Frank Baehner

Cumulative incidence rates of the mucopolysaccharidoses in Germany.

SummaryIn order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100 000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100 000 births (1.3 cases per 100 000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in 100 000 births; that for MPS IV A (Morquio syndrome) as 0.38 cases in 100 000; and that for MPS VI (Maroteaux–Lamy syndrome) as 0.23 cases per 100 000 births. Two cases of MPS IVB (β-galactosidase deficiency) have been identified, but no patients with MPS VII or MPS IX. A relatively high number of patients with MPS IIIB, MPS IVA and MPS VI were of Turkish origin. The crude rate for all types of mucopolysaccharidoses is approximately 3.53 cases in 100 000 live births. The cumulative incidence pattern of MPS in Germany was compared with the corresponding rates among other industrial nations obtained from recent literature: the crude cumulative rates for all types of mucopolysaccharidoses (3.4–4.5 in 100 000 live births) were similar among all published populations; however, different frequencies of the various forms of MPS were observed.

The mainz severity Score index: a new instrument for quantifying the anderson-fabry disease phenotype, and the response of patients to enzyme replacement therapy

Anderson–Fabry disease (AFD) is an X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system – the Mainz Severity Score Index (MSSI) – to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty‐nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT‐related treatment effects.

Cardiac manifestations of Anderson–Fabry disease in heterozygous females

OBJECTIVES We sought to define the prevalence of cardiac involvement in female patients with Anderson-Fabry disease (AFD). BACKGROUND Anderson-Fabry disease is a rare inborn X-linked lysosomal storage disorder. Globotriaosylceramide (Gb(3)), the major substrate of the deficient alpha-galactosidase A enzyme, accumulates progressively in vulnerable cells, including the cardiovascular system. It has been believed that heterozygous females have less cardiac involvement than hemizygous males with AFD. METHODS We performed two-dimensional echocardiographic examinations of female patients heterozygous for AFD. RESULTS Since 1997, a total of 55 female patients (mean age, 39.6 years; range, 6.1 to 70.8 years) with proven AFD have been investigated prospectively at our hospital. Of these, 13 (23.6%) had normal left ventricular (LV) geometry and LV mass (LVM). Seven patients (12.7%) had concentric remodeling, 29 patients (52.7%) concentric LV hypertrophy (LVH), and 6 patients (10.9%) eccentric LVH (2 with subaortic pressure gradients). There was a strong correlation between age and the severity of LVH (r(2) = 0.905; p < 0.0001), and all patients older than 45 years had LVH. With increasing LVM, there was a significant age-independent decrease in systolic and diastolic LV function. Mild thickening of the aortic valve leaflets was present in 25.5% of patients, with the same percentage demonstrating mild thickening of the mitral valve leaflets. Mild mitral valve prolapse was documented in 10.9% of patients. CONCLUSIONS Cardiac involvement, with LVH and structural valve abnormalities, is very common and worsens with age in females who are heterozygous for AFD, and they should therefore be considered candidates for enzyme replacement therapy.

Enzyme replacement therapy in heterozygous females with Fabry disease: Results of a phase IIIB study

Summary: Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency of α-galactosidase A. Affected patients experience debilitating neuropathic pain and have premature mortality due to renal failure, cardiovascular disease or cerebrovascular complications. The disease may be X-linked dominant, since most females heterozygous for Fabry disease are affected clinically. We evaluated the safety, efficacy and pharmacokinetics of agalsidase alfa (Replagal) administered intravenously to female patients with Fabry disease in an open-label, single-centre study. Fifteen severely affected patients received agalsidase alfa at 0.2 mg/kg every other week for up to 55 weeks. Agalsidase alfa was safe and well-tolerated in female patients. None of the patients developed antibodies or experienced an infusion reaction to agalsidase alfa. The pharmacokinetic profile of agalsidase alfa in female patients is comparable to the pharmacokinetics of agalsidase alfa in male patients. Mean urine sediment and plasma Gb3 levels decreased from baseline at 13, 27 and 41 weeks. A significant decrease in left ventricular mass from baseline was seen at weeks 27 (p = 0.003) and 41 (p = 0.039), and a significant reduction in QRS durations was seen at week 27 (p = 0.007). Furthermore, there was a significant improvement in quality of life. Renal function did not deteriorate in these 15 female patients over the 13- to 41-week period of observation. We conclude that enzyme replacement therapy with agalsidase alfa was safe and effective in female patients heterozygous for Fabry disease.

Onset and progression of the Anderson–Fabry disease related cardiomyopathy

BACKGROUND Cardiac involvement is responsible for substantial morbidity and mortality in Anderson-Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients. METHODS We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy. RESULTS In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m(2.7)) was found in both males and females (P<0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07+/-1.03 g/m(2.7) per year in males and by 2.31+/-0.81 g/m(2.7) in females (P<0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m(2.7) per year in males and by 1.80 g/m(2.7) in females (P=0.12). CONCLUSION AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

Cardiac manifestations of Anderson-Fabry disease in children and adolescents.

