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Background: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter protein. MCT8 deficiency induces severe X-linked psychomotor retardation. Previous reports have documented delayed myelination in the central white matter (WM) in these patients; however, the regional pattern of myelination has not been fully elucidated. Here, we describe the regional evaluation of myelination in four patients with MCT8 deficiency. We also reviewed the myelination status of previously reported Japanese patients with MCT8 deficiency based on magnetic resonance imaging (MRI). Case Reports: Four patients were genetically diagnosed with MCT8 deficiency at the age of 4-9 months. In infancy, MRI signal of myelination was observed mainly in the cerebellar WM, posterior limb of internal capsule, and the optic radiation. There was progression of myelination with increase in age. Discussion: We identified 36 patients with MCT8 deficiency from 25 families reported from Japan. The available MRI images were obtained at the age of <2 years in 13 patients, between 2 and 4 years in six patients, between 4 and 6 years in three patients, and at ≥6 years in eight patients. Cerebellar WM, posterior limb of internal capsule, and optic radiation showed MRI signal of myelination by the age of 2 years, followed by centrum semiovale and corpus callosum by the age of 4 years. Most regions except for deep anterior WM showed MRI signal of myelination at the age of 6 years. Conclusion: The sequential pattern of myelination in patients with MCT8 deficiency was largely similar to that in normal children; however, delayed myelination of the deep anterior WM was a remarkable finding. Further studies are required to characterize the imaging features of patients with MCT8 deficiency.
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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.
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Pruebas con Sangre Seca , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonía Muscular/diagnóstico , Atrofia Muscular/diagnóstico , Mutación , Tamizaje Neonatal , Simportadores/genética , Triyodotironina Inversa/sangre , Triyodotironina/sangre , Biomarcadores/sangre , Diagnóstico Precoz , Femenino , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/sangre , Discapacidad Intelectual Ligada al Cromosoma X/genética , Transportadores de Ácidos Monocarboxílicos/sangre , Transportadores de Ácidos Monocarboxílicos/deficiencia , Hipotonía Muscular/sangre , Hipotonía Muscular/genética , Atrofia Muscular/sangre , Atrofia Muscular/genética , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Simportadores/sangre , Simportadores/deficienciaRESUMEN
Primary hyperparathyroidism (PHT) causes increased bone turnover, leading to reduction in bone mineral density (BMD). Parathyroidectomy is a definitive therapy and improves BMD in adult patients with PHT. However, there are no reports regarding alterations of BMD in pediatric or adolescent patients with PHT. Here, we report a case of a 13-yr-old boy with PHT who was referred to our institution for evaluation of hypercalcemia and hyperparathyroidism. Radiological investigation revealed an ectopic parathyroid adenoma below the right thyroid lobe. A minimally invasive radio-guided parathyroidectomy was successfully performed. We followed up the patient's BMD for three years both before and after parathyroidectomy. Over the course of three years, his BMD was steadily decreased, with z-scores of +0.506 at 13 yr and 9 mo, +0.162 at 14 yr and 9 mo, and -0.411 at 15 yr and 9 mo. BMD usually increases during peak height velocity in an adolescent and improves after parathyroidectomy in adult patients with PHT. However, our patient showed decreased BMD z-scores following parathyroidectomy. Therefore, the patient had an increased risk of fracture after parathyroidectomy and was followed up closely. Both height and BMD should be carefully evaluated after parathyroidectomy in pediatric and adolescent patients with PHT.
