中国法布雷病诊疗专家共识(2021年版)

法布雷病是一种罕见的X连锁遗传溶酶体贮积症,是由于GLA基因突变导致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脂醇(GL-3)及其衍生物脱乙酰基GL-3(Lyso-GL-3)在多脏器贮积,引起多脏器病变甚至引发危及生命的并发症。由于法布雷病缺乏特异性症状,因此需结合临床表现、酶活性、生物标志物及基因检测等结果协助临床早期诊断。随着阿加糖酶β和阿加糖酶α在我国获批上市,将为我国法布雷病患者带来特异性治疗的福音。本共识以循证医学为基础,对法布雷病的临床表现、诊断方法和流程、治疗、筛查、遗传咨询与产前诊断等方面进行阐述,为推动法布雷病的规范化诊疗提供依据。     

Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP-4 in diabetic stem cell mobilopathy

Fabry disease is an X-chromosomal recessive deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3) in a variety of cells often with subsequent functional impairment. Here, the impact of Fabry disease on the biology of circulating angiogenic cells (CACs) and the endothelial response to transient ischemia was investigated. Untreated patients with Fabry disease (n?=?26), patients after initiation of alpha-Gal enzyme replacement therapy (ERT) (n?=?16) and healthy controls (n?=?26) were investigated. Endothelial function was assessed by the EndoPAT2000 device. CAC numbers were assessed by flow-cytometry, CAC function by a modified Boyden chamber assay. Fabry patients showed a pathologic endothelial response, which normalized after ERT. CACs were increased in number, but functionally impaired. Immunofluorescence and electron microscopy identified an accumulation of GL-3 in Fabry CACs. ERT attenuated CAC dysfunction and improved markers of oxidative stress response in Fabry patients via a reduction in GL-3 accumulation in vitro and in vivo. Silencing of alpha-Gal in healthy CACs impaired their migratory capacity underlining a key role of this enzyme for CAC function. CAC supernatant as well as CACs from Fabry patients impaired angiogenesis and migratory capacity of HUVECs providing a mechanistic link between CAC and endothelial dysfunction. CAC adhesion to TNF-?? pre-stimulated HUVECs and tube formation was impaired by alpha-Gal knockdown. Fabry patients show a dysfunction of CAC and a pathologic endothelial response. ERT improves CAC and endothelial function and thus may attenuate development of cardiovascular disease in the long term in this patient population.     

Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease

Fabry disease, a rare X-linked α-galactosidase A deficiency, causes progressive lysosomal accumulation of globotriaosylceramide (GL-3) in a variety of cell types. As the disease progresses, renal failure, left ventricular hypertrophy, and strokes may occur. Enzyme replacement therapy (ERT), with recombinant α-galactosidase A, is currently available for use to reduce GL-3 deposits. However, although it improves cardiac function and decreases left ventricular mass, GL-3 clearance upon ERT has been demonstrated in cardiac capillary endothelium but not in cardiomyocytes of patients. Relevant models are needed to understand the pathogenesis of cardiac disease and explore new therapeutic approaches. We generated induced pluripotent stem cells (iPSC) from Fabry patients and differentiated them into cardiomyocytes. In these cells, GL-3 accumulates in the lysosomes over time, resulting in phenotypic changes similar to those found in cardiac tissue from Fabry patients. Using this human in vitro model, we demonstrated that substrate reduction therapy via glucosylceramide synthase inhibition was able to prevent accumulation and to clear lysosomal GL-3 in cardiomyocytes. This new in vitro model recapitulates essential features of cardiomyocytes from patients with Fabry disease and therefore provides a useful and relevant tool for further investigations of new therapy.     

