Fabry病累及心脏的临床和影像学特征

目的：分析和总结Fabry病患者心脏受累的临床表现和影像学特征,旨在提高对该病的认识和诊断。材料与方法经病理证实Fabry病累及心脏的1例男性49岁患者,先后行心电图、超声心动图、肾小球滤过率(GFR)测定、选择性冠状动脉造影、主动脉增强CT及磁共振(MRI)检查。结果患者心电图示左心室高电压、一度房室传导阻滞和ST-T改变。超声心动图示左心室壁普遍增厚,左室流出道梗阻,二尖瓣SAM征(+)。双肾肾小球滤过率(GFR)明显减低,双肾摄取及清除功能明显减低。主动脉增强CT未见夹层等异常征象,双肾动脉未见狭窄。冠状动脉造影未见冠状动脉狭窄或阻塞性病变。MRI示左心房扩大,左心室心肌肥厚,延迟扫描示室间隔、左心室前壁及下后壁基底段肌壁间异常强化。结论Fabry病临床表现多样,综合临床病史、其他系统受累症状及MRI多序列成像,有助于该病的诊断与鉴别诊断。     

Inner ear pathology of alpha-galactosidase A deficient mice,a model of Fabry disease

Objective

Fabry disease is characterized by genetic alpha-galactosidase A deficiency, resulting in accumulation of glycolipids (GL-3) and tissue damage. Hearing loss is also common and attributed to GL-3 accumulation in the inner ear. The only reported histological studies dealt with murine and human specimens. Accordingly, histopathological studies of the cochlea were performed on an alpha-galactosidase A deficient murine model of Fabry disease, using C57BL6/J mice as the controls.

Methods

The hearing ability was evaluated using the ABR threshold, while cochlear specimens were observed light microscopically and ultrathin temporal bone sections by TEM.

Results

HE staining showed no accumulation of GL-3 or abnormal cochlear morphology in the alpha-galactosidase A deficient mice, but toluidine blue staining and TEM revealed GL-3 accumulation in the stria vascularis and kidney. No GL-3 accumulation was detected in the C57BL6/J controls by either HE staining or TEM. The alpha-galactosidase A deficient mice and the controls showed no clear differences in the ABR threshold (hearing acuity), but for older animals the threshold was higher in the C57BL6/J controls.

Conclusion

In summary, although the alpha-galactosidase A deficient mice showed no clear hearing loss, GL-3 accumulation was demonstrated in the cochlea.     

α-半乳糖苷酶A活性检测与Fabry病诊断筛查

目的:建立α-半乳糖苷酶A(α-GalA)活性的检测方法,为Fabry病的诊断和筛查提供依据。方法:分别采用外周血粒细胞和干燥血滴滤纸片(干血片)检测11个家系15例Fabry病患者和30名健康者的α-GalA活性,检测采用底物荧光法。比较Fabry病患者组与健康对照组间、干血片法不同保存时间组间的酶活性,并建立酶活性正常参考范围,计算2种检测酶活性方法的灵敏度。结果:正常人干血片酶活性为(3.68±0.98)nmol/(ml·h),粒细胞酶活性为(46.21±8.56)nmol/(h·mg),两者正常参考范围分别为≥1.68nmol/(ml·h)、≥25.45nmol/(h·mg)。男性半合子患者酶活性显著下降(P<0.001),干血片酶活性值<0.001)。结论:干血片检测酶活性更简易、快速、经济,便于保存运输,可用于高危人群筛查,外周血粒细胞酶活性测定对女性杂合子灵敏度更高,测定值更精确,适于家系筛查研究。酶活性检测可有效诊断和筛查男性半合子Fabry病患者。     

14例Fabry病肾损害的临床、病理及基因突变特点的分析

目的 探讨Fabry病肾损害的临床病理及α-半乳糖苷酶A(α-Gal A)基因(GLA 基因)突变的特点.方法 回顾性分析14例Fabry病患者的临床、肾脏病理及GLA基因突变等特点.结果 Fabry病肾损害在肾活检患者中检出率为0.074％,平均确诊年龄(30.57±9.32)岁,男∶女=2.5∶1.尿蛋白量中位数为1.71 g/24 h[(0.32～ 4.71)g/24 h].5例有血尿,4例有肾功能受损,肾外受累的表现以血管角质瘤最多见(10/14),其次为心脏病变(6/14).经典型患者9例,迟发型5例,其中6例有肾脏病家族史.肾脏病理光镜下可见明显的肾小球细胞空泡变性,部分患者可见硬化的肾小球.电镜下2例女性患者为部分足细胞内有髓磷脂样小体形成,其余病例所有足细胞内均可见髓磷脂样小体.4例测定α-Gal A活性的先证者均低于正常值.12例先证者进行了GLA基因突变分析,11例发现有GLA基因突变.3个新突变为碱基插入或缺失突变,临床表型均为经典型Fabry病.大多数迟发型患者携带的基因突变位于酶结构的包埋区或部分包埋区(3/11).在已证实的GLA基因突变中,携带I91T、R112H、Q312H的先证者主要表现为“迟发型”;携带W162X、F169S、S201F、N272K及L310R的先证者均表现为“经典型”.结论 本组Fabry病肾损害患者占肾活检的0.074％,常伴有血管角质瘤及心脏受累,且不同的GLA基因突变可能与患者的表型密切相关.     

