Involvement In Anderson-Fabry Disease Research Articles

Biomarkers in anderson-Fabry disease: what should we use in the clinical practice?

Major organ involvement in Anderson-Fabry disease (FD) is clinically silent for a long period and clinically heterogeneous; thus, it is difficult to identify the patients at increasing risk of a progressive disorder. Moreover, accumulating evidence suggests that early disease-specific treatment (DST) is safe and effective in preventing the progression of heart and kidney damage, with poorer results in patients with extensive myocardial fibrosis, advanced glomerulosclerosis, and/or heavy proteinuria. Therefore, biomarkers defining preclinical involvement, with a prognostic value and a correlation with response to treatment, are an urgent need in FD. Several types of biomarkers are recognized in FD, pertaining to total disease burden and specific organ involvement (central nervous system, heart, and kidney). Currently, plasma globotriaosylsphingosine (lyso-Gb3), cardiac and brain imaging, and albuminuria are recognized as the “gold standard” biomarkers of total disease burden or specific organ involvement in FD. However, severe globotriaosylceramide (Gb3) storage and organ damage may occur within the affected organs with minimal changes in these standard tests. Given the heterogeneity and rarity of the disease, the identification of new biomarkers is challenging. Several ways may be used to identify new biomarkers in FD, namely “omic” medicine, biomarkers identified in other pathological models similar to FD, and biomarkers linked to the pathophysiological pathways involved in FD. This article aims to review the clinical value of the available biomarkers in FD and give an overview of the research on new biomarkers.

The Value of Advanced Cardiac Magnetic Resonance Imaging Technologies in Detecting the Characteristics of Cardiac Involvement in Anderson-Fabry Disease

The Value of Advanced Cardiac Magnetic Resonance Imaging Technologies in Detecting the Characteristics of Cardiac Involvement in Anderson-Fabry Disease

Clinical study of left ventricular structure and function in patients with Anderson-Fabry disease before and after enzyme replacement therapy.

Cardiac left ventricular hypertrophy (LVH) is the most common manifestation of heart involvement in Anderson-Fabry disease (AFD). Conventional cardiac imaging is not sensitive enough to detect early signs of LVH in AFD. It remains uncertain whether enzyme replacement therapy (ERT) can prevent LVH progression and improve myocardial function. This study aimed to assess the effectiveness of two-dimensional speckle tracking echocardiography (2D-STE) in early detection of cardiac involvement in AFD and monitoring the efficacy of agalsidase alfa and agalsidase beta therapy. Thirteen consecutive AFD patients and 12 healthy controls underwent standard transthoracic 2D, color Doppler, tissue Doppler echocardiography, and 2D strain analysis. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Diastolic strain rate (SR) was extracted. Compared to healthy subjects, AFD patients without LVH showed lower levels of GLS (p < 0.001) and SR (p = 0.01), while there was no difference in GCS (p = 0.82). Following treatment, apical circumferential strain (ACS) showed improvement (p = 0.01). In AFD patients without LVH, there was a decrease in global and segmental LS. Higher plasma Lyso-GL-3 concentrations were associated with elevated ACS values after ERT, indicating that ACS in AFD patients without LVH, albeit normal, is involved in early LV dysfunction.

Advanced CMR Techniques in Anderson-Fabry Disease: State of the Art.

Anderson-Fabry disease (AFD) is a rare multisystem X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency. Long-term cardiac involvement in AFD results in left ventricular hypertrophy and myocardial fibrosis, inducing several complications, mainly arrhythmias, valvular dysfunction, and coronary artery disease. Cardiac magnetic resonance (CMR) represents the predominant noninvasive imaging modality for the assessment of cardiac involvement in the AFD, being able to comprehensively assess cardiac regional anatomy, ventricular function as well as to provide tissue characterization. This review aims to explore the role of the most advanced CMR techniques, such as myocardial strain, T1 and T2 mapping, perfusion and hybrid imaging, as diagnostic and prognostic biomarkers.

Electrocardiogram analysis in Anderson-Fabry disease: a valuable tool for progressive phenotypic expression tracking.

