Assuntos
Colestase , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Humanos , Masculino , Lactente , Colestase/etiologia , Colestase/diagnóstico , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/deficiência , Simportadores/genética , Ácidos e Sais Biliares/metabolismo , Fígado/patologia , Fígado/metabolismoRESUMO
BACKGROUND: Deficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan-Herndon-Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X-linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease. CASES: Patient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs. CONCLUSIONS: We aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype-genotype correlations for this rare condition.
Assuntos
Hipotonia Muscular , Humanos , Masculino , Hipotonia Muscular/genética , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/deficiência , Atrofia Muscular/genética , Atrofia Muscular/patologia , Lactente , Transtornos dos Movimentos/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Simportadores/genética , Simportadores/deficiência , Colômbia , Pré-Escolar , Fenótipo , Deficiências do Desenvolvimento/genéticaRESUMO
Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.
Assuntos
Deficiência Intelectual Ligada ao Cromossomo X , Transportadores de Ácidos Monocarboxílicos , Simportadores , Animais , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/terapia , Camundongos , Transportadores de Ácidos Monocarboxílicos/administração & dosagem , Transportadores de Ácidos Monocarboxílicos/deficiência , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Hipotonia Muscular , Atrofia Muscular , Mutação , Sorogrupo , Simportadores/administração & dosagem , Simportadores/deficiência , Simportadores/genética , Simportadores/metabolismo , Tri-Iodotironina/metabolismoRESUMO
CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.
Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Transportadores de Ácidos Monocarboxílicos/deficiência , Hipotonia Muscular/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Simportadores/deficiência , Tri-Iodotironina/análogos & derivados , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/genética , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/sangue , Hipotonia Muscular/genética , Atrofia Muscular/sangue , Atrofia Muscular/genética , Mutação , Estudos Retrospectivos , Simportadores/genética , Resultado do Tratamento , Tri-Iodotironina/administração & dosagem , Tri-Iodotironina/efeitos adversos , Tri-Iodotironina/sangue , Adulto JovemRESUMO
Citrate lies at a critical node of metabolism, linking tricarboxylic acid metabolism and lipogenesis via acetyl-coenzyme A. Recent studies have observed that deficiency of the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, dysregulates hepatic metabolism and drives pediatric epilepsy. To examine how NaCT contributes to citrate metabolism in cells relevant to the pathophysiology of these diseases, we apply 13C isotope tracing to SLC13A5-deficient hepatocellular carcinoma (HCC) cells and primary rat cortical neurons. Exogenous citrate appreciably contributes to intermediary metabolism only under hypoxic conditions. In the absence of glutamine, citrate supplementation increases de novo lipogenesis and growth of HCC cells. Knockout of SLC13A5 in Huh7 cells compromises citrate uptake and catabolism. Citrate supplementation rescues Huh7 cell viability in response to glutamine deprivation or Zn2+ treatment, and NaCT deficiency mitigates these effects. Collectively, these findings demonstrate that NaCT-mediated citrate uptake is metabolically important under nutrient-limited conditions and may facilitate resistance to metal toxicity.
Assuntos
Citratos/metabolismo , Nutrientes/metabolismo , Simportadores/metabolismo , Acetilcoenzima A/metabolismo , Adulto , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Edição de Genes , Glutamina/metabolismo , Glutamina/farmacologia , Humanos , Lipogênese , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Neurônios/citologia , Neurônios/metabolismo , Nutrientes/farmacologia , Ratos , Simportadores/deficiência , Simportadores/genética , Zinco/farmacologiaRESUMO
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
NaCT/SLC13A5 is a Na+-coupled transporter for citrate in hepatocytes, neurons, and testes. It is also called mINDY (mammalian ortholog of 'I'm Not Dead Yet' in Drosophila). Deletion of Slc13a5 in mice leads to an advantageous phenotype, protecting against diet-induced obesity, and diabetes. In contrast, loss-of-function mutations in SLC13A5 in humans cause a severe disease, EIEE25/DEE25 (early infantile epileptic encephalopathy-25/developmental epileptic encephalopathy-25). The difference between mice and humans in the consequences of the transporter deficiency is intriguing but probably explainable by the species-specific differences in the functional features of the transporter. Mouse Slc13a5 is a low-capacity transporter, whereas human SLC13A5 is a high-capacity transporter, thus leading to quantitative differences in citrate entry into cells via the transporter. These findings raise doubts as to the utility of mouse models to evaluate NaCT biology in humans. NaCT-mediated citrate entry in the liver impacts fatty acid and cholesterol synthesis, fatty acid oxidation, glycolysis, and gluconeogenesis; in neurons, this process is essential for the synthesis of the neurotransmitters glutamate, GABA, and acetylcholine. Thus, SLC13A5 deficiency protects against obesity and diabetes based on what the transporter does in hepatocytes, but leads to severe brain deficits based on what the transporter does in neurons. These beneficial versus detrimental effects of SLC13A5 deficiency are separable only by the blood-brain barrier. Can we harness the beneficial effects of SLC13A5 deficiency without the detrimental effects? In theory, this should be feasible with selective inhibitors of NaCT, which work only in the liver and do not get across the blood-brain barrier.
