Screening for Fabry disease in patients with left ventricular noncompaction

Introduction and AimIt is unclear whether left ventricular noncompaction (LVNC) is a distinct cardiomyopathy or a morphologic manifestation of different cardiomyopathies. We previously reported a case of LVNC in a Fabry disease (FD) patient, but it remains to be clarified whether LVNC is a cardiac manifestation of FD, a coincidental finding or an overdiagnosis, which has major therapeutic implications. This study aims to determine the prevalence of FD among patients with LVNC.MethodsWe performed a retrospective study including all patients diagnosed with LVNC in eight hospital centers. Diagnosis of LVNC was based on at least one echocardiographic or cardiac magnetic resonance criterion. FD screening was performed by combined enzyme and genetic testing.ResultsThe study included 78 patients diagnosed with LVNC based on the Jenni (84.6%), Stöllberger (46.2%), Chin (21.8%), Petersen (83.8%) and Jacquier (16.2%) criteria. Left ventricular systolic dysfunction was present in 48.7%. Heart failure was found in 60.3%, ventricular dysrhythmias in 21.6% and embolic events in 11.5%. FD screening found no additional cases among patients with LVNC, besides the previously described case.ConclusionNo additional FD cases were found among patients with LVNC, which argues against the hypothesis that LVNC is a cardiac manifestation of FD.     

Fabry心肌病的诊断与治疗进展

法布里病（Fabry）是一种罕见的X染色体连锁遗传性疾病, 由于a-半乳糖苷酶A( alphagalactosidase A, GLA, 一种溶酶体酶)基因发生突变或缺失,引起体内GLA部分或全部缺乏,造成其代谢底物三己糖酰基鞘脂醇( globotriaosylceramide, Gb3)在人体各器官、组织蓄积,引起多个系统损害,其中心血管系统受累常见,主要表现为心肌肥厚、瓣膜损害、收缩/舒张功能减低,心律失常等,这些病变与患者心力衰竭、心源性猝死等密切相关。为了提高临床医生对Fabry病患者心脏受累表现的认识和诊治,本文将对Fabry 心肌病诊断与治疗的新进展作一综述。     

Fabry disease in patients with hypertrophic cardiomyopathy (HCM)

Fabry disease is an X-linked recessive lysosomal storage disorder with variable phenotype characterized by the accumulation of glycosphingolipid in various tissues. Unlike patients with the classical systemic Fabry disease entity, who present with multiple organ involvement, patients with a cardiac variant of Fabry disease are characterized mainly by myocardial hypertrophy. Therefore, the cardiac variant of Fabry disease may be defined as a cardiomyocytic storage disorder, thus, mimicking the clinical features of hypertrophic obstructive and especially non-obstructive cardiomyopathy. In patients with unexplained left ventricular hypertrophy the diagnosis of a cardiac variant of Fabry disease is performed by light- and electron microscopic evaluation of endomyocardial catheter biopsy specimens and/or serologic investigations (decreased activity of alpha-galactosidase A in plasma or leucocytes). Several studies show that between 4% and 8% of unselected patients with the clinical features of hypertrophic non-obstructive cardiomyopathy have a cardiac variant of Fabry disease. In each patient with unexplained myocardial hypertrophy concealed myocardial storage disease, especially cardiac Fabry disease has to be considered and should be ruled out or confirmed by endomyocardial catheter biopsy. This is important because of the recently reported alpha-galactosidase A enzyme replacement therapy in Fabry disease. Randomized, multicenter studies are mandatory to test the hypothesis that enzyme replacement therapy leads to a beneficial clinical effect in the cardiac variant form of Fabry disease and may prevent the progression of the disease in asymptomatic patients.     