Electrocardiogram (ECG) has proven to be useful for early detection of cardiac involvement in Anderson-Fabry disease (AFD); however, little evidence is available on the association between ECG alterations and the progression of the disease. To perform a cross sectional comparison of ECG abnormalities throughout different left ventricular hypertrophy (LVH) severity subgroups, providing ECG patterns specific of the progressive AFD stages. 189 AFD patients from a multicenter cohort underwent comprehensive ECG analysis, echocardiography, and clinical evaluation. The study cohort (39% males, median age 47 years, 68% classical AFD) was divided into 4 groups according to different degree of left ventricular (LV) thickness: group A ≤ 9 mm (n = 52, 28%); group B 10-14 mm (n = 76, 40%); group C 15-19 mm (n = 46, 24%); group D ≥ 20 mm (n = 15, 8%). The most frequent conduction delay was right bundle branch block (RBBB), incomplete in groups B and C (20%,22%) and complete RBBB in group D (54%, p < 0.001); none of the patients had left bundle branch block (LBBB). Left anterior fascicular block, LVH criteria, negative T waves, ST depression were more common in the advanced stages of the disease (p < 0.001). Summarizing our results, we suggested ECG patterns representative of the different AFD stages as assessed by the increases in LV thickness over time (Central Figure). Patients from group A showed mostly a normal ECG (77%) or minor anomalies like LVH criteria (8%) and delta wave/slurred QR onset + borderline PR (8%). Differently, patients from groups B and C exhibited more heterogeneous ECG patterns: LVH (17%; 7% respectively); LVH + LV strain (9%; 17%); incomplete RBBB + repolarization abnormalities (8%; 9%), more frequently associated with LVH criteria in group C than B (8%; 15%). Finally, patients from group D showed very peculiar ECG patterns, represented by complete RBBB + LVH and repolarization abnormalities (40%), sometimes associated with QRS fragmentation (13%). ECG is a sensitive tool for early identification and long-term monitoring of cardiac involvement in patients with AFD, providing "instantaneous pictures" along the natural history of AFD. Whether ECG changes may be associated with clinical events remains to be determined.

Right ventricular strain in Fabry disease: Prognostic implications

IntroductionLeft ventricular (LV) hypertrophy is the main feature of cardiac involvement in Anderson-Fabry disease (FD), but the right ventricle (RV) is also frequently affected. Previous studies failed to demonstrate an independent association between conventional parameters of RV performance and outcomes in FD. Nevertheless, if RV free wall strain (RV-FWS), assessed by 2D speckle tracking analysis, may provide a better prognostication is currently unknown. MethodsWe retrospectively evaluated the association between RV-FWS and the occurrence of cardiovascular events in a cohort of 56 patients with FD. The study endpoint comprises cardiovascular mortality, severe heart failure symptoms, new-onset atrial fibrillation and major arrhythmias requiring device implantation. ResultsReduced RV-FWS, defined by values lower than 23%, was found in 25 (45%) patients. During a median follow-up of 47 months, 16 (29%) patients met the study endpoint. A ROC-curve analysis confirmed the threshold of reduced RV-FWS (<23%) as the best cut-off for predicting cardiovascular events, but with a lower power compared to left-sided parameters. On univariable Cox regression analysis, RV-FWS, expressed as continuous variable, was significantly associated with the study endpoint (HR: 0.795, 95% CI: 0.710–0.889, p < 0.001). However, RV-FWS did not retain a significant association with outcomes, after adjustment for LV global longitudinal strain or indexed left atrial volume (p = 0.340 and p = 0.289 respectively). ConclusionsRV-FWS was not independently associated with the occurrence of cardiovascular events in FD, confirming previous observations that prognosis is mainly driven by the severity of LV cardiomyopathy.

