【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),是由于編碼α-半乳糖苷酶A (α-galactosidase A, α-Gal A)的基因(GLA基因)突變導致患者體內(nèi)α-半乳糖苷酶A活性下降或者缺失的一種溶酶體貯積病。在過去較長時間該病被認為是隱性遺傳,攜帶有GLA突變基因的女性不發(fā)病。近年來發(fā)現(xiàn)女性Fabry病雜合子不僅僅是攜帶者,也可以表現(xiàn)出多個組織器官的受累。關(guān)于Fabry病骨骼肌病理學特點的報道還很少,該病導致的骨骼肌受損在臨床上也沒有引起足夠的重視。報道1例幼年起病,伴有骨骼肌損害的女性Fabry病患者及其家系,介紹Fabry病患者骨骼肌受累的病理學特點,復習文獻并探討女性Fabry雜合子的發(fā)病機制。方法搜集患者及其家系成員的詳細臨床資料；取先證者及其父親的肱二頭肌組織行骨骼肌病理學檢查；抽取先證者及其父親外周血提取白細胞,測定測定其外周血白細胞α-半乳糖苷酶A (α-Gal A)的活性；并對其家系成員抽取外周血,提取外周血DNA,設計引物,對其GLA基因的7個外顯子及其鄰近區(qū)域進行分段PCR擴增,產(chǎn)物純化后送至公司進行DNA測序分析。查閱復習關(guān)于Fabry病的相關(guān)文獻。結(jié)果①先證者為13歲女性,6年前開始出現(xiàn)雙足發(fā)作性刺疼,寒冷或高熱環(huán)境會誘發(fā)或加重,疼痛時服用卡馬西平后約半小時能緩解,后逐漸出現(xiàn)乏力、不易耐受疲勞,體格檢查示雙側(cè)三角肌、肱二頭肌、肱三頭肌及髂腰肌、股四頭肌肌力Ⅳ級,其余肌力肌張力均正常；其父自幼無汗,軀干部有散在分布的皮膚血管角質(zhì)瘤,30年前開始出現(xiàn)雙足發(fā)作性刺痛,6年前患心肌梗塞,自此出現(xiàn)活動后易心慌、胸悶,5年前患腦梗塞,2年前再次出現(xiàn)腦梗塞,遺留有左側(cè)肢體活動欠靈活；另外其家系中還有3名男性、5名女性有Fabry病癥狀,主要包括皮膚血管角質(zhì)瘤,皮膚無汗,足部發(fā)作性疼痛,腎臟損害,心肌梗死,腦卒中等：②先證者肌肉活檢組織病理學檢查發(fā)現(xiàn)除了肌間血管內(nèi)皮細胞以及肌間神經(jīng)內(nèi)可見有輕度的PAS染色陽性物質(zhì)分布外,結(jié)合dystrophin免疫組化染色,發(fā)現(xiàn)肌膜下、肌間質(zhì)內(nèi)均有大量團塊狀或顆粒樣的PAS陽性物質(zhì)沉積,其父肌肉活檢組織病理檢查未見明顯異常。③先證者及其父親外周血α -GalA舌性分別為15.27nmol/1h/mg,0.33nmol/1h/mg(正常值22.9-145.7nmol/1h/mg),均明顯低于正常值。④同人類基因組數(shù)據(jù)庫Genbank中公布的序列(NM_000169.2)進行對比分析,發(fā)現(xiàn)先證者GLA基因檢測顯示Exon 6 c.837GC p. Q279H錯義突變,為已知致病突變,該突變來源于其父親,其家族中其他患者也攜帶有相同的突變基因。結(jié)論Fabry病的不應再被認為是X連鎖隱性遺傳,而應僅僅是X連鎖遺傳。由于偏斜性的X染色體失活方式和細胞之間不能進行α -GalA活性互補,導致Fabry女性雜合子也可以發(fā)病。Fabry病在女性患者中早期便可以出現(xiàn)骨骼肌受累。在骨骼肌中,三聚己糖神經(jīng)酰胺不僅僅沉積于肌間血管內(nèi)皮細胞以及肌間神經(jīng)內(nèi),也可在肌漿內(nèi)以及肌膜外大量沉積。
[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.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R725.9

