Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial.

PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function.

All-cause and disease-specific mortality and morbidity in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study.

CONTEXT: Little is known about the long-term health of patients treated for congenital hypothyroidism since the neonatal period. OBJECTIVE: To evaluate the causes of mortality and comorbidity in a population-based registry of young adult patients. DESIGN, SETTING, AND PARTICIPANTS: All 1772 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France participated in the study. Follow-up data on vital status were available, in May 2010, for 99.5% of the patients. Completed questionnaires were obtained from 1202 of the selected patients. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality and comorbidity. RESULTS: All-cause mortality in the congenital hypothyroidism (CH) patients was slightly higher than expected on the basis of year, age, and sex (standardized mortality ratio [SMR] 1.24, 95% CI: 0.81-1.82). SMRs for each category of underlying cause of death showed mortality due to diseases of the central nervous system (SMR 5.22, 95% CI: 1.68-12.17) and congenital malformations (SMR 3.15, 95% CI: 1.86-6.49) to be significantly higher than expected in the CH patients. The risk of developing an associated chronic disease in the 1202 patients who completed the questionnaire was twice that for the reference population (odds ratio 2.0 [1.32-3.03]). Neurologic or mental diseases and congenital malformations were the most frequent (odds ratios 2.54 [1.12-5.86], 4.18 [1.27-13.76], and 4.36 [1.24-15.34], respectively). Overall, mortality and morbidity were not affected by sex, disease severity, cause of CH, or adequacy of treatment. CONCLUSION: Prognosis has improved considerably, but a few patients diagnosed during the first 10 years of screening in France nonetheless displayed comorbidity and mortality due to various neurodevelopmental disorders and associated malformations. These results reveal a continuing need for improvements in care and studies to provide knowledge about the full spectrum of the disease and the mechanisms underlying these developmental abnormalities.