Left atrial strain correlates with severity of cardiac involvement in Anderson-Fabry disease

ObjectivesCardiac involvement in Anderson-Fabry disease (AFD) results in myocardial lipid depositions. An early diagnosis can maximize therapeutic benefit. Thus, this study aims to investigate the potential of cardiac MRI (CMR) based parameters of left atrial (LA) function and strain to detect early stages of AFD.MethodsPatients (n = 58, age 40 (29–51) years, 31 female) with genetically proven AFD had undergone CMR including left ventricular (LV) volumetry, mass index (LVMi), T1, and late gadolinium enhancement, complemented by LA and LV strain measurements and atrial emptying fractions. Patients were stratified into three disease phases and compared to age and sex-matched healthy controls (HC, n = 58, age 41 [26–56] years, 31 female).ResultsA total of 19 early-, 20 intermediate-, and 19 advanced-phase patients were included. LV and LA reservoir strain was significantly impaired in all AFD phases, including early disease (both p < 0.001). In contrast, LA volumetry, T1, and LVMi showed no significant differences between the early phase and HC (p > 0.05). In the intermediate phase, LVMi and T1 demonstrated significant differences. In advanced phase, all parameters except active emptying fractions differed significantly from HC. ROC curve analyses of early disease phases revealed superior diagnostic confidence for the LA reservoir strain (AUC 0.88, sensitivity 89%, specificity 75%) over the LV strain (AUC 0.82).ConclusionsLA reservoir strain showed impairment in early AFD and significantly correlated with disease severity. The novel approach performed better in identifying early disease than the established approach using LVMi and T1. Further studies are needed to evaluate whether these results justify earlier initiation of therapy and help minimize cardiac complications.Key Points• Parameters of left atrial function and deformation showed impairments in the early stages of Anderson-Fabry disease and correlated significantly with the severity of Anderson-Fabry disease.• Left atrial reservoir strain performed superior to ventricular strain in detecting early myocardial involvement in Anderson-Fabry disease and improved diagnostic accuracies of approaches already using ventricular strain.• Further studies are needed to evaluate whether earlier initiation of enzyme replacement therapy based on these results can help minimize cardiac complications from Anderson-Fabry disease.

ECG as a storytelling of cardiac involvement evolution in Anderson Fabry disease

Abstract Background Cardiac involvement in Anderson-Fabry disease (AFD) is related to a progressive glycosphingolipid storage over time and is characterized by left ventricular hypertrophy (LVH), conduction abnormalities and myocardial fibrosis. ECG is useful for early recognition of AFD, however evidence is limited on the association between ECG alterations and disease stage. Purpose To assess the relationship between ECG characteristics and progressive cardiac involvement, from the pre-hypertrophic phase to phenotypes with increasing degree of LVH. Methods In a multicenter cohort, 183 AFD patients (40% male, age 47±12 years, 60% affected by “classical AFD”) underwent ECG and transthoracic echocardiography. Patients were divided into 4 groups according to the different degree of LV thickness measured in parasternal short axis view: group A ≤9 mm (N=46, 25%), group B 10–14 mm (N=77, 42%), group C 15–19 mm (N=45, 25%) and group D ≥20 mm (N=15, 8%). Patients with pacemaker and under 18 years of age were excluded. Results A normal ECG was present in 89% in group A, 59% in group B, 11% in group C and it was absent in group D. Short PR (&amp;lt;120 ms) was more frequent in group A, whereas with LVH increasing, median PR interval duration significantly prolonged among the 4 groups (136 [125–150]vs 141 [130–160] vs 160 [130–180] vs 170 [130–180] ms, p=0.002 respectively). Median P-wave duration was shorter in group A and B compared to group C and D (80 m vs 100 ms, p&amp;lt;0.001), while both QRS and QTc gradually increased. Median Sokolow-Lyon voltage criteria statistically augmented among the groups (22 [18–26] vs 27 [20–33] vs 32 [25–45] vs 35 [18–40] mm, p&amp;lt;0.001 respectively), along with right ventricular hypertrophy (0%, 1%, 11%, 8%, p=0.02). Right bundle branch block (RBBB) had a higher frequency in advanced stages (0%, 34%, 34%, 40%, p&amp;lt;0.001), with a prevalence of complete RBBB of 46% in group D. Similarly, left anterior fascicular block (0%, 7%, 18%, 46%, p&amp;lt;0.001) and QRS fragmentation (2%, 11%, 25%, 23%, p=0.009) were more common in advanced stages. No differences were found in left bundle branch block (LBBB), in low QRS voltages or in LV pre-excitation prevalence. According with the wall thickness increase, negative T waves were more frequent in lateral (4%, 21%, 70%, 77%, p&amp;lt;0.001) and inferior leads (6%, 15%, 32%, 46%, p 0.001), as well as their association with ST-T depression (4%, 17%, 64%, 46%, p&amp;lt;0.001). Giant negative T waves were present only in group C and D (16% and 31%) mainly representing a LVH distribution toward the apex. Conclusions ECG is a very useful tool to stage cardiac involvement evolution in AFD. Peculiar ECG characteristics evolve together with LV wall thickness: incomplete and progressively complete RBBB usually associated (preceding or following) LVH and/or typical repolarization abnormalities in inferior or lateral leads and giant negative T waves in the more advanced stages are the most frequent and typical ECG patterns. Funding Acknowledgement Type of funding sources: None.

