In this study we have defined the molecular basis and correlated the clinical phenotype with the α-globin genotype in a large series of patients of Sardinian descent with HbH disease. The most prevalent molecular defect was the deletion of 3 α-globin structural genes most commonly the (– –/–α^3.7) genotype (83.6%) and rarely the (– –/– α^4.2) genotype (1.4%), followed in decreasing order of incidence by the combination of deletion α°-thalassemia and initiation codon mutation of the α₂-gene (– –/α^NcoIα = 9.8%), deletion α°-thalassemia and pentanucleotide deletion of IVS-I of the α₂-globin gene, (– –/α^HphIα = 3.3%) deletion α°-thalassemia and initiation codon mutation of the α₁-gene (– –/αα^NcoI = 1.3%), a homozygous state for initiation codon mutation of the α₂-gene (α^Ncoα/α^NcoIα = 0.7%). Patients with the (– –/α^thalα) genotypes showed severer clinical and hematological features as compared to those with the (– –/–α) or those with the (– –/αα^thal) genotypes. The single patient with the (α^Ncoα/α^Ncoα) genotype had a clinical phenotype intermediate between HbH disease and the α-thalassemia carrier status. This heterogeneity depends on the fact that the α₂-globin gene produces 2-3 times α-globin chains than the α₁-gene and the single remaining α₁-like globin gene in the -α^{3 7} chromosome has a compensatory increase in the α-globin chain output. α-Globin gene mapping of HbH disease patients may be useful for predicting the clinical outcome and to improve genetic counselling.

The intraventricular injection of D-alanine-methionine-enkephalinamide (D-Ala2-Met-enkephalinamide), a synthetic analog of Met-enkephalin that is resistant to enzymatic degradation, inhibits copulatory behavior in sexually vigorous male rats in doses which do not influence motor activity or feeding behavior. This effect is prevented by naloxone, a specific inhibitor of opioid receptors. In addition, injections of naloxone induce copulatory behavior in sexually inactive male rats. These results suggest that endorphins play an important role in the regulation of sexual behavior.

Osteoporosis and osteopenia are frequent complications of thalassemia major (TM) and intermedia (TI). Osteoporosis was found in 23/25 patients with TI and in 115/239 patients with TM. In TM, no association was found with specific polymorphisms in candidate genes (vitamin D receptor, estrogen receptor, calcitonin receptor, and collagen type 1 alpha 1). Osteoporosis in female patients with TM was strongly associated with primary amenorrhea (P < .0001), while in male patients with TM, hypogonadism was not significantly related to bone mineral density (BMD) (P = .0001). Low BMD was also associated with cardiomiopathy (P = .01), diabetes mellitus (P = .0001), chronic hepatitis (P = .0029), and increased ALT (P = .01).

In this study, we have defined by molecular analysis, the alpha, beta, and delta globin genotype in a group of individuals with normal or thal-like red cell indices but borderline hemoglobin (Hb)A2 levels, who were identified in a program for beta-thal carrier screening. In 37 of 125 individuals with borderline HbA2 levels, we detected a molecular defect in the beta, in both the delta and the beta, or in the alpha globin gene. Specifically seven of these subjects were carriers of the -101 C T mutation, ten of the IVSI nt6 T C mutation, 16 were double heterozygotes for delta and beta thal, and two had the triple alpha globin gene and two the single alpha globin gene deletion. From these results, we may conclude that subjects with borderline HbA2, particularly when they marry a typical beta-thal carrier, should be extensively investigated in order not to miss heterozygous beta-thalassemia.