Elevated globotriaosylsphingosine is a hallmark of Fabry disease

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of alpha-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.     

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.     

Fabry disease,an under-recognized multisystemic disorder: expert recommendations for diagnosis,management, and enzyme replacement therapy

Fabry disease (alpha-galactosidase A deficiency) is an X-linked recessive lysosomal storage disorder. Although the disease presents in childhood and culminates in cardiac, cerebrovascular, and end-stage renal disease, diagnosis is often delayed or missed. This paper reviews the key signs and symptoms of Fabry disease and provides expert recommendations for diagnosis, follow-up, medical management, and the use of enzyme replacement therapy. Recommendations are based on reviews of the literature on Fabry disease, results of recent clinical trials, and expertise of the authors, all of whom have extensive clinical experience with Fabry disease and lysosomal storage disorders and represent subspecialties involved in treatment. All males and female carriers affected with Fabry disease should be followed closely, regardless of symptoms or treatment status. Clinical trials have shown that recombinant human alpha-galactosidase A replacement therapy--the only disease-specific therapy currently available for Fabry disease--is safe and can reverse substrate storage in the lysosome, the pathophysiologic basis of the disease. Enzyme replacement therapy in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial disease manifestations should be initiated as early as possible. Additional experience is needed before more specific recommendations can be made on optimal dosing regimens for reversal; maintenance; and prevention of disease manifestations in affected males, symptomatic carrier females, children, and patients with compromised renal function.     

Fabry disease in Italy: first epidemiologic and collaborative study

The authors sought to define the prevalence of Fabry disease and to establish the incidence and its natural history in Italy. The aim of this study was to point out the first clinical signs and symptoms to perform an early diagnosis and hence to start a specific therapeutic treatment. Fabry disease is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme alpha-galactosidase A. Fabry disease is a severe X-linked disorder presenting with a higher morbidity between the third and the fourth decade of life. Fabry disease may be confused with other diseases or completely misdiagnosed: its frequency is estimated worldwide to be 1:117000. In Italy, 65 patients have been identified by several specialized institutions; age, sex, onset of first clinical signs and symptoms were analyzed and reported. In conclusion, this is the first Italian collaborative study that allows to delineate and point out the clinical signs of Fabry disease to perform a correct and early diagnosis. Enzyme replacement therapy is now available and its early beginning can prevent renal and cardiac failure, improve the quality of life and life expectancy in these patients.     

Anderson–Fabry disease: Clinical manifestations of disease in female heterozygotes

Anderson–Fabry disease is a rare, X-chromosomal lipid storage disorder caused by a deficiency of lysosomal -galactosidase A. Clinical manifestations of Anderson–Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson–Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. It therefore appears that Anderson–Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X-linked dominant disease.     

Enzyme replacement therapy stabilizes obstructive pulmonary Fabry disease associated with respiratory globotriaosylceramide storage

Fabry disease is an X-linked glycosphingolipidosis caused by a deficiency of α-galactosidase A, a lysosomal enzyme. Symptoms in hemizygous males and heterozygous females are due to lysosomal storage of globotriaosylceramide in the central and peripheral nervous system, vascular endothelium, cardiac valves and myocytes, gastrointestinal tract, and renal epithelium. Pulmonary involvement is also a recognized manifestation of Fabry disease, but histopathological evidence of pulmonary lysosomal storage is scant. We report a 51-year-old woman with a G43R α-galactosidase A mutation and normal spirometry testing 2.5 years prior to presentation, who experienced a dry, nonproductive cough that persisted despite treatment with antibiotics and bronchodilators. Spirometry demonstrated a mixed restrictive/obstructive pattern as well as impaired gas exchange. Patchy ground-glass pulmonary interstitial infiltrates were found on plain radiography and computerized tomography. She underwent an open lung biopsy that demonstrated peribronchiolar fibrosis and smooth-muscle hyperplasia. Prominent inclusion bodies of the bronchiolar/arteriolar smooth muscle and endothelium were present. Electron microscopy indicated the inclusion bodies were lamellated zebra bodies consistent with globotriaosylceramide storage. Enzyme replacement therapy (ERT) with agalsidase-beta was instituted. Since initiation of therapy, she occasionally has a dry cough but markers of obstructive lung disease have remained stable in the past 4 years. This report demonstrates that pulmonary involvement in Fabry disease is due to lysosomal storage, and suggests that ERT is capable of stabilizing pulmonary Fabry disease. However, progressive worsening of her total lung capacity indicates that ERT cannot reverse the ongoing process of fibrosis also seen in Fabry disease.     

