scholarly journals Diagnostic and Therapeutic Challenges in the Allan—Herndon—Dudley Syndrome

2016 ◽  
Vol 12 (02) ◽  
pp. 90 ◽  
Author(s):  
Stefan Groeneweg ◽  
Robin P Peeters ◽  
Theo J Visser ◽  
W Edward Visser ◽  
◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Monocarboxylate Transporter ◽  
Normal Brain ◽  
Thyroid Function Tests ◽  
Neurocognitive Development ◽  
Transporter Protein ◽  
Male Patients ◽  
The Brain ◽  
Normal Brain Development

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan–Herndon–Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.

scholarly journals Actions of Thyroid Hormone Analogues on Chemokines

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Paul J. Davis ◽  
Gennadi V. Glinsky ◽  
Hung-Yun Lin ◽  
Shaker A. Mousa
Keyword(s):  
Thyroid Hormone ◽  
Normal Brain ◽  
Specific Receptor ◽  
Blood Vessel Formation ◽  
Inflammatory Processes ◽  
A Site ◽  
The Brain ◽  
Normal Brain Development ◽  
Receptor Cx3cr1 ◽  
Chemokine Gene Expression

The extracellular domain of plasma membrane integrinαvβ3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3′-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4and T3to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia-dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4and T3may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds toαvβ3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance.

scholarly journals Dynamic N6-methyladenosine RNA methylation in brain and diseases

Epigenomics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 371-380 ◽  
Author(s):  
Andrew M Shafik ◽  
Emily G Allen ◽  
Peng Jin
Keyword(s):  
Brain Development ◽  
Rna Modification ◽  
Normal Brain ◽  
Biological Processes ◽  
Future Directions ◽  
Body Of Knowledge ◽  
Neuropsychiatric Diseases ◽  
The Brain ◽  
Normal Brain Development

N6-methyladenosine (m6A) is a dynamic RNA modification that regulates various aspects of RNA metabolism and has been implicated in many biological processes and transitions. m6A is highly abundant in the brain; however, only recently has the role of m6A in brain development been a focus. The machinery that controls m6A is critically important for proper neurodevelopment, and the precise mechanisms by which m6A regulates these processes are starting to emerge. However, the role of m6A in neurodegenerative and neuropsychiatric diseases still requires much elucidation. This review discusses and summarizes the current body of knowledge surrounding the function of the m6A modification in regulating normal brain development, neurodegenerative diseases and outlines possible future directions.

scholarly journals Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Thyroid ◽  
2016 ◽  
Vol 26 (9) ◽  
pp. 1311-1319 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Xiao-Hui Liao ◽  
Lyndsey Braun ◽  
Soledad Bárez-López ◽  
Brian Kaspar ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Adeno Associated Virus ◽  
The Brain ◽  
Deficient Mice

Microglia and the Brain: Complementary Partners in Development and Disease

2018 ◽  
Vol 34 (1) ◽  
pp. 523-544 ◽  
Author(s):  
Timothy R. Hammond ◽  
Daisy Robinton ◽  
Beth Stevens
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Disease ◽  
Immune Cells ◽  
New Technologies ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Synaptic Maturation ◽  
The Brain ◽  
Normal Brain Development

An explosion of findings driven by powerful new technologies has expanded our understanding of microglia, the resident immune cells of the central nervous system (CNS). This wave of discoveries has fueled a growing interest in the roles that these cells play in the development of the CNS and in the neuropathology of a diverse array of disorders. In this review, we discuss the crucial roles that microglia play in shaping the brain—from their influence on neurons and glia within the developing CNS to their roles in synaptic maturation and brain wiring—as well as some of the obstacles to overcome when assessing their contributions to normal brain development. Furthermore, we examine how normal developmental functions of microglia are perturbed or remerge in neurodevelopmental and neurodegenerative disease.

scholarly journals A Thyroid Hormone Analog with Reduced Dependence on the Monocarboxylate Transporter 8 for Tissue Transport

