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Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

ObjectivesPostnatal thyroid dysfunction is common in preterm infants but the relationship between mild dysfunction and neurodevelopment is unclear. Our aim is to describe the relationship between thyroid function and neurodevelopment.DesignCohort analysis.Patients1275 infants born under 31 weeks’ gestation; there were no exclusion criteria.SettingThe infants were part of a UK daily iodine supplementation trial.Main outcomesThyroid-stimulating hormone, thyroid-binding globulin and total thyroxine levels were measured in dried blood spots on postnatal days 7, 14, 28 and the equivalent of 34 weeks’ gestation. Neurodevelopment was measured using the Bayley-III Scales of infant development at 2 years of age.ResultsNo infant was identified as hypothyroid through routine screening. The 3% of infants consistently in the top decile of gestationally age-adjusted thyroid-stimulating hormone levels had a reduction in cognitive score of 7 Bayley units when compared with those not in the top decile (95% CI –13 to –1). A reduction in motor composite score of 6 units (95% CI −12 to <−0.1) and fine motor score of 1 unit (95% CI –2 to –0.1) was also identified. The 0.7% of infants consistently in the bottom decile of age-adjusted thyroxine levels had a reduction in motor composite score of 14 units (95% CI –25 to –2) and its two subset scores, fine and gross motor, of 2 units (95% CI respectively −4.5 to <−0.1 and –4.3 to –0.3).ConclusionsPreterm infants with consistent ‘mild’ thyroid dysfunction score less on neurodevelopmental tests at 2 years of age. Many of these infants will not be detected by current clinical protocols or screening programmes.

Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC. The invasion of epithelial tumours often depends on the epithelial-mesenchymal transition. Here, the authors report that intracellular activation of thyroid hormone by the D2 deiodinase enzyme promotes invasion and progression of squamous cell carcinoma by transcriptionally up-regulating ZEB-1.

Abstract Context Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age–adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives. Objective We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study. Methods Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis. Results A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days). Conclusion Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time.

Crosstalk between peripheral metabolic organs and the central nervous system is essential for body weight control. At the base of the hypothalamus, β-tanycytes surround the portal capillaries and function as gatekeepers to facilitate transfer of substances from the circulation into the cerebrospinal fluid and vice versa. Here, we investigated the role of the neuroplasticity gene doublecortin-like (DCL), highly expressed by β-tanycytes, in body weight control and whole-body energy metabolism. We demonstrated that DCL-knockdown through a doxycycline-inducible shRNA expression system prevents body weight gain by reducing adiposity in mice. DCL-knockdown slightly increased whole-body energy expenditure possibly as a result of elevated circulating thyroid hormones. In white adipose tissue (WAT) triglyceride uptake was increased while the average adipocyte cell size was reduced. At histological level we observed clear signs of browning, and thus increased thermogenesis in WAT. We found no indications for stimulated thermogenesis in brown adipose tissue (BAT). Altogether, we demonstrate an important, though subtle, role of tanycytic DCL in body weight control through regulation of energy expenditure, and specifically WAT browning. Elucidating mechanisms underlying the role of DCL in regulating brain-peripheral crosstalk further might identify new treatment targets for obesity.

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T₃) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T₃ or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T₃ microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T₃ microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T₃ microdialysis in the PVN increased EGP by 11 ± 4% (P = 0.020), while EGP decreased by 5 ± 8% (ns) in vehicle-treated rats (T₃ vs. Veh, P = 0.030). Plasma glucose increased by 29 ± 5% (P = 0.0001) after T₃ microdialysis versus 8 ± 3% in vehicle-treated rats (T₃ vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T₃ administration. Effects of PVN T₃ microdialysis were independent of plasma T₃, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T₃ microdialysis on EGP. We conclude that stimulation of T₃-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

Chronic hemodynamic overload of the heart induces ventricular hypertrophy that may be either compensatory or progress to decompensation and heart failure. The gradual impairment of ventricular function is, at least in part, the result of a reduction of cardiac thyroid-hormone (TH) action. Here, we examined the proposed roles of increased cardiac expression of the TH-inactivating enzyme deiodinase type 3 (D3) and reduced plasma TH levels in diminishing cardiac TH levels. Using minipumps, mice were infused for one and two weeks with isoproterenol (ISO) alone or in combination with phenylephrine (PE). Remodeling of the heart induced by these adrenergic agonists was assessed by echocardiography. Left ventricular (LV) tissue and plasma TH levels (T4 and T3) were determined using liquid chromatography-tandem mass spectrometry. LV D3 activity was determined by conversion of radiolabeled substrate and quantification following HPLC. The results show that ISO induced compensated LV hypertrophy with maintained cardiac output. Plasma levels of T4 and T3 remained normal, but LV hormone levels were reduced by approximately 30% after two weeks, while LV D3 activity was not significantly increased. ISO + PE induced decompensated LV hypertrophy with diminished cardiac output. Plasma levels of T4 and T3 were substantially reduced after one and two weeks, together with a more than 50% reduction of hormone levels in the LV. D3 activity was increased after one week and returned to control levels after two weeks. These data show for the first time that relative to controls, decompensated LV hypertrophy with diminished cardiac output is associated with a greater reduction of cardiac TH levels than compensated hypertrophy with maintained cardiac output. LV D3 activity is unlikely to account for these reductions after two weeks in either condition. Whereas the mechanism of the mild reduction in compensated hypertrophy is unclear, changes in systemic TH homeostasis appear to determine the marked drop in LV TH levels and associated impairment of ventricular function in decompensated hypertrophy.

