RESUMO
Since the advent of glucocorticoid therapy for autoimmune disease in the 1940s, their widespread application has led to the concurrent therapy-limiting discovery of many adverse metabolic side effects. Unanticipated hyperglycemia associated with the initiation of glucocorticoids often leads to preventable hospital admissions, prolonged hospital stays, increased risks for infection and reduced graft function in solid organ transplant recipients. Challenges in managing steroid-induced diabetes stem from wide fluctuations in post-prandial hyperglycemia and the lack of clearly defined treatment protocols. The mainstay of treatment is insulin therapy coincident with meals. This article aims to review the pathogenesis, risk factors, diagnosis and treatment principles unique to steroid-induced diabetes.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Diabetes Mellitus/induzido quimicamente , Imunossupressores/efeitos adversos , Fígado/efeitos dos fármacos , Modelos Biológicos , Esteroides/efeitos adversos , Tecido Adiposo/metabolismo , Metabolismo dos Carboidratos/efeitos dos fármacos , Congressos como Assunto , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Glucocorticoides/efeitos adversos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fatores de RiscoRESUMO
Thyroid hormone (TH) metabolism, mediated by deiodinase types 1, 2, and 3 (D1, D2, and D3) is profoundly affected by acute illness. We examined the role of TH metabolism during ventilator-induced lung injury (VILI) in mice. Mice exposed to VILI recapitulated the serum TH findings of acute illness, namely a decrease in 3,5,3'-triiodothyronine (T(3)) and thyroid-stimulating hormone and an increase in reverse T(3). Both D2 immunoreactivity and D2 enzymatic activity were increased significantly. D1 and D3 activity did not change. Using D2 knockout (D2KO) mice, we determined whether the increase in D2 was an adaptive response. Although similar changes in serum TH levels were observed in D2KO and WT mice, D2KO mice exhibited greater susceptibility to VILI than WT mice, as evidenced by poorer alveoli integrity and quantified by lung chemokine and cytokine mRNA induction. These data suggest that an increase in lung D2 is protective against VILI. Similar findings of increased inflammatory markers were found in hypothyroid WT mice exposed to VILI compared with euthyroid mice, indicating that the lungs were functionally hypothyroid. Treatment of D2KO mice with T(3) reversed many of the lung chemokine and cytokine profiles seen in response to VILI, demonstrating a role for T(3) in the treatment of lung injury. We conclude that TH metabolism in the lung is linked to the response to inflammatory injury and speculate that D2 exerts its protective effect by making more TH available to the injured lung tissue.
Assuntos
Lesão Pulmonar Aguda/enzimologia , Iodeto Peroxidase/metabolismo , Pulmão/enzimologia , Lesão Pulmonar Induzida por Ventilação Mecânica/enzimologia , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/genética , Animais , Quimiocinas/genética , Citocinas/genética , Ativação Enzimática/fisiologia , Expressão Gênica/efeitos dos fármacos , Genótipo , Imuno-Histoquímica , Iodeto Peroxidase/genética , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Tri-Iodotironina/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/sangue , Lesão Pulmonar Induzida por Ventilação Mecânica/genética , Iodotironina Desiodinase Tipo IIRESUMO
Incorporation of selenocysteine (Sec), through recoding of the UGA stop codon, creates a unique class of proteins. Mice lacking tRNA(Sec) die in utero, but the in vivo role of other components involved in selenoprotein synthesis is unknown, and Sec incorporation defects have not been described in humans. Deiodinases (DIOs) are selenoproteins involved in thyroid hormone metabolism. We identified three of seven siblings with clinical evidence of abnormal thyroid hormone metabolism. Their fibroblasts showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2). An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2. Because SBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Incomplete loss of SBP2 function probably causes the mild phenotype.
Assuntos
Mutação de Sentido Incorreto/genética , Proteínas de Ligação a RNA/genética , Hormônios Tireóideos/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Fibroblastos/enzimologia , Heterozigoto , Homozigoto , Humanos , Iodeto Peroxidase/metabolismo , Masculino , Linhagem , Irmãos , Pele/enzimologiaRESUMO
Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.
