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.     

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.     

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.     

Non-specific gastrointestinal features: Could it be Fabry disease?

Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. The confounding clinical presentation and rarity of Fabry disease often cause long diagnostic delays and multiple misdiagnoses. Therefore, specialists involved in the clinical evaluation of non-specific upper and lower gastrointestinal symptoms should recognize Fabry disease as a possible cause of the symptoms, and should consider Fabry disease as a possible differential diagnosis. When symptoms or family history suggest Fabry disease, in men, low alpha-galactosidase A enzyme levels, and in women, specific Fabry mutations confirm the diagnosis. In addition to symptomatic treatments, disease-specific enzyme replacement therapy with recombinant human alpha-galactosidase A enzyme or chaperone therapy (migalastat) in patients with amenable mutations can improve the disease, including gastrointestinal symptoms, and should be initiated as early as possible after Fabry disease has been confirmed; starting enzyme replacement therapy at as young an age as possible after diagnosis improves long-term clinical outcomes. Improved diagnostic tools, such as a modified gastrointestinal symptom rating scale, may facilitate diagnosing Fabry disease in patients with gastrointestinal symptoms of unknown cause and thus assure timely initiation of disease-specific treatment.     

肾脏全基因组关联研究及发展方向

遗传因素在许多常见的肾脏疾病(如多囊肾病、Alport综合征、Fabry病、IgA肾病、糖尿病肾病、狼疮性肾炎等)中起着重要作用。以往数十年里,研究者为寻找这些常见肾脏疾病的基因变异,进行了大量的探索,通过连锁分析和定位克隆等技术研究明确了Alport综合征、Fabry病等单基因病的致病机制。但是,对临床上更为常见的复杂性疾病(IgA肾病、糖尿病肾病等)的基因研究进展却非常缓慢。近五年发展的全基因组关联研究(genome-wide association study,GWAS)为寻找这些疾病的易感基因提供了有力工具。     

A diagnosis of Fabry gastrointestinal disease by chance: a case report

Fabry disease is an X-linked lysosomal storage disease caused by a deficiency of alpha-galactosidase A. This determines an accumulation of globotriaosylceramide within lysosomes. The clinical picture is highly variable and depends on cellular storage deposition. Renal, cardiac and nervous system are the most frequent organs involved. Gastrointestinal involvement is also present, associated with other clinical signs of Fabry disease and sometimes can be a prominent clinical manifestation. We describe a Fabry disease case in which gastrointestinal involvement was the first and the only clinical sign of Fabry disease and a diagnosis of Fabry disease was made by chance during a family screening. Enzyme replacement therapy was started and after 3 months, there was a complete disappearance of signs.     

Simple criteria for differentiation of Fabry disease from amyloid heart disease and other causes of left ventricular hypertrophy

AIMS: Fabry disease may be difficult to differentiate from other causes of left ventricular hypertrophy such as other myocardial storage diseases (including amyloidosis), hypertrophic cardiomyopathy (HCM), or hypertensive heart disease (HHD). We sought to determine simple criteria to best differentiate the above mentioned cardiac diseases. METHODS AND RESULTS: All patients in a six-year time period with left ventricular hypertrophy due to Fabry disease (13 patients), biopsy proven cardiac amyloidosis (16 patients), non-obstructive HCM (17 patients), and 22 randomly selected patients with advanced HHD were compared. Retrospective analysis of clinical characteristics, findings of electrocardiogram (ECG) and echocardiography by blind review was performed. RESULTS: No single clinical characteristic or findings of ECG or echocardiography could reliably differentiate between the various diseases. Increased echogenicity/granular sparkling, valvular abnormalities, abnormal renal function, and diastolic function were not helpful discriminators. In a univariate analysis, four criteria (acroparesthesia, anhydrosis, absence of hypertension and presence of Sokolow criteria for left ventricular hypertrophy in the ECG) were significant for Fabry disease. By logistic regression analysis, the following most suitable discriminative parameters were identified: hypertension in HHD (specificity 82%), orthostasis and/or pericardial effusion for amyloidosis (specificity 93%), papillary muscle anomaly in non-obstructive HCM (specificity 92%), and Fabry disease if neither hypertension orthostatis, pericardial effusion nor a papillary muscle anomaly was present (specificity 87%). CONCLUSION: A combination of symptoms, echocardiographic findings and ECG in unexplained left ventricular hypertrophy may help to differentiate amyloidosis, non-obstructive HCM and hypertensive heart disease from Fabry disease. The results of this preliminary study will have to be confirmed in a prospective study.     