The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines

Summary  Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (α-Gal A), with consequent accumulation of its major glycosphingolipid substrate, globotriaosylceramide (GL-3). Over 500 Fabry mutations have been reported; approximately 60% are missense. The iminosugar 1-deoxygalactonojirimycin (DGJ, migalastat hydrochloride, AT1001) is a pharmacological chaperone that selectively binds α-Gal A, increasing physical stability, lysosomal trafficking, and cellular activity. To identify DGJ-responsive mutant forms of α-Gal A, the effect of DGJ incubation on α-Gal A levels was assessed in cultured lymphoblasts from males with Fabry disease representing 75 different missense mutations, one insertion, and one splice-site mutation. Baseline α-Gal A levels ranged from 0 to 52% of normal. Increases in α-Gal A levels (1.5- to 28-fold) after continuous DGJ incubation for 5 days were seen for 49 different missense mutant forms with varying EC₅₀ values (820 nmol/L to >1 mmol/L). Amino acid substitutions in responsive forms were located throughout both structural domains of the enzyme. Half of the missense mutant forms associated with classic (early-onset) Fabry disease and a majority (90%) associated with later-onset Fabry disease were responsive. In cultured fibroblasts from males with Fabry disease, the responses to DGJ were comparable to those of lymphoblasts with the same mutation. Importantly, elevated GL-3 levels in responsive Fabry fibroblasts were reduced after DGJ incubation, indicating that increased mutant α-Gal A levels can reduce accumulated substrate. These data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations. Competing interests: All authors are shareholders, current or former employees of Amicus Therapeutics. References to electronic databases: Fabry disease: OMIM 310500. α-Galactosidase A: EC 3.2.1.22. GLA: GenBank gDNA: X14448.1.     

Enzyme replacement therapy in Japanese Fabry disease patients: The results of a phase 2 bridging study

Summary Fabry Disease (α-galactosidase A deficiency) is an X-linked hereditary disorder leading to the pathological accumulation of globotriaosylceramide (GL-3) in lysosomes, particularly in the vascular endothelium of the kidney, heart and brain. We report the results of an open-label phase 2 study that was undertaken to evaluate whether ethnic differences exist that would affect agalsidase beta (Fabrazyme) treatment of Fabry patients in the Japanese population, relative to safety and efficacy. The study design mirrored the design of the completed phase 3 clinical trial that led to approval of the product agalsidase beta. The 13 Japanese, male Fabry patients enrolled in the study received the enzyme replacement therapy over a period of 20 weeks as biweekly infusions. All selected efficacy end points showed improvements that were comparable with findings from the phase 3 study. These improvements included reductions of GL-3 accumulation in both kidney and skin capillary endothelial cells to (near) normal levels (92% of patients). Kidney and plasma GL-3 levels decreased by 51.9% and 100%, respectively, by ELISA. Renal function remained normal. Fabry-associated pain, and quality of life, showed improvement over baseline in multiple categories. Related adverse events were mild or moderate in intensity and mostly infusion-associated (fever and rigors). As expected, IgG antibody formation was observed in 85% of the patients, but had no effect on treatment response. These results suggest that treatment with agalsidase beta is safe and effective in Japanese patients with Fabry disease. With regard to safety and efficacy, no differences were observed as compared to the caucasian population.     

两个新发现的致Fabry病基因突变位点

目的研究中国汉族人群Fabry病的致病基因突变位点,分析基因型与临床表现型的关系。方法临床诊断的Fabry病先证者两例,分别收集各先证者及其家系成员的DNA样本。聚合酶链式反应扩增DNA样本的7个外显子及其相邻序列,对扩增产物进行测序分析。对基因改变阳性者,分析其临床表现与基因改变的关系。结果在两个先证者的5’非蛋白质编码区分别发现G1168A、G1170A突变,而正常对照在该位点未发现异常。在一先证者的家族成员中,发现了3个致病突变携带者。而在另一先证者的家系成员中,未发现致病突变携带者,故该先证者为一散发病例。女性杂合子有一定程度的酶活性残留,其临床症状轻于男性患者。结论GLA基因的5’非蛋白质编码区参与了该病的发生。性别在一定程度上决定了该病的临床表现。     

Fabry disease among hypertrophic cardiomyopathy of genetic origin

Primary hypertrophic cardiomyopathy is a relatively frequent disease (1/500) which results from a mutation in a gene encoding a sarcomeric protein. In a series of 184 cases, nearly half (46 %) were secondary to a mutation in one of the 4 following genes : MYBPC3, MYH7, TNNI3, TNNT2. In Fabry disease, an exclusive or nearly exclusive cardiac expression is possible and referred to as "cardiac variant". The hypertrophic cardiomyopathy of Fabry disease is usually unspecific. Two series reported a prevalence of Fabry disease of about 6% among male cases. An Italian series of 34 female cases with hypertrophic cardiomyopathy demonstrated that it was feasible to diagnose Fabry disease in females by screening for specific lesions in myocardial biopsies. We detected a patient who initially presented with a common hypertrophic cardiomyopathy except that his ECG showed depression of ST segment and inversion of T wave in leads D1, VL and in precordial leads. The family history revealed several affected relatives and female carriers. In conclusion, an isolated common hypertrophic cardiomyopathy may be secondary to Fabry disease. Male patients should be screened systemically for enzyme defect except in cases of father-to-son transmission. In females, an affected male relative should be searched for screening or the GLA gene should be sequenced. It is important to think about a putative Fabry disease in cases with hypertrophic cardiomyopathy not associated with any obvious cause.     

