Moyamoya and stroke in sickle cell anemia: bad news and good news

If having unannounced painful crises that present with the quality of giant toothaches was not enough, some sickle cell anemia patients are also affected by devastating strokes. Dobson et al (page3144) have examined a subgroup among the sickle stroke victims: those with moyamoya. Moyamoya in Japanese means a cloud or puff of smoke, an apt name since the diagnostic images in the brain are an ethereal lace of small vessels. Dobson et al's paper brings bad news: this condition in sickle cell anemia patients doubles the chances for recurrent cerebral vascular events. The other side of the coin is that this condition has high frequency in Japan, where familialmoyamoya disease has been described and the gene responsible has been traced by Yamauchi et al (Stroke 2000;31:930-935) to chromosome 17q25, and multipoint linkage analysis also has indicated that the disease gene is contained within the 9-cM region of D17S785 to D17S836. Hence the cloning of this gene might occur in the near future.

Is this good news for some sickle cell anemia patients? No doubt. Because only a small percentage of sickle cell anemia patients have this complication, it is another example of themultigenic origin of the phenotype, while the basic genetic abnormality, the capacity of deoxyHbS to polymerize, is the monogenic event: the sickle globin mutation. So for a sickle cell anemia patient to express moyamoya the patient needs to carry, in addition to the β^S gene, a further genetic predisposition (traditionally called epistatasis, epistatic genes, or more recently, modifier genes). It is conceivable that the same gene (or a related gene) found in the Japanese familial form of moyamoya is involved. Nevertheless, it is bound to be a different mutational event interacting with the pleiotropic effects found in sickle cell patients. The cloning of the Japanese gene will allow the search of polymorphisms of this relevant gene (or genes) that might, if we are lucky, suggest therapeutic interventions or, at a minimum, permit for an early diagnosis of the risk and, hence, potential approaches for stopping its progression We are living in interesting times, a mixed blessing no doubt.