Basal Segmental Strain as a Marker of Cardiac Involvement in Anderson-Fabry Disease

Anderson-Fabry disease (AFD), an X-linked genetic disease, can lead to cardiac involvement, manifesting notably as increased left ventricular (LV) wall thickness and myocardial fibrosis in the 4th-5th decade. We sought to evaluate and validate assessment of global and segmental variations in subclinical LV function by 2D speckle tracking in AFD patients versus healthy controls.

Role of serial cardiac 18F-FDG PET-MRI in Anderson\u2013Fabry disease: a pilot study

AimWe investigated the value of serial cardiac 18F-FDG PET-MRI in Anderson–Fabry disease (AFD) and the potential relationship of imaging results with FASTEX score.Methods and resultsThirteen AFD patients underwent cardiac 18F-FDG PET-MRI at baseline and follow-up. Coefficient of variation (COV) of FDG uptake and FASTEX score were assessed. At baseline, 9 patients were enzyme replacement therapy (ERT) naïve and 4 patients were under treatment. Two patients presented a FASTEX score of 0 indicating stable disease and did not show any imaging abnormality at baseline and follow-up PET-MRI. Eleven patients had a FASTEX score > 20% indicating disease worsening. Four of these patients without late gadolinium enhancement (LGE) and with normal COV at baseline and follow-up had a FASTEX score of 35%. Three patients without LGE and with abnormal COV at baseline and follow-up had a FASTEX score ranging from 30 to 70%. Three patients with LGE and abnormal COV at baseline and follow-up had a FASTEX score between 35 and 75%. Finally, one patient with LGE and normal COV had a FASTEX score of 100%. Of the 12 patients on ERT at follow-up, FASTEX score was significantly higher in those 4 showing irreversible cardiac injury at baseline compared to 8 with negative LGE (66 ± 24 vs. 32 ± 21, p = 0.03).Conclusion18F-FDG PET-MRI may be effective to monitor cardiac involvement in AFD.

Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review.

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder leading to a wide array of clinical manifestations. Among these, gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea affect about half of the FD adults and more than half of FD children. GI symptoms could be the first manifestation of FD; however, being non-specific, they overlap with the clinical picture of other conditions, such as irritable bowel syndrome and inflammatory bowel disease. This common overlap is the main reason why FD patients are often unrecognized and diagnosis is delayed for many years. The present narrative review is aimed to promote awareness of the GI manifestations of FD amongst general practitioners and specialists and highlight the latest findings of this rare condition including diagnostic tools and therapies. Finally, we will discuss some preliminary data on a patient presenting with GI symptoms who turned to be affected by a variant of uncertain significance of alpha-galactosidase (GLA) gene.