Assuntos
Simportadores/deficiência , Animais , Barreira Hematoencefálica , Osso e Ossos/metabolismo , Ácido Cítrico/metabolismo , Ciclo do Ácido Cítrico/genética , Esmalte Dentário/metabolismo , Diabetes Mellitus/metabolismo , Transportadores de Ácidos Dicarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Dicarboxílicos/deficiência , Transportadores de Ácidos Dicarboxílicos/fisiologia , Modelos Animais de Doenças , Proteínas de Drosophila/fisiologia , Fígado Gorduroso/metabolismo , Feminino , Células Germinativas/metabolismo , Hepatócitos/metabolismo , Humanos , Recém-Nascido , Transporte de Íons , Longevidade/genética , Masculino , Camundongos , Camundongos Knockout , Mutação , Neoplasias/metabolismo , Neurônios/metabolismo , Conformação Proteica , Espasmos Infantis/genética , Especificidade da Espécie , Simportadores/antagonistas & inibidores , Simportadores/genética , Simportadores/fisiologiaRESUMO
The retina is part of the central nerve system (CNS) and has various interneurons and sensory neurons such as photoreceptor cells. Retinitis pigmentosa (RP) is an inherited condition that is characterized by photoreceptor degeneration. Herein, we developed a fluorescent probe-NeuA-for detecting retinal neuronal cells and applied NeuA to discriminate between healthy and RP retinas. The staining pattern of NeuA in the retinas of healthy and RP mouse models was examined inâ vitro, ex vivo and inâ vivo using confocal microscopy, the fluorescent fundus microscopy and optical coherent tomography (OCT). NeuA strongly stained the outer segment layer of photoreceptor cells and some bipolar cells in the healthy retina, but there was only weak staining in the photoreceptor degenerated retinas. Therefore, NeuA probe can be used as the detecting RP tools in the preclinical conditions.
Assuntos
Corantes Fluorescentes/química , Neurônios/patologia , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/patologia , Animais , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Simportadores/deficiênciaRESUMO
Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms. Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition. We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP. Continuous arterial BP and heart rate (HR) were reduced in mINDY-KO mice. Concomitantly, urinary catecholamine content was lower, and the decreases in BP and HR by mIndy deletion were attenuated after autonomic ganglionic blockade. Catecholamine biosynthesis pathways were reduced in mINDY-KO adrenals using unbiased microarray analysis. Citrate, the main mINDY substrate, increased catecholamine content in pheochromocytoma cells, while pharmacological inhibition of citrate uptake blunted the effect. Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis. Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.
Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/fisiologia , Sistema Simpático-Suprarrenal/fisiologia , Simportadores/genética , Simportadores/fisiologia , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/fisiologia , Animais , Restrição Calórica , Catecolaminas/biossíntese , Linhagem Celular , Células Cromafins/fisiologia , Transportadores de Ácidos Dicarboxílicos/deficiência , Expressão Gênica , Frequência Cardíaca/genética , Frequência Cardíaca/fisiologia , Longevidade/genética , Longevidade/fisiologia , Malatos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Atividade Motora/genética , Atividade Motora/fisiologia , Piridinas/farmacologia , Simportadores/deficiênciaRESUMO
Oligodendrocytes (OLs) are important for myelination and shuttling energy metabolites lactate and pyruvate toward axons through their expression of monocarboxylate transporter 1 (MCT1). Recent studies suggest that loss of OL MCT1 causes axonal degeneration. However, it is unknown how widespread and chronic loss of MCT1 in OLs specifically affects neuronal energy homeostasis with aging. To answer this, MCT1 conditional null mice were generated that allow for OL-specific MCT1 ablation. We observe that MCT1 loss from OL lineage cells is dispensable for normal myelination and axonal energy homeostasis early in life. By contrast, loss of OL lineage MCT1 expression with aging leads to significant axonal degeneration with concomitant hypomyelination. These data support the hypothesis that MCT1 is important for neuronal energy homeostasis in the aging central nervous system (CNS). The reduction in OL MCT1 that occurs with aging may enhance the risk for axonal degeneration and atrophy in neurodegenerative diseases.
