Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease.

BACKGROUND: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD. METHODS: In 96 patients (53% female; age 40±12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL. RESULTS: Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD -6.2, for RRT -11.8, for pain -9.1, p<0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL. CONCLUSION: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.

Gene mutations versus clinically relevant phenotypes: lyso-Gb3 defines Fabry disease.

BACKGROUND: Currently, no method is available to identify α-galactosidase A (agalA) mutations determining clinically relevant Fabry disease. In our largest European Fabry cohort, we investigated whether a biomarker, specific for the defect, could stratify persons at risk. METHODS AND RESULTS: A total of 124 individuals with agalA mutations were investigated with a comprehensive clinical workup, genetic analysis, and laboratory testing, including measurements of agalA activity and lyso-Gb3 (degradation product of the accumulating Gb3). Additionally, an extensive family screening with a clinical workup of relatives was performed. The patient population was divided into 2 samples: previously described mutations (n=72) and novel mutations (n=52). The patients with previously described mutations were subdivided into 2 groups: classical mutations, which were known to cause the classic type of Fabry disease with specific symptoms and a high risk for major events in all 3 main organs (heart, kidney, and central nervous system), and atypical mutations without the typical presentation. All patients with atypical mutations (n=17) had lower lyso-Gb3 levels than any of the patients with classical Fabry disease (n=55). A cutoff value of 2.7 ng/mL separated the 2 groups. Six out of 52 patients with novel mutations showed a lyso-Gb3 level <2.7 ng/mL. Clinical investigation, blinded to lyso-Gb3 results, revealed no classic organ involvement in these patients or their relatives. In contrast, the characterization of patients with lyso-Gb3≥2.7 ng/mL suggested classical Fabry mutations in most of the patients (93%). CONCLUSIONS: Our data show that the biomarker lyso-Gb3 may identify the clinically relevant agalA mutations leading to Fabry disease.

Reproducibility of manual and semi-automated late enhancement quantification in patients with Fabry disease.

BACKGROUND: Late enhancement (LE) imaging is increasingly used for diagnosis of non-ischemic cardiomyopathy. However, the mostly patchy appearance of LE in this context may reduce the reproducibility of LE measurement. PURPOSE: To report intra- and inter-observer variabilities of LE measurements in Fabry disease using manual and semi-automated quantification. MATERIAL AND METHODS: Twenty MRI data-sets of male patients aged 44 ± 7 years were analyzed twice (interval 12 months) by one observer and additionally once by a second observer. Left ventricular (LV) parameters were determined using cine MRI. Gradient-echo LE images were analyzed by manual planimetry and by a semi-automatic prototype software. Variabilities were determined by Bland-Altman analyses and additionally intra-class correlation coefficient (ICC) values were calculated to survey intra- and inter-observer reproducibility. RESULTS: The amount of LE was 5.2 ± 5.1 mL or 2.8 ± 2.6 % of LV mass (observer 2). LE was detected predominantly intramurally in a patchy pattern. All patients had LE restricted to the basal infero-lateral parts of the LV. The extent of LE correlated to LV mass (207 ± 70 g, P < 0.05, r = 0.6). The intra- and inter-observer variabilities were -0.6 to 1.0 mL and -0.7 to 1.6 mL, respectively (95% confidence intervals). ICC values were 0.981-0.999. The semi-automatic software allowed quantification of LE areas in all patients. The comparison of LE amount determined by semi-automatic software versus manual planimetry yielded an intra-observer variability ranging from -1.9 to 2.3 mL. CONCLUSION: Semi-automatic planimetry of patchy LE in patients with Fabry disease is feasible. The determined intra- and inter-observer variabilities for manual and semi-automatic planimetry were in the range of 20-40% of LE amount with high ICC values.

Potential role of vitamin D deficiency on Fabry cardiomyopathy.

Patients with Fabry disease frequently develop left ventricular (LV) hypertrophy and renal fibrosis. Due to heat intolerance and an inability to sweat, patients tend to avoid exposure to sunlight. We hypothesized that subsequent vitamin D deficiency may contribute to Fabry cardiomyopathy. This study investigated the vitamin D status and its association with LV mass and adverse clinical symptoms in patients with Fabry disease. 25-hydroxyvitamin D (25[OH]D) was measured in 111 patients who were genetically proven to have Fabry disease. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, BMI and season. Patients had a mean age of 40 ± 13 years (42% males), and a mean 25(OH)D of 23.5 ± 11.4 ng/ml. Those with overt vitamin D deficiency (25[OH]D ≤ 15 ng/ml) had an adjusted six fold higher risk of cardiomyopathy, compared to those with sufficient 25(OH)D levels >30 ng/ml (p = 0.04). The mean LV mass was distinctively different with 170 ± 75 g in deficient, 154 ± 60 g in moderately deficient and 128 ± 58 g in vitamin D sufficient patients (p = 0.01). With increasing severity of vitamin D deficiency, the median levels of proteinuria increased, as well as the prevalences of depression, edema, cornea verticillata and the need for medical pain therapy. In conclusion, vitamin D deficiency was strongly associated with cardiomyopathy and adverse clinical symptoms in patients with Fabry disease. Whether vitamin D supplementation improves complications of Fabry disease, requires a randomized controlled trial.