Assuntos
Cromossomos Humanos Par 15 , Elementos Facilitadores Genéticos , MicroRNAs , Repetições de Microssatélites , Mutação , Tireotropina , Animais , Feminino , Humanos , Masculino , Cromossomos Humanos Par 15/genética , MicroRNAs/genética , Repetições de Microssatélites/genética , Linhagem , Primatas/genética , Glândula Tireoide/metabolismo , Tireotropina/genéticaRESUMO
Thyroid hormones (THs) are vital for normal postnatal development. Extracellular TH distributor proteins create an intravascular reservoir of THs. Transthyretin (TTR) is a TH distributor protein in the circulatory system and is the only TH distributor protein synthesized in the central nervous system. We investigated the phenotype of TTR null mice during development. Total and free 3',5',3,5-tetraiodo-L-thyronine (T(4)) and free 3',3,5-triiodo-L-thyronine (T(3)) in plasma were significantly reduced in 14-day-old (P14) TTR null mice. TTR null mice also displayed a delayed suckling-to-weaning transition, decreased muscle mass, delayed growth, and retarded longitudinal bone growth. In addition, ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null mice were higher than in age-matched wild-type mice. In contrast to the current literature based on analyses of adult TTR null mice, our results demonstrate that TTR has an important and nonredundant role in influencing the development of several organs.
Assuntos
Transtornos do Crescimento/genética , Crescimento e Desenvolvimento/efeitos dos fármacos , Pré-Albumina/genética , Hormônios Tireóideos/farmacologia , Animais , Análise Química do Sangue , Glicemia/metabolismo , Transtornos do Crescimento/sangue , Transtornos do Crescimento/metabolismo , Crescimento e Desenvolvimento/fisiologia , Camundongos , Camundongos Knockout , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Pré-Albumina/metabolismo , Pré-Albumina/fisiologia , Testes de Função Tireóidea , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Ureia/sangueRESUMO
Liver-specific thyroid hormone receptor-ß (TRß)-specific agonists are potent lipid-lowering drugs that also hold promise for treating nonalcoholic fatty liver disease and hepatic insulin resistance. We investigated the effect of two TRß agonists (GC-1 and KB-2115) in high-fat-fed male Sprague-Dawley rats treated for 10 days. GC-1 treatment reduced hepatic triglyceride content by 75%, but the rats developed fasting hyperglycemia and hyperinsulinemia, attributable to increased endogenous glucose production (EGP) and diminished hepatic insulin sensitivity. GC-1 also increased white adipose tissue lipolysis; the resulting increase in glycerol flux may have contributed to the increase in EGP. KB-2115, a more TRß- and liver-specific thyromimetic, also prevented hepatic steatosis but did not induce fasting hyperglycemia, increase basal EGP rate, or diminish hepatic insulin sensitivity. Surprisingly, insulin-stimulated peripheral glucose disposal was diminished because of a decrease in insulin-stimulated skeletal muscle glucose uptake. Skeletal muscle insulin signaling was unaffected. Instead, KB-2115 treatment was associated with a decrease in GLUT4 protein content. Thus, although both GC-1 and KB-2115 potently treat hepatic steatosis in fat-fed rats, they each worsen insulin action via specific and discrete mechanisms. The development of future TRß agonists must consider the potential adverse effects on insulin sensitivity.
Assuntos
Acetatos/farmacologia , Anilidas/farmacologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Resistência à Insulina/fisiologia , Fenóis/farmacologia , Receptores beta dos Hormônios Tireóideos/agonistas , Animais , Gorduras na Dieta/farmacologia , Fígado Gorduroso/tratamento farmacológico , Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/fisiologia , Transportador de Glucose Tipo 4/metabolismo , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptores beta dos Hormônios Tireóideos/metabolismo , Triglicerídeos/metabolismoRESUMO
Background: Congenital hypothyroidism due to defects in iodotyrosine deiodinase has variable phenotypes and can present as hypothyroid or with normal thyroid testing. Methods: Whole exome sequencing was performed in individuals from two families originating from different regions of Sudan. Mass spectrometry of urine and serum iodotyrosines was performed on subjects from both families. Results: A novel iodotyrosine deiodinase (IYD) mutation (c.835C>T; R279C) was identified in individuals from two Sudanese families inherited as autosomal recessive. The mutation was identified by multiple in silica analyses to likely be detrimental. Serum and urine monoiodotyrosine (MIT) and diiodotyrosine (DIT) were markedly elevated in the homozygous subjects. Conclusion: Measurement of serum and urine DIT and MIT was more sensitive than that of urine iodine or serum thyroid function tests to determine the effect of the IYD mutation.
