longitudinal follow-up. The aim of this study was to compare spirometric changes in AFD patients with a matched control population and to follow the subsequent progression of the disease. MATERIALS AND METHODS: Fifty individuals (27 women, 23 men, mean age 40 +/- 14 years) with AFD from 14 families underwent a static spirometric examination under standard conditions. A set of indices was compared with that of the control population. Out of this cohort, 39 individuals not receiving enzyme replacement therapy were longitudinally evaluated (median follow-up time 24 months). RESULTS: A clinically significant reduction in spirometric parameters, corresponding to mild to severe airway obstruction, was observed in 26% of women and 61% of men. During the serial follow-up, a significant (p < 0.05) age-dependent reduction of predicted %FVC and %FEV1 values was observed in male patients, while the influence of age was not seen in female patients. The %FEF(25-75) values decreased by similar degrees in men and women and in older and younger patients, indicating that progressive bronchial disease affects the small airways first. CONCLUSIONS: We have demonstrated a clinically relevant age- and sex-dependent progressive pulmonary involvement in AFD patients. The effects of enzyme replacement therapy on pulmonary involvement remain to be demonstrated.

Cardiac involvement in Fabry disease.

UNLABELLED: Fabry disease is a rare X-linked defect of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non-significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function. CONCLUSIONS: With the advent of effective enzyme replacement therapy, early diagnosis of Fabry disease may be crucial for patient prognosis.

[Cardiac manifestation of Fabry's disease: current knowledge]. / Kardiální manifestace Fabryho choroby: soucasné znalosti.

Fabry's disease is a rare lysosomal storage disease caused by the X-linked defect of the enzyme alpha-galactosidase A leading to the intracellular accumulation of glycosphingolipids in various organs and tissues. Cardiac involvement is frequent and, in individuals with some residual enzyme activity, may be the sole manifestation of the disease. Hemizygous men are generally more seriously affected than heterozygous women. The dominant cardiac manifestations include myocardial hypertrophy of the left ventricle, which, in some patients, mimics hypertrophic cardiomypathy. Left ventricular systolic function is usually preserved, on the other hand mild to moderate diastolic dysfunction is regularly detected. Valvular abnormalities are frequently noted. However, hemodynamically significant lesions are rare. Conduction system involvement leads initially to the shortening of atrioventricular conduction, in later stages, with a progression of the disease, antrioventricular blocks and various forms of supraventricular and ventricular arrhythmias appear. Myocardial ischemia in Fabry disease has in most cases a functional origin due to endothelial dysfunction of coronary arteries and also due to the increase oxygen demand of hypertrophied myocardium. The results of so far performed studies with enzyme replacement therapy are promising in preventing further deterioration and even improving function of affected organs.

Genetic variation screening of TNNT2 gene in a cohort of patients with hypertrophic and dilated cardiomyopathy.

Mutations in troponin T (TNNT2) gene represent the important part of currently identified disease-causing mutations in hypertrophic (HCM) and dilated (DCM) cardiomyopathy. The aim of this study was to analyze TNNT2 gene exons in patients with HCM and DCM diagnosis to improve diagnostic and genetic consultancy in affected families. All 15 exons and their flanking regions of the TNNT2 gene were analyzed by DNA sequence analysis in 174 patients with HCM and DCM diagnosis. We identified genetic variations in TNNT2 exon regions in 56 patients and genetic variations in TNNT2 intron regions in 164 patients. Two patients were found to carry unique mutations in the TNNT2 gene. Limited genetic screening analysis is not suitable for routine testing of disease-causing mutations in patients with HCM and DCM as only individual mutation-positive cases may be identified. Therefore, this approach cannot be recommended for daily clinical practice even though, due to financial constraints, it currently represents the only available strategy in a majority of cardio-centers.