成人法布雷病心肌病诊断与治疗中国专家共识

法布雷病(FD)是一种X染色体连锁遗传疾病, 因GLA基因突变, 导致其编码的α半乳糖苷酶A(α-Gal A)活性降低或完全缺乏, 造成代谢底物三己糖酰基鞘(Gb3)及衍生物脱乙酰基Gb3(Lyso-Gb3)在多种细胞和组织中贮积, 引起多脏器病变。在心血管系统中, FD主要会导致左心室肥厚和(或)传导异常, 即FD心肌病。由于FD心肌病是FD成人患者死亡的主要原因, 因此结合心脏影像学、酶和底物活性、基因检测以及组织活检等方法的早期诊断, 以及早期特异性酶替代疗法对于改善患者预后非常重要。本共识综合总结国内外已发表的FD心肌病诊断与治疗的相关证据, 为FD心肌病的诊断与管理提供依据。     

法布雷病相关生物标志物新进展

法布雷病是一种罕见的X连锁遗传溶酶体贮积症,患者临床表现因受累器官不同而各不相同,急需特异性诊断与治疗方法。目前已发现,特异性生物标志物［如三己糖酰基鞘脂醇（GL-3）、脱乙酰基GL-3（Lyso-GL-3）］和器官相关生物标记物（如蛋白尿、血清胱抑素C、N末端脑钠肽前体、高敏心肌肌钙蛋白T、高敏心肌肌钙蛋白I等）对法...     

慢性肾脏病中法布里病的筛查

<正>法布里病（Fabry disease,FD）是一种多系统、X连锁溶酶体贮积性疾病,由α半乳糖苷酶A(α-Gal A）活性降低或缺乏,导致其代谢底物三己糖酰基鞘脂醇（GL-3）及其去酰化形式Lyso-GL-3不能被代谢而贮积于不同细胞的溶酶体,引起多脏器损害。GL-3主要存在于心血管系统的血管内皮细胞、平滑肌细胞和肾脏足细胞,因此影响这些器官的临床表现占主导地位。FD是一种随年龄增长而恶化的进行性疾病。筛查的意义筛查是检测受疾病潜在或早期症状影响的表面健康患者的主要过程之一,它可以对疾病进行早期诊断和有效治疗,降低医疗成本,提高生活质量。     

法布雷病1例并家系分析

患者(先证者)男, 46岁。因泡沫尿20年, 血液透析12年, GLA基因突变3个月入南京医科大学附属泰州人民医院肾内科, 诊断法布雷病, 慢性肾脏病5期, 血液透析状态。随后进行家系筛查, 确诊11例法布雷病, 男性3例, 女性8例, 均为α-半乳糖苷酶基因第6外显子c.902G>A[p.Arg301Gln]突变。患病成员的临床症状及疾病严重程度存在显著的异质性, 其中3例患者进行酶替代治疗(阿加糖酶β每2周静脉滴注1 mg/kg)及随访。通过分析该家系基因突变位点的特点及临床表现异质性的原因, 以提高临床医生对法布雷病筛查、诊断及治疗的认识水平。     

法布雷病特异性治疗进展

法布雷病是一种多系统受累的罕见遗传溶酶体贮积症,及时进行特异性治疗可改善患者的临床症状,延缓疾病进展,从而延长患者预期寿命。目前,特异性治疗方法中酶替代治疗（ERT）和分子伴侣疗法已获得批准上市,底物减少疗法、新型ERT以及基因治疗等新型治疗方案正在临床研究中。本文基于《中国法布雷病诊疗专家共识（2021年版）》的治疗...     

Fabry病生物标志物研究进展

Fabry病是一种X连锁方式遗传的溶酶体贮积病,其发病机制与编码α半乳糖苷酶A(α-Gal A)的GLA基因发生突变有关,由于相应酶功能缺失,导致神经酰胺三己糖苷(Gb3)等鞘糖脂类物质在各种组织细胞内中堆积,引起相应组织缺血和梗死从而引起病变.本文系统性回顾既往的Fabry病的诊断方法,并聚焦于生物诊断标志物的最新进展,以进一步完善现有的诊断体系.     

累及心脏的Fabry病诊疗流程

Fabry病是由于X染色体中GLA基因变异导致α半乳糖苷酶A活性丧失或减低的罕见溶酶体贮积病.其引起的三己糖酰基鞘脂醇贮积可累及包括心脏在内的多个器官.心脏受累主要表现为心肌肥厚、心力衰竭、心律失常等,易与肥厚型心肌病相混淆.引入酶替代治疗后,早期诊断和治疗对减缓疾病进展和预防心血管并发症至关重要.     

