鐮刀形紅細胞貧血症

定義

鐮刀形紅細胞貧血症（Sickle Cell Anemia）是一種常染色體隱性基因遺傳病。患病者的血液紅細胞表現為鐮刀狀，其攜帶氧的功能只有正常紅細胞的一半。現在醫生可以用regular blood transfusion避開傷害患者的大腦來阻止這類疾病的發病，但是，迄今為止還沒有能真正治癒的藥物。

主要症狀

血紅蛋白分子結構異常的遺傳性疾病，主要症狀是貧血。病人衰弱、頭暈、氣短、心臟有雜音和脈搏增高；血液血紅蛋白（Hb）含量僅及正常人（每100毫升血15～16克）的一半；紅細胞不僅數量少而且異常；出現許多長而薄，看起來像鐮刀的新月形紅細胞。

病因

當血液脫氧合（不攜氧）時，鐮刀形細胞大大增多。這種細胞極脆，易破損造成血液血紅蛋白低水平。更嚴重的後果是某些器官的毛細血管被這些長形異常細胞堵塞，這是許多鐮刀形紅細胞貧血症病人早死的主要原因。鐮刀形紅細胞貧血病是從雙親處接受Hb突變基因的一種遺傳病。只從父母一方得到此異常基因，則僅有約1%的紅細胞鐮刀形化，這種人只有輕微的鐮刀形紅細胞貧血症症狀，如避免強烈的運動或其他使循環系統緊張的狀態，可過完全正常的生活。鐮刀形紅細胞貧血症是一種“分子病”，即分子結構、特別是蛋白質分子結構發生遺傳性變化而造成的病變。異常血紅蛋白β鏈的第6位谷氨酸被纈氨酸所代替。這個疏水胺基酸正好適合另一血紅蛋白分子β鏈EF角上的“口袋”，這使兩條血紅蛋白鏈互相“鎖”在一起，最終與其他血紅蛋白鏈共同形成一個不溶的長柱形螺旋纖維束，使紅細胞扭旋成鐮刀形。至於為什麼脫氧合血紅蛋白鐮刀形化而氧合血紅蛋白（攜氧）不鐮刀形化？可以簡單解釋為：在氧合形式中，血紅蛋白亞基的重新排列使β鏈的口袋不能接受相鄰的血紅蛋白分子。

鐮刀形細胞性貧血症由β鏈基因點突變引起

該病的主要原因是因為珠蛋白的β基因發生單一鹼基突變,正常β基因的第6位密碼子為GAG,編碼谷氨酸,突變後為GTG,編碼纈氨酸,使成為HbS.在純合子狀態,當形成HbS後,HbS在脫氧狀態下聚集成多聚體,因形成的多聚體排列方向與膜平行,與細胞膜的接觸又非常緊密,所以當多聚體達到一定量時,細胞膜便由正常的雙凹形盤狀變成鐮刀形.該細胞僵硬,變形性差,易破而溶血,造成血管阻塞,組織缺氧,損傷,壞死.在雜純合子狀態,鐮刀狀細胞則是由HbS,HbA雜合而成.患者從父母繼承了一個正常的β基因和一個異常的β基因,與α組成HbS.這種患者HbS占20%~45%,其餘為HsA.患者平時往往無症狀,因HbS濃度低在一般情況下細胞並不變形.然而在特殊缺氧條件下,紅細胞可能發生鐮變,此類型往往不需要治療,但應避免高山等缺氧環境.

鐮刀形細胞性貧血症的基因診斷可採用PCR-限制性內切酶譜分析法,先用PCR從患者基因組DNA擴增含突變位點的珠蛋白基因片段,再選擇適當的限制性內切酶水解PCR產物,根據酶切產物在電泳圖譜上的片段數量和大小做出判斷.也可與特意的寡核苷酸探針進行Southern印記雜交分析,根據雜交圖譜做出判斷.

該病目前沒有特效治療手段,主要靠輸血維持,患者多在成年前死亡.此外就是套用基因診斷做出產前診斷,降低發病率.該病在美國黑人中發病率達14%.