Cardiac Anderson-Fabry disease: Lessons from a 25-year-follow up

Sarcomeric hypertrophic cardiomyopathy (HCM) is the most common genetic cause of unexplained left ventricular hypertrophy and has no specific treatment. Anderson-Fabry disease (AFD) is rare and usually multisystemic, but occasionally expresses clinically as a predominantly cardiac phenotype mimicking HCM. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of familial HCM and no identified sarcomeric mutations. Next-generation sequencing analysis identified a novel pathogenic mutation in the GLA gene, leading to a diagnosis of previously unknown multisystemic AFD, with consequent implications for the patient's treatment and prognosis and familial screening.     

Fabry disease: focus on cardiac manifestations and molecular mechanisms

PATHOGENESIS: Fabry disease is an inherited lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. The enzyme deficiency results in accumulation of glycosphingolipids in the lysosomes n nearly all cell types and tissues leading to a multisystem disease. MANIFESTATIONS include painful crisis, angiokeratomas, corneal dystrophy, and hypohydrosis. The severe renal, cerebrovascular, and cardiac involvement is predominantly responsible for premature mortality in Fabry patients. The disease is X-linked and manifests primarily in hemizygous males but also heterozygous females can be affected. CARDIAC INVOLVEMENT is frequent in Fabry disease. Patients develop hypertrophic cardiomyopathy, arrhythmias, conduction abnormalities, and valvular abnormalities. Although Fabry disease leads to a complex clinical syndrome, there are studies indicating that manifestations can be limited to the heart. The isolated cardiac variant of Fabry disease seems to be more common than previously thought: around 3-6% of male patients with left ventricular hypertrophy seem to suffer from this disease variant. ENZYME REPLACEMENT THERAPY: Recent advances in molecular biology and genetic engineering have enabled the development of enzyme replacement therapy in Fabry disease. Results from two independent therapy studies are indeed promising: Infusion of the enzyme preparation seems to be well tolerated and effective in catabolizing the lipid deposits. This enzyme replacement therapy could be one of the first examples for causal treatment of left ventricular hypertrophy. Therefore, early diagnosis of hypertrophy patients with the cardiac variant of Fabry disease is important.     

Maladie de Fabry : quand y penser ?

Fabry disease is the second most frequent lysosomal storage disorder. It is a X-linked genetic disease secondary to alpha-galactosidase A enzyme deficiency. This is a progressive and systemic disease that affects both males and females. Classical symptoms and organ involvements are acral pain crisis, cornea verticillata, hypertrophic cardiomyopathy, stroke and chronic kidney disease with proteinuria. Nevertheless, organ damages can be missing or pauci-symptomatic and other common symptoms are poorly recognised, such as gastrointestinal or ear involvement. In classical Fabry disease, symptoms first appear during childhood or teenage in males, but later in females. Patients may have non-classical or late-onset Fabry disease with delayed manifestations or with single-organ involvement. Recognition of Fabry disease is important because treatments are available, but it may be challenging. Diagnosis is easy in males, with dosage of alpha-galactosidase A enzyme activity into leukocytes, but more difficult in females who can express normal residual activity. Other plasmatic biomarkers, such as lyso-globotriaosylceramide (lyso-Gb3), are interesting in females, but need to be associated with GLA gene analysis. In this review, we aimed at summarize the main clinical manifestations of Fabry disease and propose a practical algorithm to know how to diagnose this complex disease.     

Fabry disease: percutaneous transluminal septal myocardial ablation markedly improved symptomatic left ventricular hypertrophy and outflow tract obstruction in a classically affected male

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disease in which left ventricular hypertrophy (LVH) is common, and if severe, may mimic hypertrophic obstructive cardiomyopathy. Alcohol-induced percutaneous transluminal septal myocardial ablation (PTSMA) has been used as a safe and effective method to alleviate LVH obstruction in patients with hypertrophic obstructive cardiomyopathy (HCM). We describe a case of a classically affected Fabry 53-year-old male with symptomatic HCM (NYHA class III with exertional angina) who was treated with PTSMA. The procedure safely and effectively alleviated symptomatic left ventricular outflow tract obstruction at long-term follow-up, and the patient's NYHA classification was reduced to NYHA class I to II.     

