【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(dǎo)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(shí)間該病被認(rèn)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(gè)組織器官的受累。關(guān)于Fabry病骨骼肌病理學(xué)特點(diǎn)的報(bào)道還很少,該病導(dǎo)致的骨骼肌受損在臨床上也沒有引起足夠的重視。報(bào)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(xué)特點(diǎn),復(fù)習(xí)文獻(xiàn)并探討女性Fabry雜合子的發(fā)病機(jī)制。方法搜集患者及其家系成員的詳細(xì)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(xué)檢查；抽取先證者及其父親外周血提取白細(xì)胞,測定測定其外周血白細(xì)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(shè)計(jì)引物,對其GLA基因的7個(gè)外顯子及其鄰近區(qū)域進(jìn)行分段PCR擴(kuò)增,產(chǎn)物純化后送至公司進(jìn)行DNA測序分析。查閱復(fù)習(xí)關(guān)于Fabry病的相關(guān)文獻(xiàn)。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(huì)誘發(fā)或加重,疼痛時(shí)服用卡馬西平后約半小時(shí)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(dòng)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(dòng)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(xué)檢查發(fā)現(xiàn)除了肌間血管內(nèi)皮細(xì)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(tuán)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(jìn)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(cuò)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(yīng)再被認(rèn)為是X連鎖隱性遺傳,而應(yīng)僅僅是X連鎖遺傳。由于偏斜性的X染色體失活方式和細(xì)胞之間不能進(jìn)行α -GalA活性互補(bǔ),導(dǎo)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(xì)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(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R725.9

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