【相似文獻】

相關(guān)期刊論文 前10條

1 宋穎;柳曦光;李姝瑤;;1例Fabry病的臨床表現(xiàn)及電鏡觀察[J];中國麻風皮膚病雜志;2008年04期

2 李秋芬;胡云琴;魯盈;;Fabry病4例報道并文獻復習[J];中國中西醫(yī)結(jié)合腎病雜志;2007年10期

3 Marino S.;Borsini W.;Buchner S. ;N. De Stefano;謝琰臣;;Fabry病患者的彌散結(jié)構(gòu)和代謝性腦改變[J];世界核心醫(yī)學期刊文摘(神經(jīng)病學分冊);2006年10期

4 王質(zhì)剛,鄒萬忠,郝繼英,崔焱;Fabry病及文獻復習[J];中華腎臟病雜志;1999年06期

5 歐陽彥;陳楠;;Fabry病生物標志物研究進展[J];腎臟病與透析腎移植雜志;2012年05期

6 吳靜安;Fabry氏病及其眼部改變[J];實用眼科雜志;1988年12期

7 田峰,田姝,劉曉明,寇玉紅;Fabry病(附1例臨床、病理報告)[J];中風與神經(jīng)疾病雜志;2000年04期

8 羊毅,呂冰清;Fabry病肌電圖改變1例報告[J];中國臨床康復;2002年15期

9 李曉燕,謝慧君,張賢,吳晶晶;Fabry病臨床報告及病理學研究[J];臨床心身疾病雜志;2005年04期

10 閔穎君;鐘一聲;程瑜;;Fabry病的眼科表現(xiàn)[J];國際眼科雜志;2009年04期

相關(guān)會議論文 前7條

1 胡云琴;李秋芬;魯盈;;Fabry病4例報道并文獻復習[A];第十九次全國中醫(yī)腎病學術(shù)交流會論文匯編[C];2006年

2 王朝霞;張巍;袁云;黃一寧;張英;卜定方;;Fabry病的基因改變[A];中華醫(yī)學會第七次全國神經(jīng)病學學術(shù)會議論文匯編[C];2004年

3 馬紀林;陶筱娟;陳立紅;方魯;沈福娣;;Fabry病一例[A];“中華醫(yī)學會腎臟病學分會2004年年會”暨“第二屆全國中青年腎臟病學術(shù)會議”論文匯編[C];2004年

4 陳佳韻;潘曉霞;王朝暉;呂軼倫;王偉銘;任紅;張文;陳楠;;中國人群Fabry病的臨床及GLA基因突變研究[A];2007年浙滬兩地腎臟病學術(shù)年會資料匯編[C];2007年

5 陳楠;王朝暉;任紅;王偉銘;陳佳韻;王湘玲;潘曉霞;郝翠蘭;;Fabry病的臨床特征及腎臟病理分析[A];“中華醫(yī)學會腎臟病學分會2004年年會”暨“第二屆全國中青年腎臟病學術(shù)會議”論文匯編[C];2004年

6 陳楠;;Fabry病診治進展[A];中華醫(yī)學會腎臟病學分會2006年學術(shù)年會專題講座[C];2006年

7 何靈芝;魯科達;張培培;范軍芬;陳紅波;馬紅珍;;Fabry病1例報道并文獻復習[A];2012年浙江省腎臟病學術(shù)年會論文集[C];2012年

相關(guān)重要報紙文章 前1條

1 李正紅;北京協(xié)和診斷罕見Fabry病[N];科技日報;2005年

相關(guān)碩士學位論文 前1條

1 梁宗萊;伴發(fā)骨骼肌損害的一例幼年起病女性Fabry病患者及其家系研究[D];山東大學;2016年

，

本文編號：2241411