治療方法

1 通過移植另外一個人的健康的造血幹細胞來治癒。但是這種方法對那些很難找到一個相容性供者的人來說就沒有用了。

2 為了治療鐮刀形細胞貧血症, Sloan-Kettering的科學家們發明了一種新的工程性策略，通過結合RNA干擾以及球蛋白轉基因技術創造出一種治療性的轉基因。這種新基因有兩個功能：產生正常的血紅蛋白和抑止鐮刀形血紅蛋白的形成。治療性的基因被導入病毒載體並轉化入造血幹細胞。細胞接受這種處理後，便能產生正常的血紅蛋白。

3 一氧化氮或可減輕鐮刀形紅細胞貧血症患者痛感

吸入一氧化氮（NO）氣體，也許能減輕鐮刀形紅細胞貧血症患者的痛感。這是美國科學家最新研究成果，但仍需進一步人體臨床試驗。

鐮刀形紅細胞貧血症是一種遺傳性疾病，主要由人體內合成血紅蛋白的基因突變引起。其一奇怪特徵是，血液中的紅細胞會由正常的圓形變成鐮刀狀。醫學界傳統觀念認為，變形的紅細胞會堵塞血管，使血液和氧供應量減少，造成了溶血性貧血，並導致患者關節、四肢等部位周期性地感覺劇痛。

美國國家衛生研究所格拉德溫等人的最新研究發現，對這種痛感起重要作用的可能還有由變形紅細胞釋放進入血液的血紅蛋白。血紅蛋白存在於極易碎裂的紅細胞中，其功能是運送氧到血液中去。研究人員發現，當這些血紅蛋白以自由狀態進入血液循環後，其與一氧化氮產生反應的速度，將比在紅細胞中時快出上千倍，一氧化氮因此而被過度“清除”。

格拉德溫等人10日在網路版《自然醫學》雜誌發表論文指出，一氧化氮能夠通過鬆弛血管而調節血壓，當它被自由循環的血紅蛋白“清除”後，血管可能產生不必要的收縮，從而進一步加重患者的病痛。

這一新結果意味著，吸入一氧化氮氣體，也許可以緩解鐮刀形紅細胞貧血症患者的痛感。

英文資料

Sickle cell disease

Sickle cell disease is caused by the substitution of a single amino acid in the hemoglobin protein of red blood cells. When the oxygen content of an affected individual's blood is low(at high altitudes or under physical stree, for instance), the sickle cell hemolgobin molecules crystallize by aggregating into long rods. the crystals deform the red cells into a sickle shape. Sickling of the cells, in turn, can lead to other symptoms. The mutliple effects of a double does of the sickle cell allele are an example of pleiotropy.

The non-sickle cell counterpart of the sickle cell allele is in fact only incompletely dominant to the sickle cell allele at the level of the organism. Heterozygotes--carriers of a single sickle cell allele--are said to have sickle cell trait. Such people are usually healthy, although a fraction suffer some symptoms of sickle cell disease when there is an extended reduction of blood oxygen.

Sickle-cell disease or sickle-cell anaemia (or anemia) is a blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in their restricted movement through blood vessels, depriving downstream tissues of oxygen. The disease is chronic and lifelong: individuals are most often well, but their lives are punctuated by periodic painful attacks and a risk of various other complications. Life expectancy is shortened, with older studies reporting an average life expectancy of 42 and 48 years for males and females, respectively.[1]

Sickle-cell disease occurs more commonly in people (or their descendants) from parts of sub-Saharan Africa, where malaria is or was common, but it also occurs in people of other ethnicities. This is because those with one or two alleles of the sickle-cell disease are resistant to malaria since the sickle red blood cells are not conducive to the parasites - in areas where malaria is common, there is a survival value in carrying the sickle-cell genes.

History

This collection of clinical findings was unknown until the explanation of the sickle cells in 1904 by the Chicago cardiologist and professor of medicine James B. Herrick (1861-1954) whose intern Ernest Edward Irons (1877-1959) found "peculiar elongated and sickle shaped" cells in the blood of Walter Clement Noel, a 20 year old first year dental student from Grenada after Noel was admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks". Noel completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.[14]

The disease was named "sickle-cell anaemia" by Vernon Mason in 1922. In retrospect some elements of the disease had been recognized earlier: a paper in the Southern Journal of Medical Pharmacology in 1846 described the absence of a spleen in the autopsy of a runaway slave. The African medical literature reported this condition in the 1870s where it was known locally as ogbanjes ("children who come and go") because of the very high infant mortality rate caused by this condition. A history of the condition tracked reports back to 1670 in one Ghanaian family.[15] Also, the practice of using tar soap to cover blemishes caused by sickle-cell sores was prevalent in the African American community.[citation needed]

Linus Pauling and colleagues were the first, in 1949, to demonstrate that sickle cell disease occurs as a result of an abnormality in the haemoglobin molecule. This was the first time a genetic disease was linked to a mutation of a specific protein, a milestone in the history of molecular biology.

The origin of the mutation that led to the sickle-cell gene was initially thought to be in the Arabian peninsula, spreading to Asia and Africa. It is now known, from evaluation of chromosome structures, that there have been at least four independent mutational events, three in Africa and a fourth in either Saudi Arabia or central India.[16] These independent events occurred between 3,000 and 6,000 generations ago, approximately 70-150,000 years.