Apical Left Ventricular Hypertrophy and Mid‐Ventricular Obstruction in Fabry Disease

We report the case of a rare cardiac presentation of Fabry disease. Although concentric left ventricular hypertrophy is a major cardiac finding in Fabry disease, there is no case report of dynamic obstruction at mid‐left ventricular level. We describe a 59‐year‐old‐woman suffering from a severe form of Fabry disease, mimicking an apical hypertrophic cardiomyopathy with mid‐ventricular obstruction. Differentiation of Fabry disease from hypertrophic cardiomyopathy is crucial given the therapeutic and prognostic differences. Fabry disease should always be suspected in an adult, independently of the pattern of left ventricular hypertrophy.     

The heart in Anderson Fabry disease

Anderson Fabry disease is a life threatening, X-linked inborn metabolic defect of the lysosomal enzyme áalpha-galactosidase A. The deficiency of alpha-galactosidase A leads to a progressive accumulation of globotriaosylceramide (Gb(3)), the major glycosphingolipid substrate of the enzyme, within vulnerable cells, tissues, and organs, including the cardiovascular system. Cardiac involvement is frequent and patients with cardiac affection develop progressive hypertrophic infiltrative cardiomyopathy, valvular abnormalities, arrhythmias, and conduction abnormalities and may develop coronary heart disease. Hemizygous male patients have no detectable alpha-galactosidase A activity, while affected heterozygous females may have normal level of alpha-galactosidase A activity. Death occurs in male patients at 45 to 50 years, about 15 to 20 years earlier than in female patients due to a vicious circle from chronic renal insufficiency, arterial hypertension, atherosclerotic lesions and cerebrovascular hemorrhage or insults, and cardiomyopathy. Cardiac involvement in hetero- and hemizygotes will be discussed as well as the influence of enzyme replacement of alpha-galactosidase A.     

Left ventricular noncompaction associated with a pathogenic mutation in the MYH7 gene: Known mutation,different phenotype

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy, with familial and sporadic forms, but genetic testing only identifies a pathogenic mutation in a minority of cases. The main complications are heart failure, embolism and dysrhythmias. Herein we report a familial case of LVNC associated with a mutation in the MYH7 gene and review the literature regarding controversies in LVNC. A 50-year-old woman was referred to the cardiology clinic for palpitations. She underwent echocardiography and cardiac magnetic resonance imaging that revealed mild left ventricular systolic dysfunction and LVNC criteria. She had several episodes of non-sustained ventricular tachycardia and received an implantable cardioverter-defibrillator (ICD). Genetic testing revealed the c.1003G>C (p.Ala335Pro) mutation in the MYH7 gene. Familial screening showed clear genotype-phenotype cosegregation, which provided strong evidence for the pathogenic role of this mutation. To the best of our knowledge, this is the first report of LVNC associated with the p.Ala335Pro mutation in the MYH7 gene. This mutation has been described in hypertrophic cardiomyopathy, suggesting that the same pathogenic sarcomere mutation may be associated with different cardiomyopathies. This case also highlights the current difficulties regarding decisions on ICD implantation for primary prevention of sudden cardiac death in LVNC.     

Identification of Fabry Disease in a Tertiary Referral Cohort of Patients with Hypertrophic Cardiomyopathy

Background

Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy.

Detection of preclinical left ventricular dysfunction in Fabry disease: the contribution of tissue Doppler.

