伴发骨骼肌损害的一例幼年起病女性Fabry病患者及其家系研究

发布时间：2018-09-13 14:18

【摘要】：研究背景和目的法布里病(Fabry disease)或安德森一法布里病(Andeson-Fabry disease),是由于编码α-半乳糖苷酶A (α-galactosidase A, α-Gal A)的基因(GLA基因)突变导致患者体内α-半乳糖苷酶A活性下降或者缺失的一种溶酶体贮积病。在过去较长时间该病被认为是隐性遗传,携带有GLA突变基因的女性不发病。近年来发现女性Fabry病杂合子不仅仅是携带者,也可以表现出多个组织器官的受累。关于Fabry病骨骼肌病理学特点的报道还很少,该病导致的骨骼肌受损在临床上也没有引起足够的重视。报道1例幼年起病,伴有骨骼肌损害的女性Fabry病患者及其家系,介绍Fabry病患者骨骼肌受累的病理学特点,复习文献并探讨女性Fabry杂合子的发病机制。方法搜集患者及其家系成员的详细临床资料；取先证者及其父亲的肱二头肌组织行骨骼肌病理学检查；抽取先证者及其父亲外周血提取白细胞,测定测定其外周血白细胞α-半乳糖苷酶A (α-Gal A)的活性；并对其家系成员抽取外周血,提取外周血DNA,设计引物,对其GLA基因的7个外显子及其邻近区域进行分段PCR扩增,产物纯化后送至公司进行DNA测序分析。查阅复习关于Fabry病的相关文献。结果①先证者为13岁女性,6年前开始出现双足发作性刺疼,寒冷或高热环境会诱发或加重,疼痛时服用卡马西平后约半小时能缓解,后逐渐出现乏力、不易耐受疲劳,体格检查示双侧三角肌、肱二头肌、肱三头肌及髂腰肌、股四头肌肌力Ⅳ级,其余肌力肌张力均正常；其父自幼无汗,躯干部有散在分布的皮肤血管角质瘤,30年前开始出现双足发作性刺痛,6年前患心肌梗塞,自此出现活动后易心慌、胸闷,5年前患脑梗塞,2年前再次出现脑梗塞,遗留有左侧肢体活动欠灵活；另外其家系中还有3名男性、5名女性有Fabry病症状,主要包括皮肤血管角质瘤,皮肤无汗,足部发作性疼痛,肾脏损害,心肌梗死,脑卒中等：②先证者肌肉活检组织病理学检查发现除了肌间血管内皮细胞以及肌间神经内可见有轻度的PAS染色阳性物质分布外,结合dystrophin免疫组化染色,发现肌膜下、肌间质内均有大量团块状或颗粒样的PAS阳性物质沉积,其父肌肉活检组织病理检查未见明显异常。③先证者及其父亲外周血α -GalA舌性分别为15.27nmol/1h/mg,0.33nmol/1h/mg(正常值22.9-145.7nmol/1h/mg),均明显低于正常值。④同人类基因组数据库Genbank中公布的序列(NM_000169.2)进行对比分析,发现先证者GLA基因检测显示Exon 6 c.837GC p. Q279H错义突变,为已知致病突变,该突变来源于其父亲,其家族中其他患者也携带有相同的突变基因。结论Fabry病的不应再被认为是X连锁隐性遗传,而应仅仅是X连锁遗传。由于偏斜性的X染色体失活方式和细胞之间不能进行α -GalA活性互补,导致Fabry女性杂合子也可以发病。Fabry病在女性患者中早期便可以出现骨骼肌受累。在骨骼肌中,三聚己糖神经酰胺不仅仅沉积于肌间血管内皮细胞以及肌间神经内,也可在肌浆内以及肌膜外大量沉积。
[Abstract]:BACKGROUND AND OBJECTIVE Fabry disease or Andeson-Fabry disease is a lysosomal storage disease in which mutations in the gene encoding alpha-galactosidase A (GLA) cause a decrease or deletion of alpha-galactosidase A activity in patients. In recent years, it has been found that female heterozygotes of Fabry's disease are not only carriers, but also can show multiple organ involvement. There are few reports about the pathological characteristics of skeletal muscle in Fabry's disease, and the skeletal muscle damage caused by the disease has not been caused clinically. This paper reports a case of female Fabry's disease with skeletal muscle damage and its family, introduces the pathological characteristics of skeletal muscle involvement in Fabry's disease, reviews the literature and explores the pathogenesis of female Fabry heterozygotes. Biceps muscle tissues were examined by skeletal muscle pathology; white blood cells were extracted from the peripheral blood of the proband and his father, and the activity of alpha-galactosidase A (alpha-Gal A) in the peripheral blood white blood cells was measured; peripheral blood DNA was extracted from the peripheral blood of the family members, and primers were designed to separate the seven exons of GLA gene and their adjacent regions. Results The proband was a 13-year-old woman. Paroxysmal tingling of the feet began six years ago. Cold or hot environment could induce or aggravate the pain. Carbamazepine could relieve the pain about half an hour after taking it, and then gradually appeared fatigue. Resistant to fatigue, physical examination showed bilateral deltoid, biceps brachii, triceps brachii and iliopsoas, quadriceps femoris muscle strength grade IV, the rest of the muscle tension were normal; his father from childhood no sweat, scattered in the trunk of cutaneous angiokeratoma, 30 years ago began to show bipedal tingling, six years ago suffered from myocardial infarction, since the emergence of activity prone to Panic, chest tightness, cerebral infarction 5 years ago, cerebral infarction 2 years ago again, left limb mobility is not flexible; in addition, there are 3 men, 5 women with Fabry's disease symptoms, mainly including cutaneous angiokeratoma, sweatless skin, foot paroxysmal pain, kidney damage, myocardial infarction, stroke, etc. (2) The proband muscle biopsy Histopathological examination revealed that there was a slight distribution of PAS positive substances in the endothelial cells and the nerves of the muscles, and combined with dystrophin immunohistochemical staining, a large number of mass or granular PAS positive substances were deposited in the interstitium of the muscles under the sarcolemma. Pathological examination of the paternal muscles showed no significant difference. Normal values were 22.9-145.7 nmol/1 h/mg (normal value, 22.9-145.7 nmol/1 h/mg), which were significantly lower than the normal values. Fourthly, the GLA gene of the proband was found to be wrong in Exon 6 c.837 GC p.Q279H by comparing with the sequence published in Genbank (NM_000169.2). Conclusion Fabry's disease should not be regarded as X-linked recessive inheritance, but only X-linked inheritance. Due to the skewed X-chromosome inactivation pattern and the inactivation of alpha-GalA between cells, it is impossible to complement the alpha-GalA activity of Fab. Fabry's disease can occur early in women. In skeletal muscle, trihexose-ceramide is not only deposited in the endothelial cells of the intermuscular vessels and the intermuscular nerves, but also in the intramuscular and extramuscular plasma.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R725.9

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