Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the Mainz Severity Score Index for Fabry disease.

OBJECTIVES: Fabry disease is a multisystem disorder with phenotypic heterogeneity only partially explained by genotype. Elevated interleukin-6 (IL-6) plasma levels and C-reactive protein (CRP) serum levels are associated with increased risk and worse outcome of ischaemic events, a serious prognostic sign in Fabry disease. METHODS: 56 patients (34 hemizygous males, 22 females; 5 children) were studied. A promoter polymorphism -174G > C of the IL-6 gene associated with serum IL-6 levels was compared with the Mainz Severity Score Index (MSSI) in patients with Fabry disease. CRP levels and polymorphism 1059 G > C were evaluated as markers of inflammation to ascertain the possibility of an inflammatory mechanism of IL-6. Nonparametric ANOVA, Fisher's exact, Bonferroni, and Hardy-Weinberg (HW) statistics were used. RESULTS: Mean age of adults = 42 (range 26-58) years; 29 patients received enzyme therapy (ERT). Mean total MSSI = 26.7 (range 14.2-39.2) points, i.e. moderate disease, but females were lower (total 23.4 +/- 12.6 vs 32.2 +/- 13.6). Controls but not patients were in HW equilibrium. Significant correlation existed between all sub-scores of the MSSI and IL-6 genotypes in females but only with three MSSI sub-scores for males. The IL-6 C/C genotype was significantly correlated with the neurological, general and total MSSI sub-scores, generally twofold higher. There were no statistically significant correlations with CRP levels/polymorphisms and MSSI sub-scores nor with IL-6 polymorphisms. CRP levels decreased after ERT in patients with IL-6 G/G or G/C genotypes but increased in patients with C/C (p = 0.003). CONCLUSIONS: The prevalence of the IL-6 C allele significantly influences MSSI, i.e. clinical severity, especially in females. This is unrelated to IL-6 as a pro-inflammatory marker as demonstrated by lack of correlations with CRP levels and genotypes. IL-6 -174 polymorphic C allele may be a prognostic marker in Fabry disease, especially in females.

Enzyme replacement therapy with agalsidase alfa in children with Fabry disease.

AIM: To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease. METHODS: Safety and efficacy of ERT with agalsidase alfa, 0.2 mg/kg infused over 40 minutes every 2 weeks for 23 weeks, were studied in a multicentre open-label trial in nine boys and four girls. Median age at the start of the study was 11.0 years (range 3.5-18 years). RESULTS: Fifty-four adverse events were reported in 11 patients. No serious adverse events related to ERT were reported. Twelve of the 54 adverse events were considered possibly or probably related to ERT. Infusion reactions (8 mild, 3 moderate) occurred in four boys, in seven infusions. One boy developed IgG antibodies, although he continued to make good clinical progress. At the end of the study, two of the four boys and the one girl on regular pain medication at baseline had stopped taking analgesics. Brief Pain Inventory (BPI) scores decreased in most patients by week 12 and were sustained until the end of the study. This change was greater in the boys, who had higher (worse) BPI scores at baseline. Pain-related quality of life (QoL) scores also decreased during the study. Plasma globotriaosylceramide concentrations and urinary globotriaosylceramide:sphingomyelin ratios decreased after 12 and 23 weeks of therapy, particularly in the boys. Increases in sweat volume were recorded in three out of five of the boys and in one of two girls tested after 23 weeks of treatment. CONCLUSION: ERT with agalsidase alfa in children with Fabry disease is well tolerated and, in the short term, appears to decrease pain and to improve pain-related QoL.

[Psychiatric and neuropsychological signs and symptoms in patients with fabry disease: literature review]. / Psychiatrische und neuropsychologische Auffälligkeiten bei Patienten mit Morbus Fabry: Literaturübersicht.