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4450-4458 ◽  
Author(s):  
Caterina Di Cosmo ◽  
Xiao-Hui Liao ◽  
Alexandra M. Dumitrescu ◽  
Roy E. Weiss ◽  
Samuel Refetoff
Keyword(s):  
Thyroid Hormone ◽  
Neurological Impairment ◽  
Monocarboxylate Transporter ◽  
Human Thyroid ◽  
Th Cell ◽  
Hormone Analog ◽  
Potential Clinical Utility ◽  
The Brain ◽  
Serum Tsh ◽  
Different Doses

Abstract Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent. We tested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of l-T4. As expected, physiological doses of l-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 suppressed TSH in the Wt mice, normalized TSH and brain D2 in Mct8KO mice, but produced a thyrotoxic effect on liver D1 in both genotypes. In contrast DITPA produced similar effects on TSH, D2, and D1 in both Wt and Mct8KO mice. The higher dose fully normalized all measurements and other parameters of TH action. Thus, DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver. The potential clinical utility of this analog to patients with MCT8 mutations requires further studies.

scholarly journals Early stage differentiation of glia in human and mice.

2021 ◽  
Author(s):  
Paul Frazel ◽  
David Labib ◽  
Ran Brosh ◽  
Valentina Fossati ◽  
Jef D Boeke ◽  
...  
Keyword(s):  
Stem Cells ◽  
Early Stage ◽  
Embryonic Stem ◽  
Normal Brain ◽  
Astrocyte Differentiation ◽  
Induced Pluripotent ◽  
And Function ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Normal Brain Development

Central nervous system macroglia (astrocytes and oligodendrocytes) are required for normal brain development and function, and are among the last cells to emerge during neurodevelopment. Many questions remain about their emergence in the brain and spinal cord, including how early glial fates are specified during development or differen- tiation, and similarly when subtypes of glia are specified. Here, we used single-cell RNA sequencing (scRNAseq) to analyze ~90,000 cells across multiple timepoints during the differentiation of astrocytes and oligodendrocytes from human induced pluripotent stem cells and mouse embryonic stem cells. Using time series analysis of gene expres- sion, we uncovered multiple genes involved in fate specification of glial subtypes in both species. We examined gene expression changes during intermediate states of glial specification, and were able to identify genes that were correlated with the choice between neuron versus glia in both species. Using our scRNAseq data we optimized previous mouse astrocyte differentiation protocols by highlighting and removing non-required transition states and decreasing the overall protocol from 3 weeks to less than 12 days. Our data will be useful for researchers interested in optimizing glial differentiations in either species, and provide a window into human glial differentiation, which is difficult to study given its lateness in development.

scholarly journals The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 3889-3894 ◽  
Author(s):  
Alfonso Massimiliano Ferrara ◽  
Xiao-Hui Liao ◽  
Honggang Ye ◽  
Roy E. Weiss ◽  
Alexandra M. Dumitrescu ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Energy Expenditure ◽  
Target Genes ◽  
High Serum ◽  
Metabolic Parameters ◽  
Monocarboxylate Transporter ◽  
Hormone Analog ◽  
Serum T3 ◽  
Mct8 Deficiency ◽  
The Brain

Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

scholarly journals Altered GABA Signaling in Early Life Epilepsies

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Stephen W. Briggs ◽  
Aristea S. Galanopoulou
Keyword(s):  
Brain Function ◽  
Therapeutic Potential ◽  
Physiological Role ◽  
Neuronal Morphology ◽  
Normal Brain ◽  
Pathological Conditions ◽  
Neurodevelopmental Deficits ◽  
The Brain ◽  
Normal Brain Development

The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAAsignaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAAreceptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAAsignaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

scholarly journals Morphology and Morphometry of Foetal Corpus Callosum Using MRI – A Retrospective Study

2021 ◽  
Vol 14 (02) ◽  
pp. 663-669
Author(s):  
Kirthika C P ◽  
Siva T ◽  
Rajeswaran R ◽  
Kalpana R ◽  
Yuvaraj Maria Francis
Keyword(s):  
Corpus Callosum ◽  
Brain Development ◽  
Gestational Age ◽  
Abnormal Development ◽  
Radiology Department ◽  
Normal Brain ◽  
Prenatal Ultrasonography ◽  
The Brain ◽  
Normal Brain Development ◽  
Foetal Mri