X-linked adrenoleukodystrophy (ALD) is an inherited metabolic disorder that can cause adrenal insufficiency and cerebral ALD (cALD) in childhood. Early detection prevents adverse health outcomes and can be achieved by newborn screening (NBS) followed by monitoring disease progression. However, monitoring is associated with high costs. This study evaluates the cost–effectiveness of NBS for ALD in The Netherlands compared to no screening using a health economic model. A decision tree combined with a Markov model was developed to estimate societal costs, including screening costs, healthcare costs, and productivity losses of parents, and health outcomes over an 18-year time horizon. Model parameters were derived from the literature and expert opinion. A probabilistic sensitivity analysis (PSA) was performed to assess uncertainty. The screening costs of detecting one ALD case by NBS was EUR 40,630. Until the age of 18 years, the total societal cost per ALD case was EUR 120,779 for screening and EUR 62,914 for no screening. Screening gained an average of 1.7 QALYs compared with no screening. This resulted in an incremental cost–effectiveness ratio (ICER) of EUR 34,084 per QALY gained for screening compared to no screening. Although the results are sensitive to uncertainty surrounding costs and effectiveness due to limited data, NBS for ALD is likely to be cost–effective using a willingness-to-pay (WTP) threshold of EUR 50,000– EUR 80,000 per QALY gained.

X-linked adrenoleukodystrophy (ALD) is a devastating metabolic disorder affecting the adrenal glands, brain and spinal cord. Males with ALD are at high risk for developing adrenal insufficiency or progressive cerebral white matter lesions (cerebral ALD) at an early age. If untreated, cerebral ALD is often fatal. Women with ALD are not at risk for adrenal insufficiency or cerebral ALD. Newborn screening for ALD in males enables prospective monitoring and timely therapeutic intervention, thereby preventing irreparable damage and saving lives. The Dutch Ministry of Health adopted the advice of the Dutch Health Council to add a boys-only screen for ALD to the newborn screening panel. The recommendation made by the Dutch Health Council to only screen boys, without gathering any unsolicited findings, posed a challenge. We were invited to set up a prospective pilot study that became known as the SCAN study (SCreening for ALD in the Netherlands). The objectives of the SCAN study are: (1) designing a boys-only screening algorithm that identifies males with ALD and without unsolicited findings; (2) integrating this algorithm into the structure of the Dutch newborn screening program without harming the current newborn screening; (3) assessing the practical and ethical implications of screening only boys for ALD; and (4) setting up a comprehensive follow-up that is both patient- and parent-friendly. We successfully developed and validated a screening algorithm that can be integrated into the Dutch newborn screening program. The core of this algorithm is the “X-counter.” The X-counter determines the number of X chromosomes without assessing the presence of a Y chromosome. The X-counter is integrated as second tier in our 4-tier screening algorithm. Furthermore, we ensured that our screening algorithm does not result in unsolicited findings. Finally, we developed a patient- and parent-friendly, multidisciplinary, centralized follow-up protocol. Our boys-only ALD screening algorithm offers a solution for countries that encounter similar ethical considerations, for ALD as well as for other X-linked diseases. For ALD, this alternative boys-only screening algorithm may result in a more rapid inclusion of ALD in newborn screening programs worldwide.

Currently, Dutch newborns are screened for tyrosinemia type 1 (TT1) using succinylacetone (SA) as the biomarker. Although the sensitivity of the test is high, a high number of false positives is observed. Here, the aim is to evaluate the current Dutch newborn-screening protocol and to assess alternatives, specifically the use of biomarkers that are already being measured, to increase the positive predictive value (PPV). TT1 screening was performed with the Revvity NeoBase assay between 2008 and 2017, and since 2018, the Revvity NeoBase 2 assay has been used. Data from 2018 to 2021 were used for evaluation. To simulate alternative screening protocols, these data were enriched with results of referrals from other periods and a false negative (FN) from 2010. In 2018–2021, 693,821 newborns were screened, resulting in 23 referrals, of whom two were TT1 patients. For this period, to date, no FN have been reported, resulting in a provisional sensitivity of 100%, a specificity of 99.997%, and a PPV and negative predictive value of 9% and 100%, respectively. To improve the PPV, we combined SA, tyrosine (tyr), tyr × SA and tyr/phenylalanine and achieved a PPV of 72% for this dataset without introducing FN in the original dataset. This illustrates that future screening for TT1 may benefit from the addition of these biomarkers.