INTRODUCTION: Fabry disease is a rare X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase, which results in progressive intracellular accumulation of glycosphingolipids in various tissues. Cardiac involvement is frequent, with left ventricular (LV) hypertrophy (concentric, apical or asymmetric septal) as the most common finding. Evaluating LV systolic dysfunction with conventional echocardiography is not sufficiently sensitive to detect impaired myocardial function early in the course of the disease. Doppler myocardial imaging can quantify changes in global and regional longitudinal myocardial function with great precision. AIM: To identify parameters of cardiac dysfunction in patients with Fabry disease with no cardiac symptoms using conventional or Doppler echocardiography and tissue Doppler (including tissue tracking, strain and strain rate). METHODS: Four patients with Fabry disease (3 female; mean age 47 +/- 17 years) and 29 healthy controls (19 female and 10 male; mean age 38 +/- 14 years) were studied with conventional echocardiography and tissue Doppler imaging using a Vivid 7 scanner. The following parameters were measured: LV dimensions, ejection fraction (using Simpson's rule), systolic and diastolic velocities and tissue tracking of the mitral annulus at six sites (apical views). LV peak systolic strain and strain rate were obtained in 12 segments from apical views. RESULTS: Two patients had LV hypertrophy (one concentric and one apical). Diastolic impairment was detected in three patients by reduced flow propagation velocity of early transmitral flow (Vp) and E/Vp ratio. Mitral annulus systolic velocities were lower in Fabry disease than in the controls. Peak systolic strain and strain rate were diminished in all segments in three patients, showing impaired myocardial systolic function. The results are presented for each of the four patients. CONCLUSIONS: In patients with Fabry disease, with no cardiac symptoms and normal LV systolic function on conventional echocardiography, diastolic dysfunction was detected by Vp and E/Vp ratio regardless of LV hypertrophy. However, tissue Doppler imaging was able to detect impaired myocardial systolic function, particularly in patients with LV hypertrophy.     

Left ventricular noncompaction in a patient with fabry disease: overdiagnosis, morphological manifestation of fabry disease or two unrelated rare conditions in the same patient?

We report a clinical case of a young female with Fabry disease but without left ventricular hypertrophy, which fulfills the diagnostic criteria of left ventricular noncompaction (LVNC). To our knowledge, this is the first report of LVNC in a patient with Fabry disease. The possibility of an overdiagnosis of LVNC is discussed based on the limitations of the current diagnostic criteria. This case was further investigated by genetic analysis, which came to demonstrate the limited usefulness of genetic testing in the diagnosis of LVNC. Assuming a true trabecular pattern of LVNC, the hypothesis that the same patient has two unrelated and rare conditions, although possible, is unlikely. The genetic and clinical heterogeneity of LVNC is discussed and supports, along with this clinical case, the hypothesis that LVNC is a morphological expression of different diseases rather than a distinct cardiomyopathy. Accordingly, LVNC could be a rare cardiac manifestation of Fabry disease.     

Advances in hypertrophic cardiomyopathy: What the cardiologist needs to know

Hypertrophic cardiomyopathy (HCM) is known as the most common genetic heart disease, characterized by otherwise unexplained left ventricular (LV) hypertrophy. In spite of major advances in whole genome sequence techniques, it is still not possible to identify the causal mutation in approximately half of HCM patients. Consequently, a new HCM concept, “beyond the sarcomere” is being developed, supported by data from recent HCM registries which reveal two distinct HCM subgroups: sarcomere positive HCM subgroup and nonfamilial HCM subgroup. Sarcomere positive HCM patients tend to be younger age at diagnosis, have fewer co-morbidities, present more often with reverse septal morphology, more myocardial fibrosis, less LV outflow tract obstruction, and a worse prognosis when compared to nonfamilial HCM patients. These subgroups, with different molecular basis, phenotypes and clinical profiles, will likely require specific management strategies.Important research advances have also been made concerning diagnosis, sudden cardiac death stratification and therapy. In this article, we seek to review recent relevant knowledge, summarizing the advances in this complex and heterogeneous disease.     

