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Sickle Cell Disease

Sickle cell disease is a common genetic disorder. This week we'll discuss the disease and its implications for anesthesia. Today we'll discuss the genetics of the disorder.

1.  How was sickle cell disease first noted?
2.  What are the genotypes which produce the disease?
3.  Are there other genetic factors that contribute to the severity of the disease process?

镰状细胞病是一种常见的遗传病。本周我们讨论与本病麻醉相关的一些问题。

1、  镰状细胞病最初是如何发现？
2、  导致本病的基因型是什么？
3、  有没有其他的遗传因素对疾病严重性造成影响？

参考答案：

1、  镰状细胞病最初是如何发现？

James Herrick在1911年首次报道了异常形状的红细胞即镰状细胞，但是直到1947年，Linus Pauling通过电泳技术发现代表该病的分子学差异[1]。在1957年，β球蛋白链基因发生突变（11号染色体，密码子6），取代加压素为谷氨酸，结果被认为这是镰状细胞病的原因[2]。

2、  导致本病的基因型是什么？

个体从母体的孟德尔常染色体隐性遗传获得一个β链基因。该基因型影响疾病的表达和发展。

镰状细胞特性的基因型即一个为镰状一个为正常的β基因，通常是无症状的。镰状细胞特性紊乱有时会表现为血尿、尿崩（？isothenuria，不能浓缩尿）、罕见的血管阻塞性痛危象和预期寿命正常。

镰状细胞病的基因型包括一个镰状β基因和下列之一：

  另一个镰状β基因
  一个β+或β-的地中海贫血基因
  一个血红蛋白C基因
  一个血红蛋白D基因
  一个血红蛋白E基因

这些基因型中，血红蛋白SS（血红蛋白镰状β/血红蛋白镰状β）结果最严重，预期寿命减少20年以上。血红蛋白SC或S-β+地中海贫血的患者相对罕见血管阻塞性痛危象，而S-β-地中海贫血的患者相对发生率较高。

3、  有没有其他的遗传因素对疾病严重性造成影响？

许多联合的等位基因，紧簇于11号染色体β-珠蛋白等位基因，在成熟分裂期间或之后维持镰状基因的自然关系。这些等位基因与5种不同的单倍体（Benin，Bantu，Cameroon，Indian和Senegal）有关，从而通过改变血管张力而影响镰状细胞病的严重程度，同时与其他血液共存病（维勒布兰德氏因子、α地中海贫血、X因子）和红细胞容积调控相关的疾患有关[3]。此外，如同其他的同原染色体一样，与11号常染色体遗传有关的其他因素也可对该疾患的发展造成影响。

How was sickle cell disease first noted?

While abnormal sickle shaped erythrocytes were first reported in 1911 by James Herrick, the molecular differences characterizing the disease were not determined until 1947 by Linus Pauling with the use of electrophoresis (1). By 1957, the substitution of valine for glutamic acid caused by a mutation (11th chromosome, codon 6) of the beta-globin chain gene was recognized as the cause of sickle cell anemia (2).

What are the genotypes which produce the disease?

Individuals inherit one beta chain gene from each parent in a mendelian autosomal recessive pattern. The resulting genotype affects the expression and the course of the disease.

The genotype of sickle cell trait, i.e. one sickle and one normal beta gene, is essentially asymptomatic. The sickle trait disorder is expressed with an occasional episode of hematuria, isothenuria (inability to concentrate urine), a rare vaso-occlusive pain crisis, and a normal life expectancy.

The genotype of sickle cell disease includes one sickle beta gene with one of the following:

•  another sickle beta gene
•  a beta+ or beta-o thallasemia gene
•  a hemoglobin C gene
•  a hemoglobin D gene
•  a hemoglobin E gene

Of these genotypes, hemoglobin SS (hemoglobin sickle beta/hemoglobin sickle beta) has the worst outcome,with a reduction in life expectancy by more than 20 years. Patients with hemoglobin SC or S-beta+ thal have relatively infrequent episodes of vaso-occlusive pain crises, whereas S-beta-o thal has more frequent episodes.

Are there other genetic factors that contribute to the severity of the disease process?

A number of "associated alleles", which are tightly clustered sequences next to the beta-globin allele on chromosome 11, maintain their physical relationship with the sickle genes during and after meiosis. These alleles are responsible for 5 different haplotypes (Benin, Bantu, Cameroon, Indian, and Senegal), which can influence the severity of sickle cell disease by altering vascular tone, other hematologic co-morbidities (von Willebrand's Factor, alpha thalassemia, X-linked factors), and erythrocyte volume regulatory controls (3). In addition, other factors inherited on chromosome 11 as well as other chromosomes, may have an effect on the course of the disease.

References:

1.  Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science 1949;110:543-8.
2.  Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature 1957;180:326-8.
3.  Zago MA, Silva WA Jr, Dalle B, et al. Atypical beta haplotypes are generated by diverse genetic mechanisms. Am J Hematol. 2000;63:79-84.
4.  Kaaba SA, Al Fazaa L. F cells, fetal hemoglobin levels, lymphocyte subsets, and frequency of crises in sickle-cell disease in Kuwait. Ann Hematol 2000;79:291-5.


编辑：ache