Fabry心肌病的研究进展

Fabry病是一种因GLA基因突变导致的X染色体连锁遗传性溶酶体贮积病,水解酶α半乳糖苷酶完全或部分缺乏活性,导致体内鞘糖脂无法正常降解而贮积在各种组织。心脏受累常见,称为Fabry心肌病。心脏受累是患者死亡的主要原因之一,受损部位包括心肌、传导系统、瓣膜及冠状动脉。本文就Fabry心肌病遗传机制、临床表现、诊断与治疗的新进展作一综述。     

Fabry病及其酶替代疗法

Fabry病是X性连锁隐性遗传性疾病，又称α-半乳糖苷酶缺乏症，是由于先天性α-半乳糖苷酶A缺乏所致，属于溶酶体贮积病的一种。1898年由Anderson和Johann Fabry各报告1例故名AndersonFabry病，简称Fabry病。Fabry病特征性临床表现为弥漫性皮肤血管角质瘤和发作性肢体疼痛，本病后期常出现。肾脏、心脏和脑血管等器官的进行性损害。Fabry病近年之所以引起人们的关注，     

成人Still病92例临床分析

<正>成人Still病(adult-onset still disease,AOSD)是一种病因不明的以高热、皮疹、多关节痛、淋巴结肿大、白细胞增多、肝功异常等多系统受累为主要特征的临床综合征。由于本病没有特异性的临床表现和实验室检测指标,因此诊断标准缺乏特异性,临床诊断需要在充分的鉴别诊断基础上做出,易造成误诊和漏诊~([1-2])。同时,本病对于药物的治疗反应变异很大,目前也缺乏统一的包括治疗用药、剂量等指导性     

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.     

Proposed high-risk screening protocol for Fabry disease in patients with renal and vascular disease

Summary  Fabry disease is a complex, multisystemic and clinically heterogeneous disease with prominent urinary excretion of globotriaosylceramide (Gb₃), the principal substrate of the deficient enzyme, α-galactosidase A. Some measure of specific treatment is possible with enzyme replacement therapy, which can be applied safely and effectively to Fabry patients. Incidence estimations of Fabry disease vary widely from 1:55 000 to 1:3000 male births. The true incidence is likely to be higher than originally thought, owing to the existence of milder variants of the disease. The main complications of Fabry disease are a 100-fold increased risk of ischaemic stroke, cardiac disease, a wide variety of arrhythmias, valvular dysfunction and cardiac vascular disease, as well as progressive renal failure usually associated with significant proteinuria. These clinical manifestations are non-specific and are often mistaken for symptoms of other disorders, thus complicating the confirmation of diagnosis. Other clinical features of the disease are often absent (angiokeratoma), subtle (corneal opacities and hypohidrosis), or unaccompanied by specific physical findings (acroparaesthesias) indicating the true nature of the underlying disease. We propose the hypothesis that α-galactosidase A deficiency is a modifiable cardiovascular risk factor in the general population. This hypothesis may be tested by a non-invasive high-risk screening protocol for Fabry patients with ischaemic strokes and a variety of cardiac, and renal complications. These patients would benefit from diagnosis, appropriate treatment, follow-up and surveillance. Early detection of Fabry patients would also benefit affected relatives, many of whom do not have a clear diagnosis of their clinical condition. Competing interests: None declared References to electronic databases: Fabry disease: OMIM 301500. Alpha-galactosidase A (α-Gal A) (EC 3.2.1.22).     

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.     

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.     

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.     

Efficacité clinique de l’enzymothérapie dans la maladie de Fabry. Analyse critique

Fabry disease is a X-linked lysosomal storage disorder. Two preparations of the enzyme α-galactosidase A are available in Europe since 2001: agalsidase alpha and agalsidase beta. Clinical evidence of efficacy are mandatory considering the absence of a robust biomarker. A literature review was performed to assess the clinical efficacy of these two enzyme replacement therapies. Only open or randomised controlled trials were considered. No unflawed direct comparison exists between the two drugs. Significant clinical benefits have been demonstrated with enzyme replacement therapy (ERT), mainly at an early phase of the disease, with positive effects on heart, kidneys, pain, and quality of life. Further prospective studies are required to confirm the long term clinical benefits of ERT. More specific studies are also needed in women or with ERT earlier in the course of Fabry disease to assess prevention of organ damage.     

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 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.     

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。     

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.