Assuntos
Hipotireoidismo Congênito , Di-Iodotirosina , Mutação , Humanos , Hipotireoidismo Congênito/genética , Di-Iodotirosina/genética , Iodeto Peroxidase/genética , Monoiodotirosina/genéticaRESUMO
The dynamic and continuously evolving field of ophthalmology necessitates rigorous regulatory oversight in the United States. This review outlines the multifaceted Food and Drug Administration's (FDA) approval process for ophthalmic products, detailing the classifications, pathways, and regulatory compliance for devices, drugs, biologics, and combination products. Particular emphasis is placed on distinct frameworks for Class I, II, and III devices, as well as regulations for drugs, biologics, and combination products. The organizational structure of the FDA is detailed, with highlights on specific Ophthalmology oversight divisions, historical regulatory evolution, and initiatives such as Patient-Focused Drug Development. An in-depth examination of the regulatory journey, ranging from initial research to post-marketing surveillance, includes practical guidance through stages such as Pre-Investigational New Drug/Pre-Submission consultations, clinical trials, new drug application/biologics license application/premarket approval submissions, and FDA advisory committee interactions. The article underscores the importance of early interactions with the health authorities, interdisciplinary team collaboration, adherence to current standards, and the anticipation of policy changes to ensure patient safety. It concludes with an analysis of 4 key FDA-approved ophthalmic products, including Eylea®, Luxturna®, Alphagan P®, and the Raindrop® Near Vision Inlay, detailing their contributions to ophthalmic care and offering valuable insights into their respective clinical trials, regulatory pathways, and potential implications. These case studies are included to illustrate both successful and failed ophthalmic product launches, thereby highlighting the importance of alignment with regulatory compliance.
Assuntos
Distinções e Prêmios , Produtos Biológicos , Estados Unidos , Humanos , United States Food and Drug Administration , Aprovação de Drogas , Preparações FarmacêuticasRESUMO
Over the course of the COVID-19 pandemic, SARS-CoV-2 variants of concern (VOCs) with increased transmissibility and immune escape capabilities, such as Delta and Omicron, have triggered waves of new COVID-19 infections worldwide, and Omicron subvariants continue to represent a global health concern. Tracking the prevalence and dynamics of VOCs has clinical and epidemiological significance and is essential for modeling the progression and evolution of the COVID-19 pandemic. Next generation sequencing (NGS) is recognized as the gold standard for genomic characterization of SARS-CoV-2 variants, but it is labor and cost intensive and not amenable to rapid lineage identification. Here we describe a two-pronged approach for rapid, cost-effective surveillance of SARS-CoV-2 VOCs by combining reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and periodic NGS with the ARTIC sequencing method. Variant surveillance by RT-qPCR included the commercially available TaqPath COVID-19 Combo Kit to track S-gene target failure (SGTF) associated with the spike protein deletion H69-V70, as well as two internally designed and validated RT-qPCR assays targeting two N-terminal-domain (NTD) spike gene deletions, NTD156-7 and NTD25-7. The NTD156-7 RT-qPCR assay facilitated tracking of the Delta variant, while the NTD25-7 RT-qPCR assay was used for tracking Omicron variants, including the BA.2, BA.4, and BA.5 lineages. In silico validation of the NTD156-7 and NTD25-7 primers and probes compared with publicly available SARS-CoV-2 genome databases showed low variability in regions corresponding to oligonucleotide binding sites. Similarly, in vitro validation with NGS-confirmed samples showed excellent correlation. RT-qPCR assays allow for near-real-time monitoring of circulating and emerging variants allowing for ongoing surveillance of variant dynamics in a local population. By performing periodic sequencing of variant surveillance by RT-qPCR methods, we were able to provide ongoing validation of the results obtained by RT-qPCR screening. Rapid SARS-CoV-2 variant identification and surveillance by this combined approach served to inform clinical decisions in a timely manner and permitted better utilization of sequencing resources.