Basal Segmental Longitudinal Strain: A Marker of Subclinical Myocardial Involvement in Anderson-Fabry Disease

Cardiac involvement in Anderson-Fabry disease (AFD) is associated with increased left ventricular (LV) wall thickness. The aim of this study was to evaluate if two-dimensional global and regional strain in patients with AFD can identify early myocardial involvement (when LV wall thickness and function are normal). Additionally, the association of altered strain with adverse cardiovascular events was evaluated. In a retrospective cross-sectional study, 43 patients with AFD, before enzyme replacement therapy (mean age, 44±12years; 58.1% men), were compared with age- and gender-matched healthy control subjects. The mean follow-up duration among patients with AFD for major adverse cardiovascular events (MACE) was 82months. LV ejection fraction was similar between groups (patients with AFD vs control subjects, 61±8% vs 61±6%; P=.89). However, global longitudinal strain (LS) was impaired in patients with AFD compared with control subjects (-16.5±3.8% vs -20.2±1.7%, P<.001), with greater impairment in patients with AFD with increased LV wall thickness (-15.4±3.9% vs -18.7±2.3%, P<.006). Additionally, LS was most impaired in the basal segments in patients with AFD (-14.8±3.7% vs -20.3±1.1%, P<.001). MACE occurred in 19 of 43 patients (four women, 15 men), and Kaplan-Meier analysis demonstrated that MACE were associated with impaired basal LS. In patients with AFD, altered basal LS is present even in those with normal LV wall thickness and is associated with MACE. Therefore, basal LS should be considered when screening for cardiac involvement inAFD, particularly in female patients with AFD with normal LV wall thickness.

P956 Prognostic role of right ventricular hypertrophy in anderson fabry disease

Abstract Background Right ventricular hypertrophy (RVH) is a common finding in Anderson Fabry disease (AFD). In other infiltrative and storage cardiomyopathies right ventricular (RV) involvement may influence prognostic stratification. Nevertheless, the prognostic implications of right ventricle involvement in AFD have never been assessed. Purpose Evaluation of the prognostic significance of RVH and RV systolic function in AFD cardiomyopathy. Methods Forty-five AFD patients (56% male) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 44.9 ± 8.5 months. RV systolic function was assessed by standard and tissue Doppler echocardiography and quantified using RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE) and Systolic tissue Doppler velocity of the tricuspid annulus (RV Sa). Cardiovascular events were defined as new-onset atrial fibrillation, heart failure or pace-maker implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; cerebrovascular events were defined as stroke or transient ischemic attack. The outcome was defined as the time to death or the first event in any of the above predefined categories. Results Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow-up period, 13 patients (28.8%, 11 male) experienced major events including two deaths. Pace-maker implantation (6 cases) was the most common type of event. At univariate analysis several variables were associated with the occurrence of events, including RVH and indexes of RV systolic function. However, at multivariate analysis only proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, p ˂0.001) and LV mass indexed (HR: 1.01, 95% CI: 1.00 to 1.03, p = 0.03) were independent predictors of outcome. Conclusions The presence and extension of RVH is not associated with outcome in AFD. Our study confirms that at variance with other infiltrative or storage cardiomyopathies, RV involvement in AFD is an innocent bystander and does not influence prognosis.

P900Electrocardiographic findings in Anderson-Fabry disease versus sarcomeric hypertrophic cardiomyopathy

