RESUMEN
BACKGROUND: NKX2-1 mutations have been described in several patients with primary congenital hypothyroidism, respiratory distress, and benign hereditary chorea, which are classical manifestations of the brain-thyroid-lung syndrome (BTLS). METHODS: The NKX2-1 gene was sequenced in the members of a Brazilian family with clinical features of BTLS, and a novel monoallelic mutation was identified in the affected patients. We introduced the mutation in an expression vector for the functional characterization by transfection experiments using both thyroidal and lung-specific promoters. RESULTS: The mutation is a deletion of a cytosine at position 834 (ref. sequence NM_003317) (c.493delC) that causes a frameshift with formation of an abnormal protein from amino acid 165 and a premature stop at position 196. The last amino acid of the nuclear localization signal, the whole homeodomain, and the carboxy-terminus of NKX2-1 are all missing in the mutant protein, which has a premature stop codon at position 196 (p.Arg165Glyfs*32). The p.Arg165Glyfs*32 mutant does not bind DNA, and it is unable to transactivate the thyroglobulin (Tg) and the surfactant protein-C (SP-C) promoters. Interestingly, a dose-dependent dominant negative effect of the p.Arg165Glyfs*32 was demonstrated only on the Tg promoter, but not on the SP-C promoter. This effect was also noticed when the mutation was tested in presence of PAX8 or cofactors that synergize with NKX2-1 (P300 and TAZ). The functional effect was also compared with the data present in the literature and demonstrated that, so far, it is very difficult to establish a specific correlation among NKX2-1 mutations, their functional consequence, and the clinical phenotype of affected patients, thus suggesting that the detailed mechanisms of transcriptional regulation still remain unclear. CONCLUSIONS: We describe a novel NKX2-1 mutation and demonstrate that haploinsufficiency may not be the only explanation for BTLS. Our results indicate that NKX2-1 activity is also finely regulated in a tissue-specific manner, and additional studies are required to better understand the complexities of genotype-phenotype correlations in the NKX2-1 deficiency syndrome.
Asunto(s)
Atetosis/genética , Corea/genética , Hipotiroidismo Congénito/genética , Mutación del Sistema de Lectura , Proteínas Nucleares/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Factores de Transcripción/genética , Adolescente , Atetosis/metabolismo , Corea/metabolismo , Codón de Terminación , Hipotiroidismo Congénito/metabolismo , Femenino , Células HEK293 , Células HeLa , Humanos , Masculino , Madres , Señales de Localización Nuclear , Proteínas Nucleares/metabolismo , Especificidad de Órganos , Proteínas Recombinantes/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Hermanos , Factor Nuclear Tiroideo 1 , Factores de Transcripción/metabolismoRESUMEN
Clinical observations suggest a disturbance of striatal dopaminergic function in familial paroxysmal dystonic choreoathetosis (PDC). The authors used PET with [11C]dihydrotetrabenazine (DTBZ) to study striatal dopaminergic innervation in PDC. The results did not reveal abnormal DTBZ binding potential in PDC striatum. This suggests that dopaminergic abnormalities, if present, may be due to altered regulation of dopamine release or to postsynaptic mechanisms, rather than to an altered density of nigrostriatal innervation.
Asunto(s)
Atetosis/diagnóstico por imagen , Corea/diagnóstico por imagen , Distonía/diagnóstico por imagen , Tetrabenazina/análogos & derivados , Adulto , Anciano , Atetosis/genética , Atetosis/metabolismo , Sitios de Unión , Radioisótopos de Carbono , Corea/genética , Corea/metabolismo , Distonía/genética , Distonía/metabolismo , Humanos , Cinética , Masculino , Persona de Mediana Edad , Tomografía Computarizada de EmisiónRESUMEN
OBJECTIVES: To determine whether resting metabolic rate (RMR) is higher or lower in adults with cerebral palsy compared with the RMR of control subjects and to further examine physical characteristics of cerebral palsy that might affect RMR. DESIGN: Twenty-one adults with cerebral palsy (9 women, 12 men) were compared with 50 control subjects (25 men, 25 women) within the same age range (18 through 50 years). The following measurements were made: RMR by indirect calorimetry, anthropometrics, body composition, and habitual physical activity patterns. The study was conducted at the University of Vermont General Clinical Research Center and the Ball State University Human Performance Laboratory. STATISTICAL ANALYSES: Mean values +/- standard deviations, t tests, Pearson product-moment correlation coefficients, analysis of covariance, and stepwise multiple correlation regression analysis were used to examine the relationships among variables of interest. RESULTS: No significant differences were found in body weight, body mass index, fat mass, percentage body fat, and measured RMR between the two groups. The subjects with cerebral palsy were significantly shorter, had less fat-free mass, and expended fewer kilocalories in leisure time activities than the control subjects. After statistical adjustment for differences in fat-free mass, the subjects with cerebral palsy had a 14% (P < .001) higher adjusted RMR (1,742 kcal/day) compared with that of the control subjects (1,534 kcal/day). According to stepwise regression analysis, RMR was best predicted in the entire sample by fat-free mass and the presence or absence of athetosis (multiple R = .83, P < .001). The presence of cerebral palsy alone was not significantly correlated with RMR. CONCLUSIONS: The increased energy requirements of adults with cerebral palsy can be partially explained by athetotic movements. In this sample, the presence of athetosis increased RMR by an average of 524 kcal/day.