Introduction: Corpus callosum (CC) is the largest commissural white fibres interconnecting cerebral hemispheres. The corpus callosum is responsible for interhemispheric transfer of information which is essential for cognitive function. The foetal corpus callosum serves as sensitive indicator for normal brain development and maturation. As the corpus callosum is a part of the highest order latest maturing mental network of the brain, its measurements are important to assess normal brain development and to locate structural changes. A comprehensive evaluation of normal human foetal corpus callosal development is essential to detect and understand the congenital anomalies of the brain. Thus, the prenatal diagnosis of partial or complete agenesis of the corpus callosum is important for predicting the normal development of the foetus. Foetal neural anomalies that are suspected on prenatal ultrasonography (USG) can be detected in early stage using foetal MRI. This imaging technique is highly useful for detailed visualization of normal neural development. Certain conditions like colpocephaly and widening of interhemispheric fissure can be clearly visualized using foetal MRI when compared to prenatal ultrasonography. Aim and objective: Was to establish the normal reference values for the measurement of foetal corpus callosum. The length and thickness of the foetal CC was measured corresponding to gestational age (GA) between 18-36weeks. Materials and methods: A retrospective MRI study was carried out in Radiology department of Sri Ramachandra Hospital. The study was conducted on 50 pregnant women with GA of 18-32 weeks and morphology of foetal corpus callosum was measured using MRI. The corpus callosum was visualized in a mid-sagittal plane as an anechoic structure, delimited by two echogenic lines superiorly by sulcus of the corpus callosum and inferiorly by the septum pellucidum. The length of corpus callosum was measured from the anterior most aspect of genu to the posterior most aspect of the splenium and the width of individual parts were measured and correlated with gestational age. The values obtained from the study were statistically calculated using regression coefficient method. Results: In the present study following parameters were observed such as length and width of diverse parts of Corpus callosum. The length of foetal CC ranged from 25.96 to 47.2 mm in 18 to 32 weeks of gestational age. The range of width of rostrum, genu, body and splenium were 1.2 to 2.2 mm, 1.2-2.8mm, 1.3-3.1mm and 1.36-3.2mm respectively. Conclusion: The periodic development of nervous system can be calculated more effectively with the morphometric measurement of foetal CC and its correlation with BPD. It is considered to be accurate than using BPD measurement of head circumference in USG. Hence, with the normative data of foetal CC measurements correlated with gestational age would give us accurate details of neuronal growth rather than measuring biparietal diameter (BPD) alone using USG. This knowledge will be highly helpful for the gynaecologists to predict the abnormal development of the foetus and it is advised to include foetal CC parameters as a one of the tools for early detection of CNS anomalies.

scholarly journals The Role of Hypothalamic Tri-Iodothyronine Availability in Seasonal Regulation of Energy Balance and Body Weight

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Michelle Murphy ◽  
Francis J. P. Ebling
Keyword(s):  
Body Weight ◽  
Thyroid Hormone ◽  
Energy Balance ◽  
Third Ventricle ◽  
Peripheral Circulation ◽  
Brain Cell ◽  
Monocarboxylate Transporter ◽  
Type Iii ◽  
Seasonal Regulation ◽  
The Brain

Seasonal cycles of body weight provide a natural model system to understand the central control of energy balance. Studies of such cycles in Siberian hamsters suggest that a change in the hypothalamic availability of thyroid hormone is the key determinant of annual weight regulation. Uptake of thyroid hormone into the hypothalamus from the peripheral circulation occurs largely through a specific monocarboxylate transporter expressed by tanycyte cells lining the third ventricle. Tanycytes are the principal brain cell type expressing type II and type III deiodinases, so they control the local concentrations of T4, T3, and inactive metabolites. Type III deiodinase mRNA in tanycytes is photoperiodically upregulated in short photoperiod. This would be expected to reduce the availability of T3 in the hypothalamus by promoting the production of inactive metabolites such as rT3. Experimental microimplantation of T3 directly into the hypothalamus during short-days promotes a long-day phenotype by increasing food intake and body weight without affecting the peripheral thyroid axis. Thus, thyroid hormone exerts anabolic actions within the brain that play a key role in the seasonal regulation of body weight. Understanding the precise actions of thyroid hormone in the brain may identify novel targets for long-term pharmacological manipulation of body weight.

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