THYROID-FUNCTION TESTS AND CHARACTERIZATION OF THYROXINE-BINDING GLOBULIN IN THE CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME TYPE-I

Carbohydrate-deficient glycoprotein (CDG) syndrome is a newly recogniz ed hereditary disorder that presents with psychomotor retardation, cer ebellar ataxia, peripheral sensorimotor neuropathy, and, variably, ske letal abnormalities, lipodystrophy, and retinitis pigmentosa. These ab normalities appear to be produced by a defect that causes reduced carb ohydrate content in glycoproteins. We studied seven patients with CDG type I belonging to five unrelated families. The concentration of seru m TBG, a glycoprotein of hepatic origin, was measured by RIA and T-4 s aturation and was found to be below the normal range in three of the s even patients and normal in four of them. More than half of the total serum TBG had reduced sialic acid content and localized on isoelectric focusing (IEF) as two prominent bands cathodal to the three major ban ds of normal TBG. The latter two bands are responsible for the charact eristic IEF pattern or CDG syndrome. TBG in patients with CDG had immu noreactivity indistinguishable from that of normal TBG and had normal affinity for T-4, T-3, and rT(3). Serum total T-4, T-3, and rT(3) were below the normal range in seven, five, and seven patients, respective ly. The free T-4 index was also below normal in four patients, but the free T-4 concentration, measured by equilibrium dialysis at low dilut ion, and serum TSH were in the midnormal range. The serum total T-4 an d rT(3) levels were disproportionately reduced relative to the serum T BG concentration and compared to the concentrations of these iodothyro nines in matched subjects with inherited partial TBG deficiency. Chron ic illness cannot explain these changes, because, contrary to patients with nonthyroidal illness, those with CDG had significantly higher se rum total T-3/T-4 and lower rT(3)/T-4 ratios. It is concluded that IEF of TBG is a rapid and simple method for the diagnosis of CDG type I a nd that the abnormal pattern can be detected as early as 5 days postpa rtum. Patients with CDG are chemically euthyroid, and it is postulated that the reduction in serum iodothyronine concentrations beyond that explained on the basis of low TBG levels may be due to the interferenc e with binding to TBG by an unidentified substance.