Fabry Disease on Peritoneal Dialysis with Cardiac Involvement

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from a lack of alpha-galactosidase A (AGALA) activity in lysosomes. We herein report a patient with FD revealed by a renal biopsy who survived seven years after the introduction of peritoneal dialysis despite having severe heart failure due to left ventricular hypertrophy (LVH). FD was diagnosed based on a renal biopsy and biochemical analysis showing a low enzymatic activity of AGALA. A microscopic examination at the autopsy revealed marked hypertrophy and vacuolation of cardiac muscle cells. In our case, cardiac involvement determined the prognosis. Peritoneal dialysis is the modality of choice in the long-term management of dialysis patients with FD.     

Cardiac manifestations in Fabry disease

Fabry disease is an X-linked recessive genetic disorder of glycosphingolipid metabolism, due to deficiency of the lysosomal enzymeα-galactosidase A. The disease is characterized by the progressive intracellular lysosomal accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system.It has been reported that cardiac involvement could be the sole manifestation of the disease in some patients. Myocardial abnormalities are characterized mainly by left ventricular (LV) wall thickening without significant cavity dilatation, the most frequent abnormal structural pattern being concentric LV hypertrophy (LVH). In some patients the disease mimics a typical hypertrophic obstructive cardiomyopathy. According to our experience, systolic function is largely preserved in a large majority of affected individuals. In contrast, mild to moderate impairment of diastolic filling is a relatively common finding, representing probably the most important cause of dyspnoea in patients with Fabry disease. However, in a relatively large population of affected patients, severe diastolic dysfunction, typical of restrictive cardiomyopathy, was not found. Valvular structural abnormalities are frequent due to valvular infiltration. In several patients, hypertrophy of papillary muscles and/or systolic anterior motion of the mitral leaflets associated with LV outflow obstruction may aggravate the mitral valve dysfunction. We did not confirm the previously reported high prevalence of mitral valve prolapse. Valvular regurgitation seems to be relatively frequent but mostly non-significant. Electrocardiographic changes in Fabry disease are multiple and include at rioventricular (AV) conduction abnormalities (abbreviation of the P-R interval or AV blocks), signs of LVH and repolarization abnormalities. Our observations suggest that conduction defects and repolarization changes are present predominantly in subjects with LV structural abnormalities. Cardiac symptoms inpatients with Fabry disease include shortness of breath on effort (related to LV diastolic dysfunction), vasospastic and/or exertional angina pectoris (due to LVH, endothelial dysfunction and/or fixed coronary artery stenosis) and syncope (related to AV blocks or LV outflow obstruction). The extent of cardiac involvement, in particular LV mass assessment, could represent an ideal surrogate endpoint for evaluating the efficacy of specific therapies.     

A novel 6 bp insertion in exon 7 associated with an unusual phenotype in a family with Fabry disease

A male patient presented with oligosymptomatic Fabry disease (end stage renal failure and non-obstructive cardiomyopathy) at around 30 years of age. His leukocyte alpha-galactosidase activity (alpha-gal) was 2.6% of controls. A 50-year-old sister had similar cardiac symptoms and her asymptomatic heterozygous daughter (33 years) had normal enzyme activity. All three patients carried a novel, 6bp insertion on exon 7 of the AGAL gene. The majority of male Fabry patients carrying mutations in exon 7 have residual alpha-gal below 1% and suffer from neuropathic pain. Comparable oligosymptomatic phenotypes in Caucasian patients carry a common mutation on exon 6 (R301Q) and have a significantly later onset. The course of the disease is likely to be altered by recombinant enzyme therapy in the future. Therefore, a thorough documentation of phenotypes, residual activities and underlying genotypes is of current interest.     