Assuntos
COVID-19 , Laboratórios Clínicos , Humanos , SARS-CoV-2/genética , Florida , Pandemias , COVID-19/diagnóstico , COVID-19/epidemiologia , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
For the first time in human history, obtaining a COVID-19 vaccine has become essential for the sustainability of our species. As an amazing product of collective ideation, remarkably safe and efficient vaccines have been invented, tested, distributed, and administered to the population on a voluntary basis. The fast-mutating individual behavior of the virus is probably guided by a similar goal of the sustainability of the species. With this commentary, we analyze and compare two means of sustainability through adaptability: collective ideation in the case of humans and individual mutations in the case of viruses - two very different species whose behaviors are driven by sustainability.
RESUMO
Resistance to thyroid hormone alpha (RTHα) is caused by mutations in thyroid hormone receptor α (THRA). Little is known about the natural history and treatment of RTHα, and diagnosis before the age of 1 year has not been previously reported. A de novo heterozygous THRA mutation (pC380SfsX9) was identified in a 10-month-old female investigated for developmental delay, hypotonia, macrocephaly, and severe constipation. Treatment with levothyroxine was accompanied by an appropriate rise in thyroxine (T4), triiodothyronine (T3), as well as decrease in thyrotropin levels and in the T3/T4 ratio with a trend toward normalization of peripheral markers of thyroid hormone action. THRA pC380SfsX9 results in extreme RTHα.
Assuntos
Receptores alfa dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/tratamento farmacológico , Tiroxina/uso terapêutico , Constipação Intestinal/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Diagnóstico Precoce , Intervenção Médica Precoce , Feminino , Humanos , Lactente , Megalencefalia/fisiopatologia , Hipotonia Muscular/fisiopatologia , Mutação , Síndrome da Resistência aos Hormônios Tireóideos/diagnóstico , Síndrome da Resistência aos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/fisiopatologiaRESUMO
A family with congenital hypothyroidism was identified with two novel deleterious compound heterozygous thyroid peroxidase (TPO) mutations (c.962C>A, and c.1577C>T). Serum thyroid tests showed higher-than-expected serum-free thyroxine (T4) relative to TT3, while reverse triiodothyronine (rT3) was also elevated. Two siblings manifested a more severe phenotype of developmental delay compared with another sibling and were found to harbor an additional novel heterozygous deleterious iodothyronine deiodinase 1 (DIO1) mutation (c.395G>A). In the context of L-T4 replacement, the decreased D1 activity results in abnormal thyroid hormone metabolism with decreased triiodothyronine (T3) generation from L-T4 and may result in decreased T3 bioavailability during critical stages of development.
Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/genética , Proteínas de Ligação a DNA/genética , Heterozigoto , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Mutação , Fenótipo , Adulto , Biomarcadores , Hipotireoidismo Congênito/diagnóstico , Feminino , Humanos , Masculino , Testes de Função Tireóidea , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
As vaccines against COVID-19 became available for distribution, the University of Miami addressed several challenges to facilitate vaccine allocation to the highest risk employees, patients, and students. Advanced use of technology allowed for the automation of key processes in the mass vaccination effort, which expedited vaccine outreach and scheduling, while maintaining routine delivery of healthcare services. The University's employees were initially prioritized for vaccination; employees who opted in were stratified into 5 vaccine administration phases. A similar process was implemented for students. When the state of Florida mandated expansion of vaccine allocation to include individuals aged 65 and older, an algorithm for patients was designed, taking into account age, comorbidities, date of last visit, and presence of an activated patient portal account. Innovative use of technology allowed for 19 â000 vaccines to be administered within the first 37 days, which comprised 100% vaccine allotment, without wasting a single vaccine dose.
RESUMO
Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4-5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap (p < 0.0001). Conclusions: rT3 and T3/rT3 ratio in DBS samples obtained from neonates can serve as biomarkers to detect MCT8 deficiency at birth.
