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To determine the origin of sickle cell anemia (SS) in India, we analyzed haplotypes of the beta gene cluster in beta S-carrying individuals belonging to tribal populations living in the Nilgiris region of southern India and complemented the available data on tribes of east-central India. We found that in the Nilgiris tribes chromosomes bearing the beta S gene are linked in 91% of the cases to the "Asian" (Arab-Indian) haplotype (although 25% of the haplotypes had the epsilon polymorphic site negative, making the 5' portion of the haplotype identical with the African Senegal haplotype). These XmnI (+) chromosomes were associated with high G gamma expression (67.2 +/- 5.9%) and a high percentage of Hb F (15.5 +/- 7.9%; range, 6-25.3%). We have similar findings for tribal groups from west-central India (Gujarat). In east-central India we have confirmed the data of others, finding the same haplotype linked to beta S in tribes living in the east (Orissa, Andhra Pradesh). We conclude that the beta S gene in presently isolated and disperse tribal populations in India is associated with one predominant typical haplotype, suggesting a unicentric origin of the mutation in India. In addition, this finding implies a unicentric origin of the tribal populations themselves: The gene must have arisen and spread before tribal dispersion. Furthermore, we find extremely high frequencies of the (-alpha) haplotype in the Nilgiris (0.89) and in Gujarat (0.95). The beta S gene linkage to a high Hb F-expressing haplotype and the high incidence of alpha-thalassemia predict a mild phenotypical expression of sickle cell anemia in India.

A Madagascan child was followed for an homozygous sickle cell disease from the age of 7 to the age of 9 years. The clinical course of the disease, quite moderate till the age of 7, was then made more severe because of frequent painful crises during the observation period. Genetical and haematological data of the patient and his family showed that the two parents, heterozygote for sickle cell disease, and the homozygote patient, also had alpha-thalassemia. In the propositus patient, the association of the two disorders accounts for the quite moderate anaemia (haemoglobin level between 10 and 12 g/dl) and the persistent microcytosis. So, a microcytosis without iron deficiency and an haemoglobin level above 9 g/dl should suggest such an association.

The sickle cell disease is characterized by a heterogeneous clinical and biological expression. In order to evaluate the prognostic significance of the red blood cell density distribution: D50 (median cell density of the distribution), R60 (middle density range in which 60% of the cells can be found), F4 and F5 (proportion of cells with density higher than 1.110 and 1.120 g/ml, respectively) have been determined in 50 patients with homozygous sickle cell disease. The alpha gene status was determined in 27 patients. All patients have been included in an original score of severity fitted to infancy and childhood. A positive correlation has been found between D50 and the clinical score. This result illustrates the potential clinical importance of this parameter as well as other biological indices such as the haemoglobin F level, the alpha gene status and the haplotypes of the beta-like gene cluster.