Diagnosis of Fabry disease: usefulness of the clinical investigation

Fabry disease, an X-linked lysosomal storage disorder due to alpha-galactosidase A deficiency, leads to an accumulation of globotriaosylceramide resulting in a multisystemic disorder. The initial manifestations of the disease are not specific, leading to a delayed diagnosis. We report a patient in whom the diagnosis was obtained by family screening and the confrontation of clinical signs. We also present a 4 year follow-up under enzyme replacement therapy (agalsidase β, 1 mg/kg/14 days).     

Schmerztherapie bei Morbus Fabry

Fabry’s disease is an X-chromosome linked lysosomal storage disorder with α-galactosidase A deficiency and subsequent multiple organ involvement. An early and common symptom also in later stages of the disease is pain. This pain depends on various precipitating factors and can severely compromise the quality of life. So-called Fabry crises can lead to the necessity for intensive care treatment. The pain can be classified as predominantly neuropathic and is difficult to treat. In addition, medication has to be adjusted to concomitant cardiac and renal involvement in Fabry’s disease. This review gives guidance for pain therapy in Fabry’s disease based on the available evidence and on experience.     

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 with few clinical signs and symptoms

We describe a 25-year-old man with Fabry disease who remained undiagnosed until progressive renal involvement had begun, because of few clinical signs or symptoms except intermittent acroparesthesia. He had non-nephrotic proteinuria and normal renal function. Renal biopsy revealed focal and segmental glomerular sclerosis with vacuolated podocytes. Electron microscopy demonstrated characteristic lamellated bodies. Alpha-galactosidase A (alpha-galA) activity was markedly decreased. Early diagnosis of Fabry disease is becoming important because of the prospect of recombinant alpha-galA replacement therapy. Careful history taking, physical examinations, and renal histology with electron microscopy are essential for the diagnosis in the course of the disease.     

Morbus Fabry of the heart. Why should cardiologists care?

Summary Fabry Disease is an X-linked lysosomal storage disorder leading to the accumulation of glycosphingolipids, mainly globotriaosylceramides in all tissues and solid organs of the body. The disease was described by Johannes Fabry and William Anderson coevally in 1898. Beside the involvement of the central nervous system, peripheral nerves, kidneys, skin and endovascular endothelium, the heart plays a major role in the disease. Left ventricular hypertrophy is one hallmark initially presenting with preserved ventricular function. However, with progression of the disease patients die due to heart failure. Though angina is often reported, the incidence of epicardial coronary stenosis is not a dominant feature, if at all small vessel disease can occur. In respect of arrhythmias a broad spectrum can be seen including shortened or prolonged PR-intervals, AV blocks of different degrees and sometimes malignant ventricular arrhythmias. In the past, women were considered to be carriers of the disease but hardly to develop clinical symptoms. In recent years there is evidence that female carriers may more often be affected with severe symptoms. In addition, a group of Fabry patients displaying mainly cardiac involvement were described as having a cardiac variant of the disease. This implied the hypothesis that some of those patients with unexplained myocardial hypertrophy do suffer from Fabry disease. Since 2002 enzyme replacement therapy is available and there is first evidence for its efficacy to reduce hypertrophy and increase myocardial function. If this is associated with a prognostic improvement has to be determined in future studies.     

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.     