Assuntos
Axônios/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Bainha de Mielina/metabolismo , Degeneração Neural/metabolismo , Oligodendroglia/metabolismo , Simportadores/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Transportadores de Ácidos Monocarboxílicos/deficiência , Bainha de Mielina/patologia , Oligodendroglia/patologia , Simportadores/deficiênciaRESUMO
Stroke severely impairs quality of life and has a high mortality rate. On the other hand, dietary docosahexaenoic acid (DHA) prevents neuronal damage. In this review, we describe the effects of dietary DHA on ischemic stroke-associated neuronal damage and its role in stroke prevention. Recent epidemiological studies have been conducted to analyze stroke prevention through DHA intake. The effects of dietary intake and supply of DHA to neuronal cells, DHA-mediated inhibition of neuronal damage, and its mechanism, including the effects of the DHA metabolite, neuroprotectin D1 (NPD1), were investigated. These studies revealed that DHA intake was associated with a reduced risk of stroke. Moreover, studies have shown that DHA intake may reduce stroke mortality rates. DHA, which is abundant in fish oil, passes through the blood-brain barrier to accumulate as a constituent of phospholipids in the cell membranes of neuronal cells and astrocytes. Astrocytes supply DHA to neuronal cells, and neuronal DHA, in turn, activates Akt and Raf-1 to prevent neuronal death or damage. Therefore, DHA indirectly prevents neuronal damage. Furthermore, NDP1 blocks neuronal apoptosis. DHA, together with NPD1, may block neuronal damage and prevent stroke. The inhibitory effect on neuronal damage is achieved through the antioxidant (via inducing the Nrf2/HO-1 system) and anti-inflammatory effects (via promoting JNK/AP-1 signaling) of DHA.
Assuntos
Dano Encefálico Crônico/prevenção & controle , Ácidos Docosa-Hexaenoicos/uso terapêutico , AVC Isquêmico/dietoterapia , Degeneração Neural/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Transporte Biológico , Barreira Hematoencefálica , Dano Encefálico Crônico/etiologia , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacocinética , Gorduras na Dieta/uso terapêutico , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacocinética , Ácidos Docosa-Hexaenoicos/farmacologia , Proteínas de Ligação a Ácido Graxo/fisiologia , Óleos de Peixe/administração & dosagem , Óleos de Peixe/farmacocinética , Humanos , Incidência , AVC Isquêmico/complicações , AVC Isquêmico/epidemiologia , Lipídeos de Membrana/metabolismo , Camundongos , Proteínas de Neoplasias/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Óleos de Plantas/administração & dosagem , Óleos de Plantas/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Simportadores/deficiência , Simportadores/fisiologia , Ácido alfa-Linolênico/farmacocinéticaRESUMO
SLC13A5/NaCT is a sodium-coupled citrate transporter expressed in the plasma membrane of the liver, testis, and brain. In these tissues, SLC13A5 has important functions in the synthesis of fatty acids, cholesterol, and neurotransmitters. In recent years, patients homozygous for recessive mutations in SLC13A5, known as SLC13A5 deficiency [early infantile epileptic encephalopathy-25 (EIEE-25)], exhibit severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting tooth development. Although the pathogenesis of SLC13A5 deficiency remains not clearly understood, cytoplasmic citrate deficits, decreased energy status in neurons, and citrate-zinc chelation are hypothesized to explain the neurological deficits. However, no study has examined the possibility of specific pharmacological drugs and/or lifestyle changes synergizing with heterozygosity of SLC13A5 deficiency to increase the risk of EIEE-25 clinical phenotype. Here, we report on a heterozygous SLC13A5-deficient patient who demonstrated evidence of pharmaco-synergistic heterozygosity upon administration of metformin, valproic acid, and starvation. The report illustrates the importance of careful consideration of the potential adverse effects of specific pharmacological treatments in patients with heterozygosity for disease-causing recessive mutations in SLC13A5.
