Data_Sheet_1_Neuropsychiatric Symptoms and Their Association With Sex, Age, and Enzyme Replacement Therapy in Fabry Disease: A Systematic Review.docx

Patients suffering from Fabry disease (FD) have an increased risk of developing neuropsychiatric symptoms (NPS), mostly impairment in cognitive performance and depression. Single cases of psychosis have been reported, however, their association with FD can be coincidental. Furthermore, deficits in social functioning and adaptation as well as specific coping styles in FD patients were observed. Recent studies focused on a longitudinal course of the disease and identified risk factors associated with specific NPS. Since 2001, enzyme replacement therapy (ERT) has been available and in preliminary studies seems to improve cognitive impairment and adaptive skills. In this systematic review, we analyze the available literature on the NPS in FD and investigate if there are any differences in their distribution between males and females, children/adolescents and adults, and individuals treated with ERT and untreated. We discuss the role of the psychological, environmental, and molecular alterations and their correlation to psychiatric manifestations in FD. Finally, we would like to increase awareness of the spectrum of NPS in FD.</p

Association of Klotho levels with the presence of atrial fibrillation.

<p>*Model 1: adjusted for age and gender (male).</p>†<p>Model 2: adjusted for covariates in Model 1 plus cardiovascular comorbidities and anuria.</p>‡<p>Model 3: adjusted for covariates in Model 2 plus laboratory results for mineral metabolism, calcium dialysate, potassium serum and dialysate, inflammation, cholesterol, hemoglobin and TSH.</p>§<p>per standard deviation.</p><p>Abbreviations: Ca, Calcium; CAD, coronary artery disease; CI, confidence interval; CRP, C-reactive protein; DM, diabetes mellitus; FGF23, fibroblast growth factor 23; Hb, hemoglobin; K, potassium; PAD, peripheral artery disease; TSH, thyroid stimulating hormone.</p><p>OR, odds ratio; VHD, valvular heart disease.</p

Hazard Ratios (and 95% CIs) for Death per Standard Deviation of FGF23 and Klotho levels and according to the level tertiles.

<p>*Model 1 = demographics: adjusted for age, gender (male) and by dialysis center clustering.</p>†<p>Model 2 = dialysis specific risk factors and comorbid conditions: adjusted for covariates in Model 1 plus dialysis vintage, systolic and diastolic blood pressure, body-mass index, vascular access on study enrolment (fistula, graft, catheter), coexisting conditions listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100688#pone-0100688-t001" target="_blank">Table 1</a> (coronary artery disease, valvular heart disease, atrial fibrillation, pulmonary hypertension, implantable cardioverter defibrillator carrier; diabetes mellitus, peripheral vascular disease, stroke, vasculitis, malignoma, chronic obstructive pulmonary disease), cause of renal failure (diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, polycystic kidney disease, others/unknown), medication use listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0100688#pone-0100688-t001" target="_blank">Table 1</a> (phosphate binders, vitamin D replacement, angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, aspirin, anticoagulant or clopidogrel, statin), pooled Kt/V.</p>‡<p>Model 3 = fully adjusted model: adjusted for covariates in Model 2 plus parathyroid hormone, 25(OH)vitamin D, phosphate, calcium, albumin, hemoglobin, C-reactive protein, cholesterol.</p>§<p>Patients were categorized according to Klotho level tertiles at enrolment (1^st tertile <286 pg/ml, 2^nd tertile 286–392 pg/ml, 3^rd tertile >392 pg/ml).</p>||<p>Patients were categorized according to FGF23 level tertiles at enrolment (1^st tertile <118 RU/ml, 2^nd tertile 118–468 RU/ml, 3^rd tertile >468 RU/ml).</p><p>Abbreviations: FGF23, fibroblast growth factor 23; HR, hazard ratio; R, reference.</p

Klotho and FGF23 levels in patients with and without atrial fibrillation.

<p>Klotho and FGF23 levels in patients with and without atrial fibrillation.</p

Regression analysis for Klotho tertiles with the absence of atrial fibrillation.

<p>*Model 1: adjusted for age and gender.</p>†<p>Model 2: adjusted for covariates in Model 1 plus diabetes mellitus, coronary artery disease, valvular heart disease, peripheral vascular disease, stroke and anuria.</p>‡<p>Model 3: adjusted for covariates in Model 2 plus parathyroid hormone, fibroblast growth factor 23, calcium, phosphate, albumin, calcium dialysate, potassium serum and dialysate, hemoglobin C-reactive protein, cholesterol and thyroid stimulating hormone.</p><p>Abbreviations: CI, confidence interval; OR, odds ratio.</p

Klotho (A) and FGF23 (B) levels in controls versus hemodialysis patients.

<p>Klotho (A) and FGF23 (B) levels in controls versus hemodialysis patients.</p

Cumulative survival by tertiles of secreted Klotho.

<p>Patients were stratified by their baseline Klotho levels according to the tertiles. Kaplan-Meier analysis with long-rank test did not reveal a significant difference between groups (P = 0.42).</p

Baseline characteristics and laboratory parameters according to Klotho tertiles.

<p>Plus-minus values are means ± SD. Numbers with ranges in square brackets are medians and interquartile ranges. P values are for the comparisons between the three Klotho tertiles. To convert the values for calcium to milligrams per deciliter, multiply by 4.000. To convert the values for phosphate to milligrams per deciliter, multiply by 3.0969.</p><p>*The body-mass index is the weight in kilograms divided by the square of the height in meters.</p>†<p>Based on 166 available clinically indicated transthoracic echocardiography results.</p><p><b>Abbreviations:</b> ACE-I, angiotensin-converting enzyme inhibitors; AF, atrial fibrillation; AP, alkaline phosphatase; ARB, angiotensin receptor blocker; COPD, chronic obstructive pulmonary disease; FGF23, fibroblast growth factor 23; ICD, implantable cardioverter defibrillator; IQR, interquartile range; PTFE, Polytetrafluorethylen; PTH, parathyroid hormone; PKD, polycystic kidney disease; PVD Peripheral vascular disease; T, Tertile; U, unit.</p

Cumulative survival by tertiles of Fibroblast growth factor 23 (FGF23).

<p>Patients were stratified by their FGF23 levels according to the tertiles. Kaplan-Meier analysis with long-rank test approached a significant difference between groups (P = 0.05).</p

Univariate correlations (Pearsońs r) of the plasma vasoactive peptide concentration with general and dialysis-specific parameters (n = 210–239).

<p>^# p<0.10, ^* p<0.05, ^** p<0.01, ^*** p<0.001, n.s.  =  not significant (p>0.10).</p