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BACKGROUND: Evidence is accumulating that the promoter region of the insulin-like growth factor I (IGF-I) gene polymorphism and low levels of IGF-I are associated with type 2 diabetes, cardiovascular disease and birth weight; however, the number of wild-type alleles is different in each country. OBJECTIVES: This study aimed to examine the 737/738 marker, a cytosine-adenine repeat in the promoter region of the IGF-I gene polymorphism, and plasma IGF-I levels in Japanese infants and analyze the genetic background. METHODS: Data were collected for 15 months in Kyoto Prefectural University of Medicine. The body composition parameters of all infants were determined at birth. At 5 days after birth, we took blood samples to measure the product size of the promoter region of the IGF-I gene polymorphism and plasma IGF-I. RESULTS: In a population-based sample of 160 subjects, 6 different alleles and 16 genotypes were identified in the promoter region of the IGF-I gene polymorphism. The existence of a 196-bp allele has proved to result in a low plasma IGF-I level, a small head and chest circumference (p < 0.05) and no significant for premature birth, short-birth height and low-birth weight. CONCLUSIONS: This is the first study showing the role of the promoter region of the IGF-I gene polymorphism and the level of plasma IGF-I and body composition parameters in Japanese infants. Our results suggest genetical influence on prenatal growth and serum IGF-I levels.
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Marcadores Genéticos , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/genética , Polimorfismo Genético , Tamaño Corporal , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Genotipo , Hospitales Universitarios , Humanos , Recién Nacido , Japón/epidemiología , Masculino , Regiones Promotoras Genéticas/genéticaRESUMEN
Desensitization of G-protein-coupled receptors (GPCR) includes receptor endocytosis. This phenomenon is suggested, at least for some receptors, to be associated with receptor resensitization. Here, we examined the role of receptor endocytosis for two different GPCR, the dopamine-1 (D1) receptor and the beta1-adrenoceptor (beta(1)-AR) in renal tissue. The functional role of receptor endocytosis was examined on Na+, K+ -ATPase activity in microdissected proximal tubules from rat kidney. The spatial regulation of endogenous D1 receptors and beta(1)-AR was examined by confocal microscopy techniques in LLCPK cells. Phenylarsine oxide (PAO) an endocytosis inhibitor, attenuated isoproterenol-induced decrease in Na+, K+ -ATPase activity but had no such effect on dopamine-induced decrease in Na+, K+ -ATPase activity. We have previously shown that isoproterenol sensitizes the renal dopamine system, by recruiting silent D1 receptors from the interior of the cell towards the plasma membrane. This effect was attenuated by PAO as well as by cytochalasin D while these substances had no effect on dopamine-induced D1 receptor recruitment. The beta(1)-AR was localized to the plasma membrane in control cells. Isoproterenol induced a rapid internalization of the beta(1)-AR; which was prevented by PAO. The results suggest that endocytosis of beta(1)-AR in renal proximal tubular cells is an important step in signal generation, while endocytosis of proximal tubular D1 receptor is not.
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Riñón/metabolismo , Receptores de Dopamina D1/metabolismo , Transducción de Señal/fisiología , Animales , Arsenicales , Línea Celular , AMP Cíclico/metabolismo , Dopamina/farmacología , Isoproterenol/farmacología , Riñón/citología , Masculino , Ratas , Ratas Sprague-Dawley , PorcinosRESUMEN
Nutrient-enriched milk has been advocated to enhance premature infants'growth and early nutritional intervention is effective for growth failure in very low birth weight infants (VLBWI). We studied the 3-yr-old physical growth of VLBWI who received nutrient enriched diets in the early neonatal period. VLBWI, who were born in 1996, received nutrient enriched milk around 1 mo of age. By contrast, in VLBWI born in 1998, nutrient enriched milk was started at 1-2 wk after birth. The daily calorie intake of VLBWI in 1998 had a tendency to be high compared to that of VLBWI in 1996. Height and body weight SD of 3-yr-old children who were born in 1998 tended to be greater than those of children who were born in 1996 (mean ± SD, -0.27 ± 0.54 vs. -1.01 ± 0.67; p=0.043, -0.47 ± 0.61 vs. -0.97 ± 1.10; p=0.31). Our study suggests that early feeding of nutrient-enriched milk for VLBWI in the neonatal period may affect their growth.
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A 1-year-old female with acute bilateral striatal necrosis secondary to exanthema subitum associated with human herpesvirus 6 (HHV-6) infection is reported. The patient was previously healthy. She presented with progressive neurologic signs of oral dyskinesia and involuntary movements, after suffering from exanthema subitum. Initial magnetic resonance imaging (MRI) demonstrated abnormal signals in the bilateral striatal regions. In addition, the serum HHV-6 IgM class antibody level was significantly increased. The patient is thought to be the first case of HHV-6 infection related infantile bilateral striatal necrosis (IBSN).
