A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia

Context: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albuminwith increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals. Objective: Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated. Design and Results: Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. 125I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T 4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated. Conclusions: A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein

A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations.

Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations

Homozygous Resistance to Thyroid Hormone β: Can combined anti-thyroid drug and triiodothyroacetic acid treatment prevent cardiac failure?

Resistance to Thyroid Hormone beta (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five cases reported worldwide; cardiac dysfunction, which can be life-threatening, is recognised in the disorder. Here we describe the clinical, metabolic, ophthalmic and cardiac findings in a nine-year old boy harbouring a biallelic THRB mutation (R243Q), along with biochemical, physiological and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognised features (goitre, non-suppressed TSH levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ, had died of cardiac failure at age 13 yrs. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass and improved growth and cardiac function. A combination of anti-thyroid drug and TRIAC therapy may prevent hyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.Our research is supported by funding from the Wellcome Trust (095564/Z/11/Z to K.C.), National Institute for Health Research Cambridge Biomedical Research Centre (C.M., K.C.), the Great Ormond Street Hospital Children’s Charity (F.V.K., M.D.), and Medical Research Council (MRC Programme no. U105960371 to K.W.). G.E.H. receives research funding from the National Institute for Health Research (United Kingdom) and the Foundation Fighting Blindness (United States)