New insights in cardiac structural changes in patients with Fabry's disease

BACKGROUND: Fabry's disease is an X-linked recessive genetic deficiency of the enzyme alpha-galactosidase leading to the pathologic intracellular deposition of neutral glycosphingolipids. Although cardiac involvement is frequent, there is controversy regarding the character of the associated left ventricular (LV) changes and the severity of valvular involvement. METHODS: Clinical evaluation (disease severity scaling, laboratory tests, and echocardiography) was performed in 13 hemizygous men (mean age 39 +/- 10 years) and 17 heterozygous women (mean age 35 +/- 19 years). RESULTS: LV hypertrophy (LVH) was frequent in subjects older than 30 years, more often in men (61%) than in women (18%, P <.001). The degree of LVH was independently associated with age and the logarithm of alpha-galactosidase activity (r(2) = 0.70, P <.001). The predominant LV geometric patterns were concentric LVH and remodeling, both present in 11 subjects (36%). Three patients had an asymmetric septal hypertrophy mimicking hypertrophic cardiomyopathy. In most subjects with LVH, the systolic function was normal and severe diastolic dysfunction (restrictive pattern) was not noted. Minor structural abnormalities of the mitral valve were found in 17 subjects (57%). The aortic valve was affected in 14 patients (47%). Valvular abnormalities were frequently accompanied by regurgitation of minor to mild degree. The presence of LVH or valvular changes was associated with increased disease severity. CONCLUSIONS: Echocardiographically detectable cardiac involvement is frequent with Fabry's disease, particularly in older subjects, and more pronounced in affected hemizygous men than in heterozygous women. LVH is frequently observed but usually not associated with significant systolic or restrictive diastolic dysfunction. Concentric LVH and remodeling appear to be the major manifestations of LV structural alteration. The frequently noted valvular abnormalities were not associated with a significant degree of regurgitation. Valvular and especially LV structural changes may serve as a useful marker of disease severity.     

Beware of regression of electrocardiographic abnormalities on detraining – It may not always mean ‘athlete's heart’

Hypertrophic cardiomyopathy is one of the main causes of sudden cardiac death in young athletes. Differentiating between this pathological condition and ‘athlete's heart’ can be quite challenging, warranting a thorough clinical and imaging assessment. Clinicians often rely on detraining-induced attenuation of electrocardiographic and echocardiographic findings as a means of distinguishing between pathological and physiological cardiac remodeling. This report describes detraining-related regression of left ventricular hypertrophy in a young soccer player with a diagnosis of hypertrophic cardiomyopathy. It challenges the dogma that regression of electrocardiographic abnormalities and left ventricular hypertrophy is exclusive to physiological remodeling and questions the impact of exercise training in the phenotypic expression and progression of hypertrophic cardiomyopathy.     

Early diastolic mitral annular velocity and color M-mode flow propagation velocity in the evaluation of left ventricular diastolic function in patients with Fabry disease

Fabry disease is an X-linked genetic disorder characterized by progressive intracellular accumulation of neutral glycosphingolipids. Cardiac involvement is frequent and left ventricular (LV) diastolic dysfunction is present in most of the affected subjects. Pulsed-wave tissue Doppler echocardiography (PW-TDE) and color M-mode are new Doppler methods for LV diastolic function evaluation. Their role in the assessment of Fabry disease-related cardiomyopathy remains to be established. In this study we aimed to determine the utility of PW-TDE and color M-mode-derived parameters in the assessment of LV diastolic function in patients with Fabry disease. Eighty-one echocardiographic examinations performed in 35 patients affected by Fabry disease were retrospectively analyzed. Early diastolic lateral mitral annular velocity (E_m) determined by PW-TDE and color M-mode flow propagation velocity (V_p) were measured and compared to LV filling patterns obtained using standard Doppler indexes. The receiver operating characteristics (ROC) curves method was used to determine the summary measure of relative accuracy for E_m and V_p. A comparison of ROC curves showed a significant difference for areas under the curve in favor of E_m (P < 0.001). Pseudonormal filling pattern, higher LV mass index, higher relative wall thickness, larger left atrial diameter, and older age were more frequent (all P < 0.001) in patients with incorrect diagnosis of normal LV diastolic function based on the measurement of V_p. E_m appears to be superior to V_p in the assessment of LV diastolic function in patients with Fabry disease. V_p fails to detect abnormal LV diastolic function in subjects with pronounced concentric LV remodeling and pseudonormal filling pattern.