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。     

Alpha-galactosidase A in vascular disease

Deficiency of alpha-galactosidase A (GLA) (Fabry disease) leads to the accumulation of glycosphingolipids in the vasculature leading to multiorgan pathology. In addition to well-described microvascular disease, deficiency of GLA is also characterized by premature macrovascular events such as stroke and possibly myocardial infarction. The mechanisms by which GLA may influence macrovascular disease are unclear. A mouse model of GLA deficiency has facilitated the study of glycosphingolipid metabolism abnormalities on macrovascular end points. This review addresses some of the potential pathways by which GLA deficiency may contribute to vascular complications.     

Clinical and genetic investigation of a Japanese family with cardiac fabry disease. Identification of a novel α-galactosidase A missense mutation (G195V)

Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.     

Screening for Fabry Disease in Left Ventricular Hypertrophy: Documentation of a Novel Mutation

Background

Fabry disease is a lysosomal storage disease caused by enzyme α-galactosidase A deficiency as a result of mutations in the GLA gene. Cardiac involvement is characterized by progressive left ventricular hypertrophy.

Objective

To estimate the prevalence of Fabry disease in a population with left ventricular hypertrophy.

Methods

The patients were assessed for the presence of left ventricular hypertrophy defined as a left ventricular mass index ≥ 96 g/m² for women or ≥ 116 g/m² for men. Severe aortic stenosis and arterial hypertension with mild left ventricular hypertrophy were exclusion criteria. All patients included were assessed for enzyme α-galactosidase A activity using dry spot testing. Genetic study was performed whenever the enzyme activity was decreased.

Results

A total of 47 patients with a mean left ventricular mass index of 141.1 g/m² (± 28.5; 99.2 to 228.5 g/m²] were included. Most of the patients were females (51.1%). Nine (19.1%) showed decreased α-galactosidase A activity, but only one positive genetic test − [GLA] c.785G>T; p.W262L (exon 5), a mutation not previously described in the literature. This clinical investigation was able to establish the association between the mutation and the clinical presentation.

Conclusion

In a population of patients with left ventricular hypertrophy, we documented a Fabry disease prevalence of 2.1%. This novel case was defined in the sequence of a mutation of unknown meaning in the GLA gene with further pathogenicity study. Thus, this study permitted the definition of a novel causal mutation for Fabry disease - [GLA] c.785G>T; p.W262L (exon 5).     

一例Fabry病患者α-半乳糖苷酶基因突变和酶活性分析

目的 分析1例临床诊断的15岁典型Fabry病男性患者的临床表现、α-半乳糖苷酶A(α-GalA)基因(GLA)突变位点及其活性,并对无临床表现的患者母亲进行了相应的对照分析.方法 收集该例患者的临床资料,提取患者及其母亲、1名健康对照者的外周血基因组DNA,PCR分段扩增GLA基因的7个外显子,产物纯化后克隆入T载体进行DNA测序,检测是否存在突变位点,进一步应用荧光底物法榆测α-Gala的活性.结果 基因检测证实患者GLA基凶第7号外显子发生一个错义突变,即10036-10038位的AAG缺失(10036-10038delAAG),导致其编码的第374位的赖氨酸和第375位甘氨酸突变成精氨酸,该突变位点经国内外文献检索未见报道.该患者为带有突变基因的半合子,母亲为携带突变基因的杂合子,健康对照者未发现突变.α-GalA酶活性检测结果显示,携带该突变位点GLA基因的患者,其α-GalA酶活性只有健康对照者的50%左右,患者母亲的α-GalA酶活性为健康对照者的70%左右.结论 对临床疑似的Fabry病患者及其亲属,进行GLA基冈突变检测,结合α-GalA酶活性检测,有助于早期筛选出家系中的其他患者,能更加深入地了解Fabry病的分子发病机制.     