Histopathological evidence of Fabry disease in a female patient with left ventricular noncompaction

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase gene. The most frequent cardiac presentation of Fabry disease is cardiomyopathy characterized by left ventricular (LV) hypertrophy, usually concentric.Heart disease in affected females tends to be clinically recognized later than in males and cardiac complications are the most frequently reported cause of death in females with Fabry disease. There are few data regarding the association between Fabry disease and LV noncompaction. We report a case of a 30-year-old asymptomatic woman, heterozygous for a nonsense alpha-galactosidase gene mutation (p.R220X), who presented LV noncompaction on cardiac magnetic resonance imaging, without LV wall hypertrophy. Histopathological examination of myocardial fragments showed marked deposition of glycosphingolipids in cardiomyocytes, confirming the diagnosis of Fabry cardiomyopathy. Based on this finding, the patient was proposed for enzyme replacement therapy. This case illustrates the role of endomyocardial biopsy in the clarification of doubtful or atypical findings related to cardiac Fabry disease, even in heterozygous women, and corroborates the contention that Fabry disease should be included in the differential diagnosis of LV hypertrabeculation/noncompaction.     

Preselective gene therapy for Fabry disease

Fabry disease is a lipid storage disorder resulting from mutations in the gene encoding the enzyme alpha-galactosidase A (alpha-gal A; EC ). We previously have demonstrated long-term alpha-gal A enzyme correction and lipid reduction mediated by therapeutic ex vivo transduction and transplantation of hematopoietic cells in a mouse model of Fabry disease. We now report marked improvement in the efficiency of this gene-therapy approach. For this study we used a novel bicistronic retroviral vector that engineers expression of both the therapeutic alpha-gal A gene and the human IL-2Ralpha chain (huCD25) gene as a selectable marker. Coexpression of huCD25 allowed selective immunoenrichment (preselection) of a variety of transduced human and murine cells, resulting in enhanced intracellular and secreted alpha-gal A enzyme activities. Of particular significance for clinical applicability, mobilized CD34(+) peripheral blood hematopoietic stem/progenitor cells from Fabry patients have low-background huCD25 expression and could be enriched effectively after ex vivo transduction, resulting in increased alpha-gal A activity. We evaluated effects of preselection in the mouse model of Fabry disease. Preselection of transduced Fabry mouse bone marrow cells elevated the level of multilineage gene-corrected hematopoietic cells in the circulation of transplanted animals and improved in vivo enzymatic activity levels in plasma and organs for more than 6 months after both primary and secondary transplantation. These studies demonstrate the potential of using a huCD25-based preselection strategy to enhance the clinical utility of ex vivo hematopoietic stem/progenitor cell gene therapy of Fabry disease and other disorders.     

End-stage cardiac manifestations and autopsy findings in patients with cardiac fabry disease

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of alpha-galactosidase A with multi-organ dysfunction. Patients with manifestations limited to the heart have been reported recently as a disease variant. We have previously reported a 3% prevalence of this cardiac variant in men with left ventricular hypertrophy, which we designated cardiac Fabry disease. The purposes of the current study were to evaluate the end-stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS and RESULTS: We evaluated five autopsied male patients with cardiac Fabry disease. One died of ventricular fibrillation and four of heart failure. Electrocardiograms obtained at hospitalization revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings showed the presence of left ventricular hypertrophy in all patients. Localized thinning of the basal posterior wall of the left ventricle was detected in four patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells showed glycosphingolipid accumulation in all of the patients but no accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction, conduction disturbances and ventricular arrhythmias occur in end-stage cardiac Fabry patients. Furthermore, left ventricular hypertrophy commonly associated with thinning of the base of the left ventricular posterior wall is present. The accumulation of glycosphingolipids can be observed in myocardial cells but not in other organs.     

Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and functional correction in multiple organs of Fabry mice

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzyme deficiency leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop painful neuropathy and vascular occlusions that progressively lead to cardiovascular, cerebrovascular, and renal dysfunction and early death. Although enzyme replacement therapy and bone marrow transplantation have shown promise in the murine analog of Fabry disease, gene therapy holds a strong potential for treating this disease in humans. Delivery of the normal alpha-gal A gene (cDNA) into a depot organ such as liver may be sufficient to elicit corrective circulating levels of the deficient enzyme. To investigate this possibility, a recombinant adeno-associated viral vector encoding human alpha-gal A (rAAV-AGA) was constructed and injected into the hepatic portal vein of Fabry mice. Two weeks postinjection, alpha-gal A activity in the livers of rAAV-AGA-injected Fabry mice was 20-35% of that of the normal mice. The transduced animals continued to show higher alpha-gal A levels in liver and other tissues compared with the untouched Fabry controls as long as 6 months after treatment. In parallel to the elevated enzyme levels, we see significant reductions in Gb3 levels to near normal at 2 and 5 weeks posttreatment. The lower Gb3 levels continued in liver, spleen, and heart, up to 25 weeks with no significant immune response to the virus or alpha-gal A. Also, no signs of liver toxicity occurred after the rAAV-AGA administration. These findings suggest that an AAV-mediated gene transfer may be useful for the treatment of Fabry disease and possibly other metabolic disorders.     

Hearing loss in a family affected by Fabry disease

Summary Fabry disease is an inborn error of metabolism due to deficient activity of the lysosomal enzyme α-galactosidase A. The enzyme defect leads to the systemic accumulation of neutral glycosphingolipids in tissues. Otological manifestations consist of hearing loss and mild vestibular disorders. In this report we describe a family of five members affected by Fabry disease with four subjects showing inner ear involvement. Competing interests: None declared     

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.     

The 30-year Natural History of Non-classic Fabry Disease with an R112H Mutation

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the alpha-galactosidase A (GLA) gene that results in deficiency of the enzyme GLA and leads to the accumulation of globotriaosylceramide (GL-3) in cells. The accumulation of GL-3 may lead to life-threatening complications. Significant advances in genetic sequencing technology have led to a better understanding of genotype-phenotype interactions in Fabry disease. Fabry disease with an R112H mutation is known as the non-classic type. However, the long-term clinical course of the disease remains unknown. We herein report a patient with a 30-year natural history of non-classic Fabry disease with an R112H mutation.     

High prevalence of subclinical hypothyroidism in patients with Anderson–Fabry disease

Summary Anderson–Fabry disease is a rare lysosomal storage disorder. It results from a deficiency of the lysosomal α-galactosidase A and leads to progressive accumulation of globotriaosylceramide in the endothelium and tissue cells of various organs. Some of the typical clinical findings such as tiredness, dry skin, myalgia and arthralgia as well as vague gastrointestinal complaints are also symptoms of hypothyroidism. Therefore, we studied the thyroid function in patients with Anderson–Fabry disease. Thyroid function was studied in 11 patients (6 female, 5 male) with Anderson–Fabry disease by measuring thyroid-stimulating hormone (TSH) and free thyroxine serum levels. Nine patients had chronic kidney disease with stage 1 and two with stage 5. Subclinical hypothyroidism (normal serum free thyroxine concentrations along with elevated serum TSH levels) was found in 4 of 11 patients (36.4%). Subclinical hypothyroidism was observed in both male and female patients as well as in patients with stage 1 and stage 5 kidney disease. Subclinical hypothyroidism is a common finding in patients with Anderson–Fabry disease, showing an excess prevalence as compared to the normal population. The high frequency seems to be relevant regarding the potential consequences of a hypothyroid state.     

Enzymatic and functional correction along with long-term enzyme secretion from transduced bone marrow hematopoietic stem/progenitor and stromal cells derived from patients with Fabry disease.