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease.

The X-chromosomal-linked lysosomal storage disorder Fabry disease can lead to life-threatening manifestations. The pathological significance of the Fabry mutation D313Y is doubted, because, in general, D313Y patients do not present clinical manifestations conformable with Fabry disease. This is in contrast to the analysis of the alpha-galactosidase A activity, which is reduced in D313Y patients. We report a comprehensive clinical, biochemical and molecular genetic analysis of two patients with a D313Y mutation. The alpha-galactosidase A activity was reduced in both patients. No Fabry symptoms or Fabry organ involvement was detected in these patients. The new biomarker lyso-Gb3, severely increased in classical Fabry patients, was determined and in both patients lyso-Gb3 was below the average of a normal population.Our data for the first time not only clinically but also biochemically supports the hypothesis that the D313Y mutation is not a classical one, but a rare variant mutation.

Cross-sectional baseline analysis of electrocardiography in a large cohort of patients with untreated Fabry disease.

BACKGROUND: Morphology and function of Fabry cardiomyopathy has been previously studied by echocardiography and cardiac magnetic resonance (CMR). However, the value of electrocardiography (ECG) in relation to these two techniques remains largely unknown. METHODS: One hundred fifty genetically confirmed Fabry patients were investigated using a comprehensive clinical workup comprising 12-lead ECG, echocardiography, and CMR. RESULTS: ECG parameters at rest [PR, P wave, QT, QTc, QT dispersion and time interval from the peak to the end of the T wave (Tpeak to Tend)] were normal in the entire cohort and did not distinguish between males and females or stages of cardiomyopathy. A significant positive correlation was found between left ventricular (LV) mass on CMR and both the QRS duration and the LV Sokolow index, with the highest values in male patients with an advanced cardiomyopathy stage. No prediction of late enhancement on CMR (a sign for replacement fibrosis) was possible by a single ECG parameter. However, the absence of ST or T alterations (in 37 of 38 patients) specifically excluded late enhancement on CMR. CONCLUSION: Our data in a large cohort of Fabry patients, including all cardiomyopathy stages, show, in contrast to former assumptions, that ECG parameters are not suitable to stage Fabry cardiomoypathy. Most ECG parameters were normal in the complete cohort. However, the absence of ST or T alterations seems to almost exclude late enhancement on CMR in these patients.

Cerebral blood flow in patients with Fabry disease as measured by Doppler sonography is not different from that in healthy individuals and is unaffected by treatment.

OBJECTIVES: The purpose of this study was to investigate cervical and cerebral blood flow characteristics in patients with Fabry disease at baseline and under enzyme replacement therapy. METHODS: In this case-control study we prospectively studied 68 patients with Fabry disease with extracranial and transcranial Doppler sonography. We compared extracranial and transcranial cervical and cerebral blood flow properties in all patients with Fabry disease and in subgroups of those with or without enzyme replacement therapy, male and female, and with normal or impaired renal function. Eight male patients were investigated at baseline and 1 year after initiation of enzyme replacement therapy. RESULTS: We show that cervical and cerebral blood flow parameters in patients with Fabry disease are not different from normal values regardless of sex, renal function, or enzyme replacement therapy. CONCLUSIONS: Cervical and cerebral blood flow measured with extracranial and transcranial Doppler sonography is not altered in patients with Fabry disease. Enzyme replacement therapy does not change blood flow characteristics.

MR-based analysis of regional cardiac function in relation to cellular integrity in Fabry disease.