Young woman with recurrent ischemic strokes diagnosed as Fabry disease: lessons learned from a case report

Several epidemiologic studies suggest that Fabry disease should be considered in young patients with cryptogenic stroke. We report a case of a young woman presenting with recurrent ischemic strokes who was finally diagnosed with Fabry disease after impaired kidney function had been identified. Fabry disease should be considered in unexplained cases of first or recurrent strokes in young patients disregarding the gender of the patient, especially when chronic kidney disease and/or proteinuria are present. Renal function should be closely monitored in patients with strokes and followed up after the event. In this case, intravenous thrombolysis was performed after the second ischemic event. No other case of thrombolysis for ischemic stroke in Fabry disease has been described in the literature.     

Non-invasive high-risk screening for Fabry disease hemizygotes and heterozygotes

The most appropriate time for screening for Fabry disease (FD) is school age. For this reason, we developed non-invasive methods for measuring urinary alpha-galactosidase A (alpha-gal A) protein, using enzyme-linked immunosorbent assay (ELISA), and for globotriaosylceramide (GL-3), using tandem mass spectrometry (MS/MS). We measured these two biomarkers in the urine of previously diagnosed FD hemizygotes and heterozygotes, and in controls. All the classic FD hemizygotes were clearly distinguished from controls by either method alone, and combining the two assays produced 96% sensitivity for detecting heterozygotes. To assess the utility of these methods for screening school children and adults at high risk of FD, a pilot study was conducted. To distinguish FD from 432 controls, cut-off values for alpha-gal A protein and GL-3 were set at the 5th and 95th centile values of the controls, respectively. Among the high-risk patients, the measurements exceeded the cut-off values for both biomarkers in male and female subjects and were strong indicators for Fabry hemizygotes and heterozygotes. However, we recommend that if the results of the first measurements exceed the cut-off values for only one of these biomarkers, another urine sample should be requested for re-assay to confirm the result.     

Fabry disease caused by the GLA p.Phe113Leu (p.F113L) variant: Natural history in males

Background, aims and methodsThe α-galactosidase gene (GLA) c.337T>C/p.Phe113Leu variant was originally described in patients with late-onset cardiac forms of Fabry disease (FD), who had residual α-galactosidase activity. It has since emerged as the most commonly reported GLA variant in Portuguese subjects diagnosed with FD but is also prevalent in the Italian population, where two boys carrying the GLA Leu113 allele were identified in a large-scale newborn screening program, the variant allele segregating in both cases with the same surrounding haplotype. To further delineate the genotype-phenotype correlations of this GLA variant, we have reviewed the natural history and clinical phenotypes of 11 symptomatic Portuguese males, from 10 unrelated families originating from several different areas in mainland Portugal and Madeira Island, who were diagnosed with FD associated with the GLA Leu113 allele in a diversity of clinical and screening settings. Nine of the patients were the probands of their respective families. To test whether the GLA Leu113 allele inherited by the 10 Portuguese and the two Italian families resulted from independent mutational events, we have additionally performed a haplotype analysis with 5 highly polymorphic, closely linked microsatellite markers surrounding the GLA gene.Results and conclusionsHemizygosity for the GLA Leu113 variant allele is associated with a late-onset form of FD, invariably presenting with severe cardiac involvement. Clinically relevant cerebrovascular and kidney involvement may also occur in some patients but the pathogenic relationship between the incomplete α-galactosidase deficiency and the risks of stroke and of chronic kidney disease is not straightforward. The observation that the Leu113 allele segregated within the same GLA microsatellite haplotype in both the Portuguese and Italian families suggests its inheritance from a common ancestor.     

Screening of Fabry disease in patients with end-stage renal disease of unknown etiology: the first Thailand study

We aimed to explore the prevalence of Fabry disease in Thai patients who were diagnosed with end-stage renal disease (ESRD) of an unknown origin. Venous blood samples were collected from ESRD patients for biochemical and molecular studies. Alpha-galactosidase A (α-GAL A) screening was performed from dried-blood spots using fluorometry. Molecular confirmation was performed using DNA sequencing of the GLA gene. A total of 142 male and female patients were included in this study. Ten patients (7.04%) exhibited a significant decrease in α-GAL A activity. There were no definitive pathogenic mutations observed in the molecular study. However, four patients revealed a novel nucleotide variant at c.1 -10 C>T, which was identified as a benign variant following screening in the normal population. In conclusion, the α-GAL A assay utilizing dried-blood spots revealed a significant false positive rate. There was no definitive Fabry disease confirmed in Thai patients diagnosed with ESRD of unknown etiology.     

三个Fabry病家系GLA基因突变与临床表型

目的 分析3个Fabry病家系GLA基因突变及其与临床表型的关系.方法 应用PCR结合DNA测序技术,检测先证者及相关成员GLA基因编码序列与剪切位点DNA序列变异,分析致病性突变与临床表型关系.结果 在家系1先证者GLA基因第5外显子中发现1个未经报道的错义突变c.797A＞C(D266A),家系2先证者GLA基因第5外显子中发现1个错义突变c.644A＞G(N215S),家系3先证者GLA基因第2外显子中发现1个无义突变c.355C＞T(Ql19X).家系1与家系3先证者主要表现为皮肤损害和慢性肾功能不全,家系2先证者临床则以肥厚性心肌病为特点.结论 首次发现的GLA基因c.797A＞C(D266A)突变是第266位密码子第6个被证实的错义突变,已报道的另5种突变均有致病性,在正常非相关对照中未发现该突变,提示GLA基因c.797A＞C突变很可能是该家系的致病原因.N215S和Q119X系首次发现于中国Fabry病家系的突变.GLA基因不同位点的突变具有较为显著的表型差异.