Fabry Disease (FD) is an X-linked lysosomal storage disorder (prevalence about 1 : 100 000) caused by a genetic defect associated with a lack of alpha-galactosidase A (alpha-GAL) enzyme activity. As a consequence, neutral glycosphingolipides can not be cleaved and metabolized, and accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. The most prominent symptoms comprise pain attacks and acroparesthesia, angiokeratoma, corneal opacity, renal and cardiac dysfunction, hypo- and anhidrosis, gastrointestinal symptoms, and cerebrovascular dysfunction with vertigo, headache, and cerebral ischemia. Characteristic symptoms of FD can occur in male and female patients with the same prevalence, while females with FD seem to be less severely affected. The course of untreated illness is progressive with considerable interindividual variability. Since 2001 two enzyme replacement therapies are approved which can possibly stop the disease progress and alleviate symptoms. The very few reports and clinical observations have shown that a very high proportion of FD patients develop neuropsychiatric symptoms. However, accurate data are lacking. Although the pathophysiologic mechanisms are quite unknown, it is surmised that sphingolipid deposits in the endothelium of small cerebral vessels lead to regional cerebral ischemia accompanied by neuropsychiatric symptoms and deficits. Furthermore, patients with FD are chronically distressed by pain attacks and additional somatic and psychological impairment. Frequently, pain attacks are triggered by psychosocial stress. The high interindividual variability can, thus, also be interpreted on the basis of existing stress and coping models. The present paper will review the presently available psychiatric and neuropsychological findings in FD and will discuss difficulties associated with classification and differential diagnosis of psychiatric disorders occurring in patients with FD.

Successful pregnancy outcome in a patient with Fabry disease receiving enzyme replacement therapy with agalsidase alfa.

Fabry disease is an inherited lysosomal storage disease caused by deficiency of alpha-galactosidase A. Enzyme replacement therapy for this multisystem progressive disease has been available only since 2001. We here report the first known successful pregnancy of a female patient receiving such therapy.

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 pattems). Those patients with RV hypertrophy and severely compromised systolic and diastolic function had the highest LV masses (92 +/- 11.7 g/m(2.7)). CONCLUSION: RV involvement is common in Fabry disease and ultimately progresses to severe systolic and diastolic RV dysfunction. These findings might explain why patients with preserved LV function can develop clinical features such as reduced exercise capacity, organomegaly and lymphoedema.

Cumulative incidence rates of the mucopolysaccharidoses in Germany.

In 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 (beta-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 alpha-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.

[Fabry's disease, glomerulonephritis with crescentic and granulomatous interstitial nephritis. Case of one family]. / Morbus Fabry, Glomerulonephritis mit Halbmondbildung und granulomatöse interstitielle NephritisBericht über eine Familie.

A 26-year-old female patient was admitted to the hospital because of fever of unknown origin and renal failure. Diagnosis of Fabry's disease, extracapillary proliferative (crescentic) glomerulonephritis and granulomatous interstitial nephritis was made by histological, immunohistochemical and electron microscopical diagnosis in a kidney biopsy and confirmed by further investigations. Years ago the brother of the patient had a kidney biopsy diagnosed as metabolic disease. The re-evaluation of this biopsy confirmed Fabry's disease while in this patient an association with tubulointerstitial nephritis occurred. To our knowledge this is the first family with two members having Fabry's disease combined with further kidney diseases.

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

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency of alpha-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.

Electrocardiographic signs of hypertrophy in fabry disease-associated hypertrophic cardiomyopathy.

AIMS: Fabry disease results from deficient activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation of the major substrates leads, in both men and women, to progressive hypertrophic cardiomyopathy. We aimed to evaluate the utility of different electrocardiographic (ECG) parameters for assessing the degree and severity of hypertrophic cardiomyopathy in patients with Fabry disease. METHODS: A total of 166 ECGs of 94 hemi- and heterozygous patients with Fabry disease were analysed and compared with echocardiographic-estimated left ventricular mass (LVM). RESULTS: There was a significant (p < 0.0001) correlation between QRS duration (R2 = 0.59), 12-lead amplitude/duration product (R2 = 0.61), Sokolow-Lyon voltage/duration product (R2 = 0.52) and LVM. Analysis of receiver operating characteristics revealed that the 12-lead amplitude/duration product had the highest sensitivity-specificity relationship (p < 0.01 compared with the Cornell index). CONCLUSION: In general, ECG signs of left ventricular hypertrophy correlated well with LVM as revealed by echocardiography. Of the parameters studied, the 12-lead amplitude/duration product was the most successful at describing the severity of cardiac involvement in Fabry disease. These data suggest that ECG parameters have potential for use as a simple and cost-effective means of screening for hypertrophic cardiomyopathy in patients with Fabry disease.

Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.

Anderson-Fabry disease is a rare, X-chromosomal lipid storage disorder caused by a deficiency of lysosomal alpha-galactosidase A. Clinical manifestations of Anderson-Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson-Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. It therefore appears that Anderson-Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X-linked dominant disease.