Fabry disease is a lysosomal storage disorder that is due to a deficiency in alpha-galactosidase A (alpha-gal A). Previously we have shown that a recombinant retrovirus synthesized for the transfer of the human alpha-gal A coding sequence was able to engineer enzymatic correction of the hydrolase deficiency in fibroblasts and lymphoblasts from Fabry patients. The corrected cells secreted alpha-gal A that was taken up and utilized by uncorrected bystander cells, thus demonstrating metabolic cooperativity. In separate experiments we used transduced murine bone marrow cells and successfully tested and quantitated this phenomenon in vivo. In the present studies, which were designed to bring this therapeutic approach closer to clinical utility, we establish that cells originating from the bone marrow of numerous Fabry patients and normal volunteers can be effectively transduced and that these target cells demonstrate metabolic cooperativity. Both isolated CD34+-enriched cells and long-term bone marrow culture cells, including nonadherent hematopoietic cells and adherent stromal cells, were transduced. The transferred gene generates increased intracellular alpha-gal A enzyme activity in these cells. Further, it causes functional correction of lipid accumulation and provides for long-term alpha-gal A secretion. Collectively, these results indicate that a multifaceted gene transfer approach to bone marrow cells may be of therapeutic benefit for patients with Fabry disease.     

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.     

Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach

Fabry disease is a disorder of alpha-D-galactosyl-containing glycolipids resulting from a deficiency of alpha-galactosidase A. Patients have a poorly understood vascular dysregulation. We hypothesized that disease-related perturbation by using enzyme replacement therapy in the murine model of Fabry disease would provide insight into abnormal biological processes in Fabry disease. Gene expression analyses of the heart, aorta, and liver of male alpha-galactosidase A knockout mice 28 weeks of age were compared with that of WT mice. Microarray analyses were performed before and after six weekly injections of alpha-galactosidase A. Alteration of Rpgrip1 ranked highest statistically in all three organs when knockout mice were compared with WT, and its splice variants responded in a unique way to alpha-galactosidase A. Enzyme replacement therapy tended to not only normalize gene expression, e.g., reduce the overexpression of securin, but also specifically modified gene expression in each tissue examined. Following multiple comparison analysis, gene expression correlation graphs were constructed, and a priori hypotheses were examined by using structural equation modeling. This systems biology approach demonstrated multiple and complex parallel cellular abnormalities in Fabry disease. These abnormalities form the basis for informed, in a Bayesian sense, sequential, hypothesis-driven research that can be subsequently tested experimentally.     

Structural and functional changes in peripheral vasculature of Fabry patients

Summary Objective: Fabry disease is a lysosomal storage disorder due to deficient α-galactosidase A activity, which leads to glycosphingolipid accumulation especially in vascular smooth-muscle and endothelial cells. Little is known about the effects of Fabry disease on peripheral artery function and structure. Therefore, we aimed to further characterize the peripheral vascular structural and functional changes in Fabry disease. Methods and results: We measured structural and functional vascular parameters, including intima-media thickness (IMT) of brachial and carotid arteries and abdominal aorta, carotid and aortic compliance, and brachial artery flow-mediated dilatation (FMD) in 17 Fabry patients and 34 healthy controls matched for age, sex and smoking. Carotid IMT (0.64 ± 0.15 vs 0.57 ± 0.12 mm), brachial IMT (1.02 ± 0.25 vs 0.74 ± 0.18 mm), and aortic IMT (0.31 ± 0.09 vs 0.26 ± 0.04 mm) were significantly increased, and brachial FMD was significantly impaired (6.3 ± 5.0 vs 9.7 ± 3.9%) in Fabry patients compared to healthy controls (p < 0.05 in all comparisons after adjustments for age, LDL-cholesterol, and systolic blood pressure). No differences were observed in arterial compliance between the groups. Conclusions: These data suggest that Fabry disease affects arterial function and structure by disturbing peripheral endothelial function and promoting intima-media thickening. Competing interests: None declared     

Fabry病一例报道并文献复习

目的：探讨Fabry 病的临床表现、诊断及鉴别诊断，提高临床医师对Fabry病的认识，降低漏诊率。方法：报道1例罕见的Fabry病肾损害，结合文献对该病的临床表现、诊断、鉴别诊断及治疗和预后进行探讨。结果：患者为中年男性，发病年龄为30岁，临床表现主要为肾脏损伤及周围神经病变，伴有尿毒症家族史，中性粒细胞测α-半乳糖苷酶示酶活性：0nmol/mg/hr，基因突变：p.H125T（c.373C>T），最终确诊Fabry病。患者曾至多家医院就诊，均未明确病因，漏诊率高。结论：Fabry病属于遗传性肾脏疾病，为临床罕见性疾病，容易漏诊，确诊需仔细的询问病史、肾脏病理检查、测定血清α-半乳糖苷酶水平及基因诊断。