Assuntos
Epilepsia/genética , Metformina/efeitos adversos , Simportadores/deficiência , Ácido Valproico/efeitos adversos , Adulto , Substituição de Aminoácidos , Amônia/sangue , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Transtorno Autístico/genética , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/genética , Citratos/sangue , Transportadores de Ácidos Dicarboxílicos/fisiologia , Proteínas de Drosophila/fisiologia , Epilepsia/sangue , Epilepsia/induzido quimicamente , Epilepsia/etiologia , Feminino , Privação de Alimentos , Heterozigoto , Humanos , Lactatos/sangue , Longevidade/genética , Metformina/uso terapêutico , Camundongos , Mutação de Sentido Incorreto , Mutação Puntual , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Psicotrópicos/uso terapêutico , Piruvatos/sangue , Recidiva , Espasmos Infantis/genética , Espasmos Infantis/metabolismo , Simportadores/genética , Simportadores/fisiologia , Anormalidades Dentárias/genética , Ácido Valproico/uso terapêuticoAssuntos
Ácidos Cólicos/sangue , Vesícula Biliar/anormalidades , Cálculos Biliares/genética , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Erros Inatos do Metabolismo de Esteroides/genética , Simportadores/deficiência , Adolescente , Animais , Ácidos Cólicos/metabolismo , Modelos Animais de Doenças , Feminino , Vesícula Biliar/patologia , Cálculos Biliares/metabolismo , Cálculos Biliares/patologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Especificidade da Espécie , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/metabolismo , Erros Inatos do Metabolismo de Esteroides/patologia , Simportadores/genéticaRESUMO
OBJECTIVES: The aim of the study was to explore the significance of sodium taurocholate cotransporting polypeptide (NTCP) deficiency and its clinical features in Chinese children presenting with isolated persistent hypercholanemia. METHODS: The exon and adjacent regions of SLC10A1, the gene encoding NTCP, were sequenced in 33 Chinese children presenting with isolated hypercholanemia. Clinical history and medical data were reviewed. Growth milestones were compared with the national standard. The serum direct bilirubin concentration at last follow-up was compared with age- and sex-matched controls. RESULTS: A variant, c.800C>T, p. S267F of SLC10A1 was detected in all subjects; 30 patients were homozygotes and 3 were compound heterozygotes. Nine patients presented with transient neonatal cholestasis, and 1 with a persistent mild conjugated hyperbilirubinemia. The serum direct bilirubin level in NTCP-deficient patients was significantly higher than age- and sex-matched controls even after the neonatal cholestasis stage (2.85â±â1.50 vs 1.49â±â0.70âµmol/L, Pâ=â0.00008). No growth delay or other severe long-term clinical consequences were observed. CONCLUSIONS: NTCP deficiency is the exclusive or major cause of isolated hypercholanemia in Han Chinese children, with c.800C>T the major contributing genetic variation. The defect may affect bilirubin metabolism and present as transient neonatal cholestasis and/or persistent mild conjugated hyperbilirubinmia, but with no apparent long-term clinical consequences.
Assuntos
Bilirrubina , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Criança , Homozigoto , Humanos , Recém-Nascido , Transportadores de Ânions Orgânicos Dependentes de Sódio/deficiência , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Simportadores/deficiência , Simportadores/genéticaRESUMO
Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.