Description of a new mutation in a female patient with Fabry disease

Fabry disease is caused by intracellular accumulation of glycosphingolipids in various tissues, secondary to mutations in the GLA gene (Xq22). Classically described as affecting hemizygous males with no residual alpha-galactosidase A activity, it is now known to affect both sexes, with later and less severe manifestations in females. The manifestations of this disease are systemic: neurological, cutaneous (angiokeratomas), renal, cardiovascular (left ventricular hypertrophy, valve thickening or rhythm disturbances), cochlear-vestibular, and cerebrovascular. In the absence of treatment there is progressive damage to vital organs with renal failure, stroke, heart failure or rhythm perturbations, leading to severe impairment of quality of life as well as reduced life expectancy. We describe the case of a female patient with a history of cryptogenic ischemic stroke at the age of 38 years and chronic renal failure with proteinuria, who presented to the emergency room with atrial fibrillation. The echocardiogram revealed concentric left ventricular hypertrophy, diastolic dysfunction and decreased longitudinal strain in the basal septum. In the context of a screening protocol, she was diagnosed with Fabry disease and a previously undescribed mutation was identified.     

Association between polymorphisms of endothelial nitric oxide synthase gene (NOS3) and left posterior wall thickness (LPWT) of the heart in Fabry disease

Fabry disease is an X-chromosomal storage disorder due to loss-of-function mutations of the GLA gene encoding the lysosomal enzyme α-galactosidase A. Accumulating glycosphingolipid deposits disturb the function of various cells, in particular that of myocytes, arterial smooth-muscle cells, and vascular endothelium. Hypertrophic cardiomyopathy, for example measured by left posterior wall thickness (LPWT) of the heart, represents a major component of Fabry disease morbidity in adult patients. Endothelium-derived nitric oxide (eNO), produced by eNO synthase (eNOS), is a key regulator of vessel wall function and cardiovascular homeostasis. We analysed the effect of the polymorphisms c.894G > T (p.Glu298Asp) in exon 7 and the 27 bp tandem repeat (VNTR; allele a: 4 and allele b: 5 repeats) in intron 4 of the NOS3 gene, encoding eNOS, on LPWT of 102 patients with Fabry disease. For the association analysis, the distance of each patient's LPWT value from the cohort-specific, age-dependent regression line point (expected values) was used. In the cohort of 46 male patients, LPWT mean value of the group with GG genotype at position c.894 was smaller by 1 mm than that of (GT + TT) (p = 0.058). LPWT of patients with bb was thicker by 1.4 mm than that of (ab + aa) (p = 0.022). In patients with haplotype Ga, a thinner LPWT was seen than in those with Tb (p = 0.006). While no correlation was found between the GLA genotype and LPWT, the difference of 2.44 mm between the relative LPWT mean values of the two extreme NOS3 groups corresponds to the absolute LPWT increase that an average male patient with Fabry disease experiences during about 12 years. These are the first data showing a significant association of non-GLA-derived sequence variants with the cardiac phenotype in Fabry disease that may in part explain the great phenotypic variability of the disease.     

Prognostic Indicators of Renal Disease Progression in Adults with Fabry Disease: Natural History Data from the Fabry Registry

Background and objectives: These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease.Design, setting, participants, & measurements: Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included.Results: Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > −1 ml/min per 1.73 m² per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P < 0.0001). Patients were grouped into quartiles based on averaged UP/Cr; renal function in men declined more rapidly with higher UP/Cr, with the steepest declines observed in men with UP/Cr > 1.5 (mean eGFR slope, −5.6 ml/min per 1.73 m² per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, −1.3 ml/min per 1.73 m² per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function.Conclusions: Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease.Fabry disease is an X-linked lysosomal storage disorder, characterized by decreased or absent activity of lysosomal α-galactosidase A (1), with progressive accumulation of globotriaosylceramide (GL-3) and other glycosphingolipids within many cells, including the vascular endothelium. In the kidney, this accumulation is observed in all glomerular cells, peritubular capillaries, vascular endothelial and smooth muscle cells, and distal tubular cells (2–4). Progressive GL-3 accumulation is associated with life-threatening complications, renal failure, cardiovascular dysfunction, and stroke (1,5).Whereas the development of enzyme replacement therapy (ERT) represented a major advance in treating Fabry disease (6–8), patients with advanced renal disease have poorer clinical outcomes in response to ERT than do Fabry patients with milder disease (3,9). A better understanding of the natural history of Fabry disease may provide valuable information about the progressive loss of kidney function and risk of progressing to ESRD, as well as providing an appropriate context for evaluating response to therapy. The Fabry Registry is an observational database that compiles clinical and laboratory data on patients with Fabry disease. Longitudinal data from the Fabry Registry were analyzed to characterize changes in kidney function and cardiac and cerebrovascular events over time in adult Fabry patients before the initiation of ERT.     