Fabry disease: clinic and enzymatic diagnosis of homozygous and heterozygous. New therapeutic prospects

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a partial or complete deficiency of alpha-galactosidase A. Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme, leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction and early death. Men are predominantly affected but many female carriers have similar clinical involvement, including increased risk of stroke. Physical stigmata, such as angiokeratomas in skin and mucous membranes and characteristic benign corneal abnormalities, facilitate identification of Fabry disease. The finding of a marked decreased activity of (alpha-galactosidase A in plasma, white blood cells or cultured skin fibroblasts confirms the diagnosis. Treatment thus far has been symptomatic only. Etiology-based therapies are being developed that include enzyme replacement therapy, gene therapy, and substrate deprivation. The recently completed double-blind, placebo-controlled trials of intravenous infusions of (alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. We report a family with Fabry disease composed of hemicygous and heterocygous. The propositus developed chronic renal failure and received a cadaver renal transplant, which remained with adequate renal function during 15 years.     

Pulmonary involvement in Fabry disease: Overview and perspectives

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, which leads to storage of sphingolipids in virtually all human cells and consequently to organ dysfunction. Pulmonary involvement is still debated. But, obstructive lung disease is up to ten times more prevalent in patients with FD compared to general public. Also, an accelerated decline in forced expiratory volume in one second (FEV1) over time was observed in these patients. Lysosomal storage of glycosphingolipids is considered leading to small airway disease via hyperplasia of the bronchiolar smooth muscle cells. Larger airways may become involved with ongoing disease process. There is no evidence for involvement of the lung interstitium in FD. The effect of enzyme replacement therapy on respiratory involvement remains to be determined in large, prospective controlled trials.     

Fabry disease and cystinosis, two lysosomal diseases: similarities and differences

Fabry disease and cystinosis are both lysosomal diseases. Some clinical features (such as renal and corneal involvement) are shared by both diseases whereas many other features are different (mode of inheritance, rate of progression, mechanism of lysosomal storage, therapeutic modalities etc.). Intermediary mechanisms that lead from lysosomal overload to lesions and disease are still incompletely understood.     

Fabry disease exhibiting recurrent stroke and persistent inflammation

We describe two cases of Fabry disease in non-blood-related Japanese men, manifesting recurrent stroke even after the start of enzyme replacement therapy. Both exhibited chronic inflammation and ocular involvement with elevated levels of serum C reactive protein prior to the onset of stroke. We, therefore, suggest the association among persistent inflammation, ocular involvement and recurrent stroke in a certain subset of Fabry disease patients. Both cases received enzyme replacement therapy with no improvement in inflammatory signs or laboratory data. These cases suggest that Fabry disease should be considered in young patients with cryptogenic stroke or CNS manifestations and fever of unknown origin.     

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.     

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。     

Morbus Fabry of the heart Why should cardiologists care?

Fabry Disease is an X-linked lysosomal storage disorder leading to the accumulation of glycosphingolipids, mainly globotriaosylceramides in all tissues and solid organs of the body. The disease was described by Johannes Fabry and William Anderson coevally in 1898. Beside the involvement of the central nervous system, peripheral nerves, kidneys, skin and endovascular endothelium, the heart plays a major role in the disease. Left ventricular hypertrophy is one hallmark initially presenting with preserved ventricular function. However, with progression of the disease patients die due to heart failure. Though angina is often reported, the incidence of epicardial coronary stenosis is not a dominant feature, if at all small vessel disease can occur. In respect of arrhythmias a broad spectrum can be seen including shortened or prolonged PR-intervals, AV blocks of different degrees and sometimes malignant ventricular arrhythmias. In the past, women were considered to be carriers of the disease but hardly to develop clinical symptoms. In recent years there is evidence that female carriers may more often be affected with severe symptoms. In addition, a group of Fabry patients displaying mainly cardiac involvement were described as having a cardiac variant of the disease. This implied the hypothesis that some of those patients with unexplained myocardial hypertrophy do suffer from Fabry disease. Since 2002 enzyme replacement therapy is available and there is first evidence for its efficacy to reduce hypertrophy and increase myocardial function. If this is associated with a prognostic improvement has to be determined in future studies.