Aim: Fabry disease (Fabry) is a rare X‐linked disorder caused by a deficiency of the lysosomal enzyme α‐galactosidase A. The progressive accumulation of the major substrate, globotriaosylceramide, leads to renal dysfunction and hypertrophic cardiomyopathy, which are reported to become apparent in the third decade. This study was performed to determine if signs of cardiac manifestations of Fabry are seen in younger Fabry patients.

Cardiac Involvement in Anderson-Fabry Disease

Anderson-Fabry disease results from hereditary deficiency of the lysosomal enzyme -galactosidase A. This disease is marked by progressive intracellular accumulation of globotriaosylceramide (Gb3) and digalactosylceramide, the major glycosphingolipid substrates of -galactosidase A. Many cell types are affected, including renal epithelial cells, myocardial cells and neuronal cells, endothelial cells, pericytes, and vascular smooth muscle cells (1). Cardiac involvement in Anderson-Fabry disease (AFD) is frequent, due to structural and functional changes related to glycosphingolipid deposition in the myocardium, valves, and conduction system. Deposition of Gb3 in the heart is similar to deposition in other organs (2). It may be found in all cardiac tissues, with the greatest concentrations occurring in the left ventricular myocardium, the mitral valve, and the left atrium. In contrast, increased deposition of digalactosylceramide was found only in the lungs and right heart tissues (3). Accumulation of Gb3 in the heart leads to an increase in ventricular wall thickness, mitral valve prolapse (4), and electrocardiographic abnormalities, including various degrees of atrioventricular conduction block, tachyarrhythmias, and ST-segment/T-wave abnormalities (5). Rarely, in the socalled “cardiac-variant,” cardiomyopathy is the principle manifestation of AFD (6). Little is known about the timing of onset of cardiac involvement or its progression relative to other end-organ manifestations of AFD. This may be the result of the heterogeneous clinical symptoms leading to delayed diagnosis and because of uncertainty regarding the true incidence of the cardiac variant of AFD, which was mostly diagnosed by postmortem examinations. Indeed, AFD may account for up to 3% of men with hypertrophic cardiomyopathies, suggesting that the cardiac variant may be more common than previously thought (7). Clinical manifestations of AFD have been reported in female heterozygotes, but these complications were felt to be uncommon and usually mild. For example, it has been estimated that severe manifestations occur in only approximately 1% of female carriers (8). In a recent study however, 12% of patients with AFD being treated with dialysis in the United States were

The right ventricle in Fabry disease.

Aim: Left ventricular (LV) hypertrophy is a common feature in Fabry disease‐related progressive infiltrative hypertrophic cardiomyopathy and affects both men and women, but at different ages. To date, however, little is known about the role of right ventricular (RV) function in Fabry disease. Therefore, this study aimed to investigate the extent of RV involvement in patients with Fabry disease. Methods: Echocardiographic examination of the right and left ventricle was carried out in 129 patients (80 women and 49 men) with Fabry disease. Results: RV hypertrophy was present in 46 patients (35.7%). Of these patients, 13 showed signs of severely depressed right systolic function (tricuspid annulus movement <10 mm and a prolonged RV pre‐ejection period/pulmonary ejection time ratio) and six patients showed additional severe depression of parameters of diastolic function (pseudo‐normal or restrictive RV filling patterns). Those patients with RV hypertrophy and severely compromised systolic and diastolic function had the highest LV masses (92±11.7 g/m2.7).

IgA nephropathy in two adolescent sisters heterozygous for Fabry disease

We report a 16-year-old girl and her one-year-younger sister, both heterozygous for the c.34del24 mutation of the GLA (alpha-galactosidase A) gene, which they inherited from their father who is affected by Fabry disease (FD). Both girls presented with macrohematuria and rapidly progressing proteinuria. Urine analysis revealed glomerular hematuria and a nephrotic range of proteinuria suggesting a concomitant glomerulonephritis. Light microscopy of kidney biopsy was characteristic of IgA nephropathy (IgA deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity), whereas electron microscopy showed changes typical of Fabry disease (multiple osmiophilic inclusions in the subendothelial and mesangial areas). These two cases and similar reports in the literature suggest that IgA nephropathy in FD is not merely coincidental.

Pharmacokinetics of agalsidase alfa in male and female patients with Fabry disease

clearance compared with other drug products or proteins provides support for mannose-6-phosphate (M6P) receptor clearance of agalsidase alfa. The percentage of administered agalsidase alfa found in a patient’s liver decreased as the dose increased on a mg/ kg basis. At the two lowest doses, 0.007 and 0.014 mg/ kg, the percentage of agalsidase alfa recovered in the liver 44 hours after dosing was approximately 25–30%. In contrast, at 0.11 mg/kg, only 14% of administered agalsidase alfa was found in the liver. Saturation of liver uptake of agalsidase alfa occurred when maximum drug product concentrations exceeded the Kd for the M6P receptor (2 £ 10¡ mol/l). Conclusions: Based on these results, the estimated amount of the commercial dose of agalsidase alfa (Replagal2; 0.2 mg/kg) taken into the liver is approximately 2–3 mg for a 75 kg patient. The remainder of the dose (12–13 mg) is available for uptake into key organs affected by Fabry disease.