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.     

Cardiac involvement in Fabry's disease - typical disease course and diagnostic problems

Fabry disease is a rare X-linked recessive lysosomal storage disease, which can cause a wide range of systemic symptoms. A deficiency of the enzyme alpha galactosidase A due to mutation causes a glycolipid to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of proper heart function. Wide range of symptoms makes diagnosis difficult. We present a case of a 43 year-old male with typical Fabry disease.     

Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease

Summary Fabry disease is an X-linked disorder of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme α-galactosidase A. This deficiency leads to the progressive accumulation, in lysosomes of visceral tissues and in body fluids of hemizygotes, of the glycosphingolipids globotriaosylceramide (CTH, Gb₃ or GL-3) and galabiosylceramide (CDH) and to a lesser extent the blood group AB and B related glycolipids. Elevated levels of the glycosphingolipids are found in the urine of hemizygous males with the classic phenotype, but it is not known whether all symptomatic or asymptomatic heterozygotes have elevated levels. We have therefore measured CTH and CDH quantitatively in a multiplex assay using tandem mass spectrometry in urine from a large cohort (44) of genetically proven or obligate heterozygotes including four with the N215S mutation, from classic hemizygotes (28), from cardiac variant hemizygotes with the N215S mutation (6) and from normal controls. The levels of CTH and CDH were related to both creatinine and sphingomyelin. Urinary CTH was elevated in all 28 classic hemizygotes but only in 4/6 of the cardiac variants. The level was within or just above the normal reference range in the four individuals heterozygous for the N215S mutation but was elevated in 38/40 of the other heterozygotes. Similar results were obtained for CDH, except that only 34/40 heterozygotes had an elevated level. The level of CDH was not elevated in the four heterozygotes and 4/6 of the hemizygotes for the N215S mutation. Combining the levels of CTH and CDH did not improve the discrimination of heterozygotes from controls. The ratio of CDH to CTH was higher in heterozygotes than in hemizygotes. Measurement of urinary CTH gave the best discrimination of heterozygotes from controls.     

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.     

Fabry disease. Clinical and genetic aspects. Therapeutic perspectives

INTRODUCTION: This review presents the clinical and genetic aspects of Fabry disease, along with recent advances in research. CURRENT KNOWLEDGE AND KEY POINTS: Fabry disease is an X-linked inborn error of metabolism due to a deficient activity of the lysosomal enzyme alpha-galactosidase A. The enzymatic defect leads to the systemic accumulation of neutral glycosphingolipids in plasma and tissues. Clinical manifestations in affected hemizygous males are primarily due to progressive disease of small vessels, including angiokeratoma, autonomic dysfunction, and lifelong debilitating pain. Renal failure and vasculopathy of the heart and brain lead to early demise in adulthood. Demonstration of alpha-galactosidase A deficiency in leukocytes or plasma is the definitive method for the diagnosis of affected hemizygous males. Most female carriers are clinically symptomatic, they may present isolated acroparesthesia, cardiac symptoms, or the characteristic benign corneal dystrophy. Due to random X-chromosomal inactivation, enzymatic detection of carriers is often inconclusive. A reliable molecular test for detection of heterozygosity is therefore highly desirable for accurate genetic counselling. The GLA gene has been mapped to chromosome Xq22, and cloned. Several studies have shown the molecular heterogeneity of the disease. Currently, no standard treatment exists for Fabry disease. Symptomatic treatment is provided as appropriate. In addition, renal transplantation or dialysis is available for patients experiencing end-stage renal failure. FUTURE PROSPECTS AND PROJECTS: The ability to produce high doses of recombinant alpha-galactosidase A in vitro has opened the way to preclinical studies in the mouse model and led to the development of the first clinical trials with enzyme replacement therapy in patients with Fabry disease.