Veloso Valeria Soares Pigozzi, Ataides Thiago Lacerda, Canziani Maria Eugênia Fernandes, Veloso Mariana Pigozzi, da Silva Nilzio Antônio, Barreto Daniela Veit, Pereira Edna Regina Silva, de Moura Luiz Antonio Ribeiro, Barreto Fellype Carvalho
Department of Internal Medicine, Universidade Federal de Goiás, Goiânia, Brazil.
Nephron. 2018;138(2):147-156. doi: 10.1159/000479895. Epub 2017 Sep 12.
BACKGROUND/AIMS: Fabry disease (FD), an X-linked lysosomal storage disorder, leads to accumulation of globotriaosylceramide. Screening in dialysis patients may identify genetic variants of unknown clinical significance. We aimed to characterize the pathogenicity of a novel GLA gene mutation identified during hemodialysis screening and the histologic findings of early Fabry nephropathy.
One out of 108 male hemodialysis patients screened for FD presented low α-galactosidase A activity. A novel missense mutation (p.G35V) in the GLA gene was detected. Family screening identified 11 additional cases (8 women). Clinical investigation was conducted in 10 patients (index case and 9 relatives). Pathogenicity of the new mutation was investigated by clinical and laboratory tests, cardiac and cranial magnetic resonance imaging, and kidney biopsy.
Cardiac manifestations were detected in most patient from both genders, such as left ventricular hypertrophy and short PR interval. White matter lesion was present in 3 women. Pulvinar lesion of the thalamus and ischemic stroke were detected in male patients. Abnormal glomerular filtration rate (GFR) and/or albuminuria were present in 5 patients (3 women). Renal biopsies (n = 7) revealed globotriaosylceramide deposits in different cell types and foot processes effacement in all patients, including women with normal albuminuria. Despite a normal GFR, tubulointerstitial fibrosis ranging from 5 to 20% was present in young women and men with normal or high albuminuria, respectively.
The novel missense mutation p.G35V leads to severe systemic manifestations of FD in men and women. Kidney histological changes, including tubulointerstitial fibrosis, may predate albuminuria and GFR changes in adult women. Novel non-invasive markers are required for early detection of Fabry nephropathy.
背景/目的：法布里病（FD）是一种X连锁溶酶体贮积症，可导致球三糖神经酰胺蓄积。对透析患者进行筛查可能会发现临床意义不明的基因变异。我们旨在确定在血液透析筛查中发现的一种新的GLA基因突变的致病性以及早期法布里肾病的组织学表现。
在108名接受FD筛查的男性血液透析患者中，有1名患者的α-半乳糖苷酶A活性较低。检测到GLA基因中的一种新的错义突变（p.G35V）。家族筛查又发现了11例（8名女性）。对10名患者（索引病例和9名亲属）进行了临床调查。通过临床和实验室检查、心脏和头颅磁共振成像以及肾活检研究了新突变的致病性。
大多数男女患者均有心脏表现，如左心室肥厚和PR间期缩短。3名女性存在白质病变。男性患者检测到丘脑枕部病变和缺血性中风。5名患者（3名女性）存在肾小球滤过率（GFR）异常和/或蛋白尿。肾活检（n = 7）显示，所有患者（包括蛋白尿正常的女性）的不同细胞类型中均有球三糖神经酰胺沉积，且足突消失。尽管GFR正常，但蛋白尿正常或升高的年轻女性和男性分别存在5%至20%的肾小管间质纤维化。
新的错义突变p.G35V可导致男性和女性出现严重的FD全身表现。肾脏组织学改变，包括肾小管间质纤维化，可能在成年女性蛋白尿和GFR改变之前出现。早期检测法布里肾病需要新的非侵入性标志物。