Abstract Background Cardiac involvement is one of the most frequent and disabling organ damage in Anderson-Fabry (AF) disease, causing hypertrophic cardiomyopathy (HCM), conduction disturbances, arrhythmias and coronary disease. Differential diagnosis from sarcomeric HCM is often very challenging, especially for patients with exclusive cardiac involvement. Purpose To gain new insights from standard electrocardiogram (ECG) in AF disease, and identify ECG differences from sarcomeric HCM. Methods Sixty-two consecutive patients (27 males, mean age: 62±16 years) with definite diagnosis of AF disease from 2 Italian centres were evaluated for ECG analysis and divided in 2 groups, according to the presence (Group A, N=39) or the absence (Group B, N=26) of cardiac involvement [hypertrophy detected at echocardiogram or cardiac magnetic resonance (CMR)]. All ECGs were analysed by 2 independent investigators. For Group A, when CMR was performed, a correlation between CMR and ECG was assessed. Patients with cardiac involvement were matched with 78 sarcomeric HCM patients according to sex, age and septal wall thickness on echocardiogram. Results Two AF patients out 39 with cardiac involvement (5%) had normal ECG. Short PR and I degree atrio-ventricular (AV) block were both reported in 6 (15%) cases. Twenty-six (67%) patients showed left ventricular hypertrophy and the majority (85%) had abnormal repolarization. CMR was performed in 22 patients (56%); the 11 (50%) patients with replacement fibrosis had a higher mean Sokolow-Lyon score (4.1±1.8 vs 2.9±1.0 mV; p=0.05), more frequent ST segment depression (82 vs 27%; p=0.03) and negative T waves (91 vs 36%; p=0.027; sensitivity: 90%; specificity: 63%), compared with the 11 without replacement fibrosis. When compared with sarcomeric HCM, AF patients with cardiac involvement had a significantly wider QRS (120±30 vs 100±16 msec; p&lt;0.0001), a higher frequency of right bundle branch block (RBBB) (18 vs 3%; p=0.01), ST segment depression (54 vs 20%; p&lt;0.0001) and negative T waves (72 vs 46%; p=0.01), typically in the inferior leads (44 vs 14%; p&lt;0.0001). No significant differences in terms of pseudo-necrosis and QRS voltages were found. Among Group B AF patients (26, mean age: 36±12 years), 4 had short PR and 5 incomplete RBBB. Four had an abnormal ECG (1 left atrial enlargement, 2 unspecific repolarization abnormalities, 1 Sokolow score of 3.5 mV). Conclusions Standard ECG can detect cardiac involvement in AF disease. A good correlation was reported between repolarization abnormalities and replacement fibrosis on CMR. Wide QRS and RBBB were more frequent among AF patients compared to age-sex-matched sarcomeric HCM ones, probably due to the different aetiology of the diseases (infiltrative disease vs pure hypertrophy).

Quali alterazioni dell’esame urine possono preludere ad un interessamento renale della malattia di Fabry

The markers of renal involvement in Anderson-Fabry disease are defects of urine concentration, presence of cells with lipid cytoplasmatic inclusions (mulberry bodies) and podocyturia. The loss of urine concentrating capacity is not easy to detect and the search for cellular inclusions is a complex technique. Moreover, none of the markers has any clear correlation with the stage of the disease. The occurrence of podocytes in the urine (podocyturia) correlates with both renal involvement and clinical outcome; therefore, podocyturia seems to be a promising early indicator of nephropathy. However, a common agreement on the laboratory assay used to measure is still needed.

Quali alterazioni dell’esame urine possono preludere ad un interessamento renale della malattia di Fabry

Urinary markers in Anderson-Fabry nephropathyThe markers of renal involvement in Anderson-Fabry disease are defects of urine concentration, presence of cells with lipid cytoplasmatic inclusions (mu...

Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease.

Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by 123I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by 123I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n=10); (2) unmatched, with MIBG defect but without fibrosis (n=5); and (3) matched abnormal, with MIBG defect and fibrosis (n=10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p=0.008), LV hypertrophy (p=0.05), and enzyme replacement therapy (p=0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r2=0.98, p<0.001), MIBG defect size was larger than fibrosis size (26±23 vs. 18±13%LV, p=0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, 123I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD.

Heart involvement in Anderson-Fabry disease: Italian recommendations for diagnostic, follow-up and therapeutic management

Anderson-Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes alpha-galactosidase A. It is characterized by a multisystemic involvement: the renal, neurological, heart, cochleovestibular and cutaneous systems are the most damaged. Morbidity and mortality of Anderson-Fabry disease depend on renal insufficiency, heart failure and nervous system involvement. Left ventricular hypertrophy is the most common cardiac manifestation followed by conduction system disease, valve dysfunction, and arrhythmias. Mild to moderate left ventricular hypertrophy may simulate a non-obstructive hypertrophic cardiomyopathy. Management of Anderson-Fabry disease starting from the diagnosis of cardiac involvement, the prevention of complications, the therapeutic aspects, up to appropriate clinical follow-up, requires a multidisciplinary approach. According to recent management guidelines, only few evidence-based data are available to guide the clinical and therapeutic approach to this rare disease. An Italian Board, composed by nephrologists, cardiologists, geneticists, pediatricians and neurologists has been established in order to approve by consensus a diagnostic and therapeutic management protocol. The authors report the results of this cardiologic management consensus.

Natural history of the respiratory involvement in Anderson–Fabry disease

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. 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). 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. 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 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