Assuntos
Teste em Amostras de Sangue Seco , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/diagnóstico , Atrofia Muscular/diagnóstico , Mutação , Triagem Neonatal , Simportadores/genética , Tri-Iodotironina Reversa/sangue , Tri-Iodotironina/sangue , Biomarcadores/sangue , Diagnóstico Precoce , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/genética , Transportadores de Ácidos Monocarboxílicos/sangue , Transportadores de Ácidos Monocarboxílicos/deficiência , Hipotonia Muscular/sangue , Hipotonia Muscular/genética , Atrofia Muscular/sangue , Atrofia Muscular/genética , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Simportadores/sangue , Simportadores/deficiênciaRESUMO
Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 (MCT8), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 µg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 µg/dL and TSH <0.01 mU/L compared with the average in untreated MCT8-deficient infants of 5.1 µg/ and >8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.
Assuntos
Antitireóideos/uso terapêutico , Terapias Fetais/métodos , Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Hipotonia Muscular/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Propiltiouracila/uso terapêutico , Tiroxina/uso terapêutico , Adulto , Líquido Amniótico , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico por imagem , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/diagnóstico por imagem , Hipotonia Muscular/fisiopatologia , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/fisiopatologia , Gravidez , Simportadores/genética , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismoRESUMO
Mutations in the cell membrane thyroid hormone (TH) transporter monocarboxylate transporter (MCT) 8 produce severe neuropsychomotor defects and characteristic thyroid function test (TFT) abnormalities. Two children with mild neurological phenotypes and normal TFTs were found to harbor MCT8 gene variants of unknown significance (VUS), MCT8-R388Q that occurred de novo, and MCT8-Q212E. Normal TH transport and action in fibroblasts of MCT8-R388Q was demonstrated in a novel nonradioactive functional assay measuring the intracellular TH availability after L-T3 treatment. No genotype-phenotype correlation was found in additional family members carrying MCT8-Q212E. For the field of MCT8 deficiency, it is important to assess the significance of MCT8 gene VUS.
Assuntos
Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/genética , Atrofia Muscular/genética , Mutação , Simportadores/genética , Criança , Humanos , Masculino , Hipotonia Muscular/sangue , Atrofia Muscular/sangue , Linhagem , Fenótipo , Hormônios Tireóideos/sangue , Sequenciamento do ExomaRESUMO
The thyroglobulin (TG) gene encodes a protein required for thyroid hormone synthesis and iodine storage. Deleterious TG mutations produce congenital hypothyroidism (CH) often presenting with undetectable serum TG. Alu elements, common throughout the human genome, have a poly(dA) region in the 3' end of the strand. Herein two of four siblings of a consanguineous Sudanese family with CH, goiter, high initial serum thyrotropin, and undetectable TG were found to have a novel frameshift insertion of an Alu element within an exon of the TG gene: c.7909ins p.Y3637Ffs. This report demonstrates a novel Alu element insertion within TG causing CH.
Assuntos
Elementos Alu , Hipotireoidismo Congênito/genética , Mutagênese Insercional , Tireoglobulina/genética , Criança , Pré-Escolar , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/tratamento farmacológico , Feminino , Humanos , Tireoglobulina/sangue , Tiroxina/uso terapêuticoRESUMO
CONTEXT: Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10% to 15% of subjects worldwide but accounts for 60% of CH cases in the Sudan. OBJECTIVE: To investigate the molecular basis of CH in Sudanese families. DESIGN: Clinical phenotype reporting and serum thyroid hormone measurements. Deoxyribonucelic acid extraction for whole-exome sequencing and Sanger sequencing. SETTING: University research center. PATIENTS: Twenty-six Sudanese families with CH. INTERVENTION: Clinical evaluation, thyroid function tests, genetic sequencing, and analysis. Our samples and information regarding samples from the literature were used to compare TG (thyroglobulin) and TPO (thyroid peroxidase) mutation rates in the Sudanese population with all populations. RESULTS: Mutations were found in dual-oxidase 1 (DUOX1), dual-oxidase 2 (DUOX2), iodotyrosine deiodinase (IYD), solute-carrier (SLC) 26A4, SLC26A7, SLC5A5, TG, and TPO genes. The molecular basis of the CH in 7 families remains unknown. TG mutations were significantly higher on average in the Sudanese population compared with the average number of TG mutations in other populations (P < 0.05). CONCLUSIONS: All described mutations occur in domains important for protein structure and function, predicting the CH phenotype. Genotype prediction based on phenotype includes low or undetectable thyroglobulin levels for TG gene mutations and markedly higher thyroglobulin levels for TPO mutations. The reasons for higher incidence of TG gene mutations include gene length and possible positive genetic selection due to endemic iodine deficiency.
Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Mutação , Tireoglobulina/genética , Adolescente , Criança , Pré-Escolar , Hipotireoidismo Congênito/epidemiologia , Oxidases Duais/genética , Família , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Prevalência , Sudão/epidemiologiaRESUMO
CONTEXT: Selenocysteine insertion sequence binding protein 2 (SECISBP2, SBP2) is an essential factor for selenoprotein synthesis. Individuals with SBP2 defects have characteristic thyroid function test (TFT) abnormalities resulting from deficiencies in the selenoenzymes deiodinases. Eight families with recessive SBP2 gene mutations have been reported to date. We report 2 families with inherited defect in thyroid hormone metabolism caused by 4 novel compound heterozygous mutations in the SBP2 gene. CASE DESCRIPTIONS: Probands 1 and 2 presented with growth and developmental delay. Both had characteristic TFT with high T4, low T3, high reverse T3, and normal or slightly elevated TSH. The coding region of the SBP2 gene was sequenced and analysis of in vitro translated wild-type and mutant SBP2 proteins was performed. Sequencing of the SBP2 gene identified novel compound heterozygous mutations resulting in mutant SBP2 proteins E679D and R197* in proband 1, and K682Tfs*2 and Q782* in proband 2. In vitro translation of the missense E679D demonstrated all four isoforms, whereas R197* had only 2 shorter isoforms translated from downstream ATGs, and Q782*, K682Tfs*2 expressed isoforms with truncated C-terminus. Reduction in serum glutathione peroxidase enzymatic activity was also demonstrated in both probands. CONCLUSIONS: We report 2 additional families with mutations in the SBP2 gene, a rare inherited condition manifesting global selenoprotein deficiencies. Report of additional families with SBP2 deficiency and their evaluation over time is needed to determine the full spectrum of clinical manifestations in SBP2 deficiency and increase our understanding of the role played by SBP2 and selenoproteins in health and disease.
Assuntos
Proteínas de Ligação a RNA/genética , Selenoproteínas/deficiência , Doenças da Glândula Tireoide/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Adulto JovemRESUMO
By proposing TSH as a key negative regulator of bone turnover, recent studies in TSH receptor (TSHR) null mice challenged the established view that skeletal responses to disruption of the hypothalamic-pituitary-thyroid axis result from altered thyroid hormone (T(3)) action in bone. Importantly, this hypothesis does not explain the increased risk of osteoporosis in Graves' disease patients, in which circulating TSHR-stimulating antibodies are pathognomonic. To determine the relative importance of T(3) and TSH in bone, we compared the skeletal phenotypes of two mouse models of congenital hypothyroidism in which the normal reciprocal relationship between thyroid hormones and TSH was intact or disrupted. Pax8 null (Pax8(-/-)) mice have a 1900-fold increase in TSH and a normal TSHR, whereas hyt/hyt mice have a 2300-fold elevation of TSH but a nonfunctional TSHR. We reasoned these mice must display opposing skeletal phenotypes if TSH has a major role in bone, whereas they would be similar if thyroid hormone actions predominate. Pax8(-/-) and hyt/hyt mice both displayed delayed ossification, reduced cortical bone, a trabecular bone remodeling defect, and reduced bone mineralization, thus indicating that the skeletal abnormalities of congenital hypothyroidism are independent of TSH. Treatment of primary osteoblasts and osteoclasts with TSH or a TSHR-stimulating antibody failed to induce a cAMP response. Furthermore, TSH did not affect the differentiation or function of osteoblasts or osteoclasts in vitro. These data indicate the hypothalamic-pituitary-thyroid axis regulates skeletal development via the actions of T(3).