CLINICAL-FEATURES AND MOLECULAR ANALYSIS OF THE ALPHA-THALASSEMIA MENTAL-RETARDATION SYNDROMES .2. CASES WITHOUT DETECTABLE ABNORMALITY OF THE ALPHA-GLOBIN COMPLEX

Abstract

We have identified five unrelated patients, all of north European origin, who have hemoglobin H (Hb H) disease and profound mental handicap. Surprisingly, detailed molecular analysis of the .alpha. globin complex is normal in these subjects. Clinically, they present with a rather uniform constellation of abnormalities, notably severe mental handicap, microcephaly, relatively hypertelorism, unusual facies and genital anomalies. Hematologically, their Hb H disease has subtly but distinctly milder properties than the recognized Mendelian forms of the disease. These common features suggest that these five "nondeletion" patients have a similar underlying mutation, quite distinct from the 16p13.3 deletion associated with .alpha. thalassemia and mild to moderate mental retardation described in the accompanying paper. We speculate that the locus of this underlying mutation is not closely linked to the .alpha. globin complex and may encode a trans-acting factor involved in the normal regulation of .alpha. globin expression.