LOW INTELLIGENCE BUT NOT ATTENTION-DEFICIT HYPERACTIVITY DISORDER IS ASSOCIATED WITH RESISTANCE TO THYROID-HORMONE CAUSED BY MUTATION R316HIN THE THYROID-HORMONE RECEPTOR-BETA GENE

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiv eness of tissues to thyroid hormone. The clinical manifestations are v ariable and 46-50% of children with RTH have attention deficit hyperac tivity disorder (ADD). We present a new family with RTH (F120) found t o have a mutation R316H in the thyroid hormone receptor beta (TR beta) gene identical for that reported in an unrelated family. Assignment o f the mutant allele and haplotyping based on CA repeat polymorphism we re done on 16 family members. Semistructured diagnostic interviews and psychometric testing were used to determine the psychiatric diagnosis or 12 family members by examiners blinded to the genotype. Three subj ects were identified to have the R316H allele as well as mildly elevat ed free T-4 index (168 +/- 12; normal range 77-135) and nonsuppressed TSH (4.1 +/- 1.7 mU/L). Only 2 of the subjects with RTH were found to have ADD, while one family member homozygous for the wild type TR beta and normal thyroid function tests also had ADD. Unaffected family mem bers had higher full scale intelligence quotients (IQ) (93 +/- 7) than any of the 3 family members with RTH (77 +/- 5, p = 0.006). These dat a do not support the genetic linkage of ADD and RTH, but do suggest th at RTH is associated with lower IQ scores that may confer a high likel ihood of exhibiting ADD symptoms.