BACKGROUND: Fabry cardiomyopathy is characterized by left ventricular (LV) hypertrophy and regional fibrosis. Recent high-end echocardiography studies of selected LV sections suggest an interrelation between regional fibrosis, impaired function, and hypertrophy possibly changing under specific enzyme replacement therapy (ERT). METHODS: Magnetic resonance imaging (MRI) was used for a region dependent study of cardiac function, morphology and late enhancement (LE) in 25 Fabry patients before and after 12 months of ERT in comparison to 43 healthy volunteers. RESULTS: Fabry patients presented with LV increased wall thickness (EDWT) and reduced wall thickening (WT) with a focus on basal and midventricular regions corresponding to areas of LE. The degree of hypertrophy and hypokinesia were the highest if LE was detectable. A significant decrease of the EDWT under ERT was observed in LE negative patients accompanied by a decline of hypokinesia with regional differences. CONCLUSIONS: Regional differences of LV hypertrophy and wall motion were detected corresponding to the distribution of myocardial fibrosis (LE). Functional impairment was closely restricted to fibrotic regions while morphologic changes slightly exceeded the areas of fibrosis. ERT resulted in regional improvements whereby absence of fibrosis was connected to a better outcome.

Interdisciplinary approach towards female patients with Fabry disease.

BACKGROUND: Fabry disease (FD) is a rare X-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs. DESIGN: Being X-chromosomal-linked, most studies in the past have focused on involvement in male patients. However, it has been elucidated recently that female patients can present typical organ involvement and thus need to be treated, respectively. CONCLUSIONS: This review wants to give a systematical overview of the typical organ involvement in female patients with FD. Moreover, therapy recommendations especially for female patients are discussed.

Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy.

Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function.

Tei index in fabry disease.

BACKGROUND: Systolic and diastolic dysfunction of the left ventricle are present in patients with cardiac involvement in Fabry disease. The aim of this study was to investigate the diagnostic value of the Tei index, a marker for combined diastolic and systolic function, in patients with Fabry disease. METHODS: A total of 66 consecutive patients with genetically confirmed Fabry disease were included in this study. Standard echocardiography, including the Tei index, and magnetic resonance imaging were performed. Patients were followed for 2.9 ± 1.9 years; 56 patients received enzyme replacement therapy, and 10 patients had natural history follow-up. Patients were subdivided into three groups: (1) those without cardiac involvement, (2) those with left ventricular (LV) hypertrophy and without late enhancement on magnetic resonance imaging, and (3) those with late enhancement on magnetic resonance imaging. RESULTS: The Tei index was significantly higher in the groups 2 (0.56 ± 0.10) and 3 (0.60 ± 0.16) compared with patients without cardiac involvement (0.44 ± 0.10) (P < .001). All patients with Tei indexes > 0.64 showed signs of cardiomyopathy. In contrast, ejection fractions were normal in all three patient groups and therefore not useful for the detection of cardiac involvement. A significant positive correlation was observed between LV wall thickness and the Tei index in the complete patient cohort. Moreover, receiver operating characteristic analysis revealed a large area under the curve for Tei index and hypertrophy, while the area under the curve for fibrosis was small. The Tei index remained unchanged in the natural history and enzyme replacement therapy groups during follow-up. CONCLUSIONS: In this cohort, the Tei index was of limited value to detect myocardial fibrosis and monitor enzyme replacement therapy. However, the progression of cardiomyopathy toward LV hypertrophy seems to be paralleled by global functional impairment, which can be assessed by the Tei index but not by ejection fraction. Thus, the Tei index seems to be a global parameter that can detect LV functional reduction in patients with Fabry disease.

A distinct urinary biomarker pattern characteristic of female Fabry patients that mirrors response to enzyme replacement therapy.

Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naïve female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naïve Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.

Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment.

OBJECTIVES: We hypothesized that Fabry cardiomyopathy in female patients might differ substantially from that in male patients and sought to prove this hypothesis in a large cohort consisting of 104 patients with Fabry disease. BACKGROUND: Fabry cardiomyopathy in male patients is characterized by left ventricular (LV) hypertrophy, impaired myocardial function, and subsequent progressive myocardial fibrosis. In contrast, the occurrence of these 3 cardiomyopathic hallmarks in female patients remains unknown. METHODS: In 104 patients (58 females, age 42 ± 16 years; 46 males, age 42 ± 13 years) with genetically proven Fabry disease, LV hypertrophy, regional myocardial deformation and myocardial fibrosis were assessed by standard echocardiography, strain rate imaging, and cardiac magnetic resonance (CMR) imaging-guided late enhancement (LE). RESULTS: In men, end-diastolic left ventricular wall thickness (LVWT) ranged from 6 to 19.5 mm (LV mass CMR 55 to 200 g/m(2)), and LE was never seen with LVWT <12 mm (LV mass <99 g/m(2)). In contrast in female patients, LVWT ranged from 5 to 15.5 mm, LV mass ranged from 39 to 146 g/m(2), and LE was already detectable with an LVWT of 9 mm (LV mass 56 g/m(2)). When LV mass was examined in CMR, LE was detected in 23% of the female patients without hypertrophy (n=9), whereas LE was never seen in male patients with normal LV mass. LE was always associated with low systolic strain rate, but the severity of impairment was independent of LVWT in female patients (lateral strain rate in patients with LV hypertrophy with LE -0.7 ± 0.2 s(-1); patients without LV hypertrophy with LE -0.8 ± 0.2 s(-1); p=0.45). CONCLUSIONS: In contrast to male patients, the loss of myocardial function and the development of fibrosis do not necessarily require myocardial hypertrophy in female patients with Fabry disease. Thus, in contrast to actual recommendations, initial cardiac staging and monitoring should be based on LV hypertrophy and on replacement fibrosis in female patients with Fabry disease.

Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy.

Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients.

Urinary total globotriaosylceramide and isoforms to identify women with Fabry disease: a diagnostic test study.

BACKGROUND: Fabry disease is a treatable X-linked lysosomal storage disorder caused by alterations in the structural gene (GLA) of α-galactosidase A (AGAL), manifesting with cardiovascular and/or kidney disease and decreased life span. Although males as well as females can be affected, females cannot be identified using AGAL activity. We evaluated urinary total globotriaosylceramide (Gb3) and single N-acyl isoforms for the detection of Fabry disease in female patients with and without chronic kidney disease (CKD). STUDY DESIGN: Diagnostic accuracy study. SETTING & PARTICIPANTS: 28 untreated women with Fabry disease and 335 female outpatients without Fabry disease with (n = 213) and without CKD (n = 122). INDEX TEST: Assessment of urinary Gb3 using electrospray ionization tandem mass spectrometry, including 6 N-acyl isoforms, total Gb3 related to urinary creatinine, and ratios of Gb3-24 to Gb3-18 and Gb3-24 to urinary AGAL. REFERENCE TEST: Fabry disease, diagnosed by identification of known pathogenic GLA mutations in patients or their male relatives. RESULTS: 6 parameters (ratio of Gb3-24 to urinary AGAL activity; Gb3-24; ratio of Gb3-24 to Gb3-18; Gb3-22; Gb3-16; and total Gb3) were highly informative for the diagnosis of Fabry disease independent of the presence or absence of CKD (area under the receiver operating characteristic curve, 0.876-0.927; all P < 0.001). LIMITATIONS: Because of low signal-to-noise ratios, 15.8% of samples had to be excluded. CONCLUSION: Total urinary Gb3 and Gb3 isoforms can be used for the diagnosis of Fabry disease in women.

Cardiac energy metabolism is disturbed in Fabry disease and improves with enzyme replacement therapy using recombinant human galactosidase A.

AIMS: In vitro studies have shown impairment of energy metabolism in cardiac fibroblasts from Fabry patients. A recent in vivo study reported an association between cardiac energy metabolism and increased myocardial mass in Fabry patients. We therefore assessed possible disturbances of cardiac energy metabolism in Fabry patients by in vivo (31)P-MR-spectroscopy. Additionally, the effect of enzyme replacement therapy (ERT) on cardiac energetics was tested. METHODS AND RESULTS: Twenty-three patients (41 ± 9 years; 10 females) with genetically proven Fabry disease were examined with a 1.5 T Scanner, and compared with an age-matched healthy control group. Eight patients underwent ERT and had follow-up examinations after 3 and 14 months. The high-energy phosphate molecules phosphocreatine (PCr) and adenosine triphosphate (ATP) were quantified in localized 31P-spectra by SLOOP (spectral localization with optimum point spread function). Cine- and late gadolinium enhancement (LGE) studies were also performed. When compared with healthy controls, Fabry patients demonstrated reduced PCr- (6.1 ± 1.9 vs. 8.8 ± 2.6 mmol/kg; P = 0.003) and ATP concentrations (3.9 ± 1.5 vs. 4.6 ± 1.0 mmol/kg; P = 0.048). During ERT, PCr concentrations increased (7.1 ± 1.5 mmol/kg vs. 6.1 ± 1.9; P < 0.05) and left ventricular mass decreased (215 ± 55 vs. 185 ± 45 g; P = 0.012). Disturbances in cardiac energetics were not correlated to the presence or absence of cardiac fibrosis on LGE. CONCLUSION: Cardiac energy metabolism is disturbed in Fabry disease; this may play an important role in the pathogenesis of Fabry cardiomyopathy. Enzyme replacement therapy ameliorates energetic depression.