Asunto(s)
Atetosis/metabolismo , Parálisis Cerebral/metabolismo , Metabolismo Energético , Adolescente , Adulto , Antropometría , Calorimetría Indirecta , Parálisis Cerebral/clasificación , Femenino , Hemiplejía/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Espasticidad Muscular/metabolismo , Paraplejía/metabolismo , Cuadriplejía/metabolismo , Análisis de RegresiónRESUMEN
Twenty-three children with 4 clinical subtypes of cerebral palsy were studied using 2-deoxy-2(18F)fluoro-D-glucose (FDG) and positron emission tomography (PET). Subtypes included spastic quadriparesis (N = 6), spastic diplegia (N = 4), infantile hemiplegia (N = 8), and choreoathetosis (N = 5). FDG-PET images were correlated with magnetic resonance imaging or computed tomography. Although the location of glucose metabolic abnormalities corresponded, in general, to abnormalities of brain structure demonstrated by structural imaging studies, the distribution of metabolic impairment almost invariably extended beyond the region of anatomic involvement. The following observations in specific subtypes of cerebral palsy were determined with FDG-PET: (1) In spastic diplegic patients, PET revealed focal areas of cortical hypometabolism in the absence of apparent structural abnormality; (2) A relatively normal pattern of cortical metabolism was observed in most patients with choreoathetoid cerebral palsy, despite marked hypometabolism in the thalamus and lenticular nuclei; and (3) In patients with infantile hemiplegia, FDG-PET disclosed symmetric cerebellar glucose metabolism with absence of crossed cerebellar hypometabolism (diaschisis). This finding is contrary to the typical persistence of crossed cerebellar diaschisis in adult patients with acquired cerebral lesions and suggests metabolic recovery due to developmental plasticity. The possibility that FDG-PET may be clinically useful in identifying the cerebral palsy patient with potential learning handicap and in the study of functional recovery or sparing following brain injury should be explored further.
Asunto(s)
Encéfalo/metabolismo , Parálisis Cerebral/metabolismo , Glucosa/metabolismo , Adolescente , Atetosis/diagnóstico por imagen , Atetosis/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Parálisis Cerebral/clasificación , Parálisis Cerebral/diagnóstico por imagen , Niño , Preescolar , Corea/diagnóstico por imagen , Corea/metabolismo , Femenino , Hemiplejía/diagnóstico por imagen , Hemiplejía/metabolismo , Humanos , Lactante , Masculino , Espasticidad Muscular , Plasticidad Neuronal , Paraplejía/diagnóstico por imagen , Paraplejía/metabolismo , Estudios Prospectivos , Tomografía Computarizada de EmisiónRESUMEN
This report analyzes a rare case of double athetosis with Bielschowsky bodies. These bodies are pleomorphic intra-neuronal PAS positive deposits mainly found in the lateral palladium of both sides. Clinically the patient was diagnosed as "double athetosis" and mild mental retardation. In her childhood she went through seizure attacks several times. The degree of athetosis was more severe in the upper extremities than in the lower ones. At the age of 25 she died from suffocation. Post-mortem findings: The brain weighed 1520 g. The cerebral cortex and cerebellum were not atrophic and externally not remarkable. Microscopically the most remarkable finding was PAS positive intra neuronal inclusions mainly restricted to the lateral pallidum, which are known as "Bielschowsky bodies." They varied in size and shape, and divided into 2 types according to their structural features. One is rather round type mostly in the intra-neuronal perikarya, and the other is small round but sometimes sausage-like in shape which is thought to be intra-axonal. We investigated the distribution of these deposits in and around the lateral pallidum. The distribution was different between these 2 types, that is, small and intra-axonal inclusions were seen "diffuse" all over the lateral pallidum and a little were in medial lamina which lies between lateral and medial pallidum, while large intra-perikaryal type were strictly restricted in the lateral pallidum and dominantly found near the internal capsule. This patient experienced generalized convulsion several times in her childhood but severe ischemic change was not seen in cerebral structures, especially in the hippocampus. Electron microscopically these bodies consisted of the accumulation of irregular fine fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Atetosis/patología , Globo Pálido/ultraestructura , Adulto , Atetosis/metabolismo , Femenino , Globo Pálido/metabolismo , Glucosa/metabolismo , Glucógeno/metabolismo , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/ultraestructura , Neuronas/metabolismo , Neuronas/patologíaAsunto(s)
Atetosis/metabolismo , Corea/metabolismo , Hipoxantina Fosforribosiltransferasa/sangre , Ácido Úrico/sangre , Adolescente , Eritrocitos/enzimología , Fibroblastos/enzimología , Humanos , Hipoxantinas/metabolismo , Discapacidad Intelectual/metabolismo , Masculino , Pentosiltransferasa/metabolismo , Automutilación/metabolismoRESUMEN
We studied five patients with paroxysmal kinesigenic choreoathetosis (PKC) to evaluate the minimum effective plasma concentration of phenytoin. In two children, the minimum concentration necessary to control symptoms approximated the concentrations necessary to control epileptic seizures. In three adults, symptoms were controlled with concentrations of phenytoin well below the therapeutic range of phenytoin in epilepsy. These findings suggest an age-dependent change in the disease state, and support the concept that the clinical course of PKC may be explained by delayed maturation of extrapyramidal systems.