Assuntos
Transportadores de Ácidos Monocarboxílicos/deficiência , Simportadores/deficiência , Hormônios Tireóideos/administração & dosagem , Hormônios Tireóideos/farmacologia , Administração Intranasal , Animais , Encéfalo/citologia , Camundongos , Transportadores de Ácidos Monocarboxílicos/genética , Mutação , Transdução de Sinais/efeitos dos fármacos , Simportadores/genética , Hormônios Tireóideos/sangueRESUMO
Lipids and essential fatty acids are required for normal brain development and continued photoreceptor membrane biogenesis for the maintenance of vision. The blood-brain barrier and blood-eye barriers prohibit the free diffusion of solutes into the brain and eye so that transporter-mediated uptake predominates at these barriers. The major facilitator superfamily of transporters constitutes one of the largest families of facilitative transporters across all domains of life. A unique family member, major facilitator superfamily domain containing 2a (Mfsd2a) is a lysophosphatidylcholine (LPC) transporter expressed at the blood-brain and blood-retinal barriers and demonstrated to be the major pathway for brain and eye accretion of docosahexaenoic acid (DHA) as an LPC. In addition to LPC-DHA, Mfsd2a can transport other LPCs containing mono- and polyunsaturated fatty acids. Mfsd2a deficiency in mouse and humans results in severe microcephaly, underscoring the importance of LPC transport in brain development. Beyond its role in brain development, LPC-DHA uptake in the brain and eye negatively regulates de novo lipogenesis. This review focuses on the current understanding of the physiological roles of Mfsd2a in the brain and eye and the proposed transport mechanism of Mfsd2a.
Assuntos
Encéfalo/metabolismo , Olho/metabolismo , Simportadores/metabolismo , Animais , Transporte Biológico , Barreira Hematoencefálica , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Simportadores/deficiênciaRESUMO
BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.
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Biomarcadores/análise , Transtornos Mentais/patologia , Transportadores de Ácidos Monocarboxílicos/deficiência , Doenças Musculares/patologia , Transtornos do Neurodesenvolvimento/patologia , Simportadores/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Agências Internacionais , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Doenças Musculares/etiologia , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Simportadores/genética , Adulto JovemRESUMO
Monocarboxylate transporter 1 (MCT1) deficiency was first described in 2014 by Hasselt et al. as a novel genetic cause of recurrent ketoacidosis. Patients present in the first year of life with acute episodes of ketoacidosis triggered by fasting or infections. Patients with homozygous mutations are known to have a more severe phenotype with mild to moderate developmental delay and an increased prevalence of epilepsy. There is only one recent report of the neuroimaging findings of this disorder as reported by Al-Khawaga et al. (Front Pediatr. 7:299, 2019). We report the neuroimaging abnormalities in two siblings with similar clinical presentation of recurrent ketoacidosis, seizures, and developmental delay. Whole exome sequencing in the younger sibling confirmed a known pathogenic homozygous mutation in MCT1, also known as SLC16A1 gene. Brain MRI showed a similar very distinctive pattern of signal abnormality at the gray-white matter junction, basal ganglia, and thalami in both patients. Both siblings had agenesis of the corpus callosum. Knowledge of this pattern of brain involvement might contribute to an earlier diagnosis and timely management of this rare and under recognized disorder.
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Encefalopatias/diagnóstico por imagem , Encefalopatias/genética , Transportadores de Ácidos Monocarboxílicos/deficiência , Neuroimagem/métodos , Simportadores/deficiência , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/genética , Feminino , Mutação da Fase de Leitura , Humanos , Lactente , Cetose/genética , Convulsões/genética , IrmãosAssuntos
Acidose/metabolismo , Dieta Cetogênica/efeitos adversos , Epilepsia Tipo Ausência/metabolismo , Transportadores de Ácidos Monocarboxílicos/deficiência , Índice de Gravidade de Doença , Simportadores/deficiência , Acidose/genética , Pré-Escolar , Epilepsia Tipo Ausência/dietoterapia , Epilepsia Tipo Ausência/genética , Feminino , Humanos , Transportadores de Ácidos Monocarboxílicos/genética , Simportadores/genéticaRESUMO
Schwann cell (SC)-specific monocarboxylate transporter 1 (MCT1) knockout mice were generated by mating MCT1 f/f mice with myelin protein zero (P0)-Cre mice. P0-Cre+/- , MCT1 f/f mice have no detectable early developmental defects, but develop hypomyelination and reduced conduction velocity in sensory, but not motor, peripheral nerves during maturation and aging. Furthermore, reduced mechanical sensitivity is evident in aged P0-Cre+/- , MCT1 f/f mice. MCT1 deletion in SCs impairs both their glycolytic and mitochondrial functions, leading to altered lipid metabolism of triacylglycerides, diacylglycerides, and sphingomyelin, decreased expression of myelin-associated glycoprotein, and increased expression of c-Jun and p75-neurotrophin receptor, suggesting a regression of SCs to a less mature developmental state. Taken together, our results define the contribution of SC MCT1 to both SC metabolism and peripheral nerve maturation and aging.