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Enfermedades de los Ganglios Basales , Cuerpo Estriado , Infecciones por Herpesviridae , Herpesvirus Humano 6/metabolismo , Necrosis/patología , Enfermedades de los Ganglios Basales/patología , Enfermedades de los Ganglios Basales/fisiopatología , Enfermedades de los Ganglios Basales/virología , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Cuerpo Estriado/virología , Femenino , Infecciones por Herpesviridae/patología , Infecciones por Herpesviridae/fisiopatología , Infecciones por Herpesviridae/virología , Humanos , Lactante , Imagen por Resonancia MagnéticaRESUMEN
Immature renal tubules are more tolerant to ischemia than mature renal tubules. Here we compared the developmental pattern for some cellular responses evoked by hypoxia and reoxygenation in renal proximal tubules from 10- and 40-day-old rats. Redistribution of Na(+)-K(+)-ATPase from the plasma membrane was studied by confocal microscopy techniques in primary cultured renal proximal tubular cells. The developmental expression of Na(+)-K(+)-ATPase, micro-calpain and heme oxygenase-1 was measured by RT-PCR techniques in rat renal cortex. In response to hypoxia Na(+)-K(+)-ATPase redistribution from the plasma membrane was almost 2-fold increased in cells isolated from mature kidneys compared with cells isolated from immature kidneys. Reoxygenation resulted in a complete reestablishment of Na(+)-K(+)-ATPase in the plasma membrane in the immature but not in the mature cells. The dissociation of Na(+)-K(+)-ATPase from the plasma membrane was associated with a reduced activity and a reduced expression of Na(+)-K(+)-ATPase in the mature but not in the immature tubular cells. The expression of micro-calpain, a factor shown to induce ischemic injury to proximal tubular cells, was significantly lower in the immature compared with the mature kidney, whereas the expression of heme oxygenase-1, a factor shown to protect from renal ischemic injury, was significantly higher in the immature kidney. The results help to explain the increased tolerance of the immature kidney to injury caused by ischemia and reperfusion.
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Hipoxia/patología , Túbulos Renales Proximales/patología , Animales , Animales Recién Nacidos , Secuencia de Bases , Calpaína/metabolismo , Cartilla de ADN , Hemo Oxigenasa (Desciclizante)/metabolismo , Hipoxia/enzimología , Inmunohistoquímica , Túbulos Renales Proximales/enzimología , Masculino , Microscopía Confocal , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
Renal dopamine1 receptor (D1R) can be recruited from intracellular compartments to the plasma membrane by D1R agonists and endogenous dopamine. This study examines the role of the cytoskeleton for renal D1R recruitment. The studies were performed in LLCPK-1 cells that have the capacity to form dopamine from L-dopa. In approximately 50% of the cells treated with L-dopa the D1R was found to be translocated from intracellular compartments towards the plasma membrane. Disruption of the microtubulin network by nocodazole significantly prevented translocation. In contrast, depolymerization of actin had no effect. In control cells D1R colocalized with NBD-C(6)-ceramide, a trans-Golgi fluorescent marker. This colocalization was disrupted in L-dopa-treated cells. Tetanus toxin, an inhibitor of exocytosis, prevented L-dopa-induced receptor recruitment. L-Dopa treatment resulted in activation of protein kinase C (PKC). To test the functional effect of D1R recruitment, the capacity of D1R agonists to activate PKC was studied. Activation of D1R significantly translocated PKC-alpha from intracellular compartments to the plasma membrane. Disruption of microtubules abolished D1R-mediated - but not phorbol-ester-mediated - translocation of PKC. We conclude that renal D1R recruitment requires an intact microtubulin network and occurs via Golgi-derived vesicles. These newly recruited receptors couple to the PKC signaling pathway.