Asunto(s)
Atetosis/tratamiento farmacológico , Atetosis/metabolismo , Corea/tratamiento farmacológico , Corea/metabolismo , Fenitoína/uso terapéutico , Acetilcolina/metabolismo , Atetosis/genética , Niño , Preescolar , Corea/genética , Dopamina/metabolismo , Femenino , Humanos , Masculino , Fenitoína/sangreAsunto(s)
Conducta , Química Encefálica , Encéfalo/metabolismo , Animales , Atetosis/metabolismo , Conducta Animal , Aminas Biogénicas/metabolismo , Catecolaminas/metabolismo , Corea/metabolismo , Depresión/metabolismo , Dopamina/farmacología , Humanos , Ácido Hidroxiindolacético/metabolismo , Hipercinesia/metabolismo , Monoaminooxidasa/metabolismo , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Serotonina/metabolismo , Conducta Sexual/efectos de los fármacos , Tirosina/metabolismo , Ácido Vanilmandélico/metabolismoAsunto(s)
Atetosis/metabolismo , Discapacidad Intelectual/metabolismo , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , Automutilación/metabolismo , Gota/diagnóstico , Gota/etiología , Humanos , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/etiología , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/metabolismo , Tamizaje Masivo , Aberraciones Cromosómicas Sexuales , Ácido Úrico/orinaAsunto(s)
Atetosis/metabolismo , Discapacidad Intelectual/genética , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , Purinas/metabolismo , Automutilación/genética , Atetosis/genética , Corea/genética , Conducta Compulsiva , Enfermedades en Gemelos , Femenino , Humanos , Recién Nacido , Síndrome de Lesch-Nyhan/genética , Síndrome de Lesch-Nyhan/metabolismo , Masculino , Mutación , Embarazo , Ácido Úrico/sangreAsunto(s)
Actividad Motora/efectos de los fármacos , Atetosis/tratamiento farmacológico , Atetosis/metabolismo , Catecolaminas/metabolismo , Inhibidores de la Colinesterasa/metabolismo , Corea/tratamiento farmacológico , Corea/metabolismo , Dihidroxifenilalanina/metabolismo , Dopamina/metabolismo , Tractos Extrapiramidales/fisiopatología , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/metabolismo , Trastornos del Movimiento/fisiopatología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Fenotiazinas/metabolismo , Reserpina/uso terapéutico , Tetrabenazina/uso terapéuticoAsunto(s)
Atetosis/diagnóstico , Errores Innatos del Metabolismo de la Purina-Pirimidina/diagnóstico , Automutilación/diagnóstico , Alopurinol/uso terapéutico , Atetosis/complicaciones , Atetosis/tratamiento farmacológico , Atetosis/metabolismo , Azatioprina/uso terapéutico , Benzofuranos/uso terapéutico , Niño , Preescolar , Guanina , Humanos , Hipoxantinas/sangre , Hipoxantinas/orina , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/metabolismo , Japón , Cetonas/uso terapéutico , Síndrome de Lesch-Nyhan/diagnóstico , Síndrome de Lesch-Nyhan/terapia , Masculino , Paraplejía/etiología , Pentosiltransferasa/metabolismo , Fenoles/uso terapéutico , Errores Innatos del Metabolismo de la Purina-Pirimidina/complicaciones , Errores Innatos del Metabolismo de la Purina-Pirimidina/tratamiento farmacológico , Errores Innatos del Metabolismo de la Purina-Pirimidina/metabolismo , Espasmo/etiología , Ácido Úrico/sangre , Ácido Úrico/orina , Xantinas/sangre , Xantinas/orinaRESUMEN
Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-(14)C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol. In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-(14)C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of (14)C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does not contribute significantly to the formation of uric acid in either normal man or in patients with HG-PRTase deficiency.HG-PRTase was not completely absent in red blood cells from a boy with the Lesch-Nyhan syndrome; with hypoxanthine as substrate, the activity in erythrocyte hemolysates was 0.64% of normal values.