Prominent papillary muscles in Fabry disease: a diagnostic marker?

Fabry disease is often linked with a prominent papillary muscle. It remains unknown whether this sign could be used as a diagnostic marker to screen for Fabry patients. Standard echo was performed in 101 consecutive patients with concentric left ventricular (LV) hypertrophy (28 Fabry, 30 Friedreich, 34 isolated arterial hypertension, 9 amyloidosis) and 50 healthy controls. In addition, the areas of both papillary muscles, as well as the LV endocardial circumference, were manually traced in short axis views. A ratio of papillary muscle size to LV circumference was calculated (PM_LV_ratio). The papillary muscle area was positively correlated to LV wall thickness in this cohort (p < 0.0001; r = 0.58). In all patient subgroups, the absolute papillary muscle area was significantly enlarged and the PM_LV_ratio was significantly higher when compared with controls. However, Fabry patients showed a significantly larger absolute papillary muscle area than Friedreich and amyloidosis patients and a higher PM_LV_ratio than hypertensive and amyloidosis patients. Enlarged absolute papillary muscle area was evidenced in 21 (75%), and increased PM_LV_ratio was found in 22 (78%) of 28 Fabry patients. Combining these two parameters yields a sensitivity of 75% and specificity of 86% for diagnosing Fabry disease with LV hypertrophy. Only 10 of 73 non-Fabry patients (14%) (4 Friedreich, 1 amyloidosis, 5 hypertensive) showed an increased absolute papillary muscle area and PM_LV_ratio. In conclusion, this study confirmed the assumption that the prominent papillary muscle could be an echocardiographic marker for detection of Fabry patients with concentric LV hypertrophy.

The right ventricle in Fabry disease: natural history and impact of enzyme replacement therapy.

BACKGROUND: Storage of globotriaosylceramides is present in the left and right ventricles of patients with Fabry disease. Improvement of left ventricular morphology and function during enzyme replacement therapy (ERT) has previously been reported. OBJECTIVES: To analyse the effects of long term ERT on right ventricular morphology and function. METHODS: This was a prospective follow-up of 75 genetically confirmed consecutive Fabry patients for 3.1±1.8 years. According to treatment guidelines the natural history was followed in 18 patients, whereas 57 patients received ERT. Standard echocardiography, strain rate imaging for regional deformation of the right and left ventricle, and magnetic resonance tomography with late enhancement (LE) imaging for the detection of fibrosis were all performed at yearly intervals. RESULTS: Right ventricular hypertrophy was evident in 53 patients (71%) at baseline. A significant positive correlation was found between left and right ventricular wall thickness (r=0.76; p<0.0001). LE was detected in half of the patients (n=38) in the left ventricle at baseline while no patient ever had LE of the right ventricle. Patients with LE in the left ventricle presented with the lowest right ventricular deformation properties. In contrast to the left ventricle, there was no change in right ventricular wall thickness (baseline 6.9±1.6 mm vs follow-up 6.7±1.5 mm; p=0.44) or systolic strain rate (2.2±0.7/s vs 2.1±0.8/s; p=0.31) during follow-up with ERT. CONCLUSION: The degree of right ventricular involvement in Fabry disease is related to the left ventricular cardiomyopathy stage. ERT seems to have no direct impact on right ventricular morphology and function.

[Females with Fabry's disease - an interdisciplinary diagnostic and therapeutic challenge]. / Frauen mit Morbus Fabry - eine interdisziplinäre diagnostische und therapeutische Herausforderung.

Fabry's disease is a rare genetic storage disorder leading to an accumulation of globotriaosylceramides in the lysosomes of various organs. Being X-chromosomal-linked, most studies in the past focused on involvement in male patients. However, it has been elucidated recently that female patients can present typical organ involvement and, thus, have to be treated respectively. This synopsis wants to systematically review the typical organ involvement in female Fabry patients. Moreover, therapy recommendations especially for female patients are discussed.

Department-related tasks and organ-targeted therapy in Fabry disease: an interdisciplinary challenge.

Fabry disease is a rare X-linked storage disorder leading to an accumulation of globotriaosylceramides in all cells carrying lysosomes. As the accumulation occurs in most organs, different medical specialties are involved in the diagnostics and therapy of Fabry disease. With this review of the 3 main specialties (cardiology, nephrology, and neurology) and, in addition, the adjacent specialties (ophthalmology and dermatology), we aim to discuss the division-related responsibilities and want to suggest an organ-related additional therapy besides enzyme replacement therapy.