RESUMEN
A 7-month-old-term male infant presented with cough, tachypnoea, hypoxaemia and post-tussive emesis. Clinical history was significant for respiratory failure and pulmonary hypertension in the neonatal period requiring assisted ventilation, congenital hypothyroidism, mild hypotonia, recurrent respiratory infections, hypoxaemia requiring supplemental oxygen and nasogastric tube feeds. Physical examination showed tachypnoea, coarse bilateral breath sounds and mild hypotonia. Chest radiograph revealed multifocal pulmonary opacities with coarse interstitial markings and right upper lobe atelectasis. Following antibiotic therapy for suspected aspiration pneumonia, chest CT scan was performed and showed multiple areas of pulmonary consolidation and scattered areas of bilateral ground-glass opacities. Genetic studies showed a large deletion of chromosome 14q13.1-14q21.1, encompassing the NK2 homeobox 1 (NKX2-1) gene consistent with a diagnosis of brain-thyroid-lung (BTL) syndrome. Our case highlights the importance of genetic studies to diagnose BTL syndrome in infants with hypothyroidism, hypotonia and lung disease.
Asunto(s)
Atetosis/diagnóstico , Corea/diagnóstico , Deleción Cromosómica , Cromosomas Humanos Par 14/genética , Hipotiroidismo Congénito/diagnóstico , Hipoxia/genética , Hipotonía Muscular/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Atetosis/complicaciones , Atetosis/genética , Atetosis/terapia , Corea/complicaciones , Corea/genética , Corea/terapia , Hipotiroidismo Congénito/complicaciones , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/terapia , Nutrición Enteral , Fluidoterapia , Pruebas Genéticas , Humanos , Hipoxia/diagnóstico , Hipoxia/terapia , Lactante , Intubación Gastrointestinal , Pulmón/diagnóstico por imagen , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/terapia , Oxígeno/administración & dosificación , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Factor Nuclear Tiroideo 1/genética , Tomografía Computarizada por Rayos XRESUMEN
RATIONALE: Mutations of the NKX2-1 gene are associated with brain-lung-thyroid syndrome, which is characterized by benign hereditary chorea, hypothyroidism, and pulmonary disease with variable presentation. Surfactant protein C (SFTPC) gene mutations result in chronic interstitial lung disease in adults or severe neonatal respiratory distress syndrome. PATIENT CONCERNS: Recurrent hypoxemia was observed shortly after birth in a baby at a gestational age of 40 weeks and birth weight of 3150âg. The need for respiratory support gradually increased. He had hypothyroidism and experienced feeding difficulties and irritability. DIAGNOSIS: Genetic examination of the peripheral blood revealed combined mutations of the NKX2-1 and SFTPC genes. INTERVENTIONS: The patient was administered respiratory support, antibiotics, low-dose dexamethasone, supplementary thyroxine, venous nutrition, and other supportive measures. OUTCOMES: The patient's guardian stopped treatment 3 months after commencement of treatment, due to the seriousness of his condition and the patient died. LESSONS: Combined mutations of NKX2-1 and SFTPC genes are very rare. Thus, idiopathic interstitial pneumonia with hypothyroidism and neurological disorders require special attention.
Asunto(s)
Atetosis/genética , Corea/genética , Hipotiroidismo Congénito/genética , Proteína C/metabolismo , Surfactantes Pulmonares/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Factor Nuclear Tiroideo 1/genética , Atetosis/sangre , Atetosis/diagnóstico , Atetosis/terapia , Corea/sangre , Corea/diagnóstico , Corea/terapia , Hipotiroidismo Congénito/sangre , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/terapia , Resultado Fatal , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/etiología , Humanos , Hipotiroidismo/diagnóstico , Hipotiroidismo/etiología , Hipoxia/diagnóstico , Hipoxia/etiología , Recién Nacido , Cariotipificación , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Masculino , Mutación , Cuidados Paliativos/métodos , Recurrencia , Síndrome de Dificultad Respiratoria del Recién Nacido/sangre , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/etiología , Síndrome de Dificultad Respiratoria del Recién Nacido/terapiaRESUMEN
We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.
Asunto(s)
Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/patología , Proteinosis Alveolar Pulmonar/genética , Proteína B Asociada a Surfactante Pulmonar/deficiencia , Factor Nuclear Tiroideo 1/genética , Adolescente , Adulto , Atetosis/complicaciones , Atetosis/genética , Atetosis/patología , Líquido del Lavado Bronquioalveolar/química , Niño , Corea/complicaciones , Corea/genética , Corea/patología , Hipotiroidismo Congénito/complicaciones , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/patología , Femenino , Francia/epidemiología , Genes Homeobox , Humanos , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/terapia , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/terapia , Masculino , Mutación , Pronóstico , Proteinosis Alveolar Pulmonar/complicaciones , Proteína B Asociada a Surfactante Pulmonar/genética , Surfactantes Pulmonares/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/etiología , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Pruebas de Función Respiratoria/métodos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Brain-lung-thyroid syndrome (BLTS) characterized by congenital hypothyroidism, respiratory distress syndrome, and benign hereditary chorea is caused by thyroid transcription factor 1 (NKX2-1/TTF1) mutations. We report the clinical and molecular characteristics of four cases presenting with primary hypothyroidism, respiratory distress, and neurological disorder. Two of the four patients presenting with the triad of BLTS had NKX2-1 mutations, and one of these NKX2-1 [c.890_896del (p.Ala327Glyfs*52)] is a novel variant. The third patient without any identified NKX2-1 mutations was a carrier of mitochondrial mutation; this raises the possibility of mitochondrial mutations contributing to thyroid dysgenesis. Although rare, the triad of congenital hypothyroidism, neurological, and respiratory signs is highly suggestive of NKX2-1 anomalies. Screening for NKX2-1 mutations in patients with thyroid, lung, and neurological abnormalities will enable a unifying diagnosis and genetic counseling for the affected families. In addition, identification of an NKX2-1 defect would be helpful in allaying the concerns about inadequate thyroxine supplementation as the cause of neurological defects observed in some children with congenital hypothyroidism.
Asunto(s)
Atetosis/genética , Corea/genética , Hipotiroidismo Congénito/genética , Mutación , Proteínas Nucleares/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Factores de Transcripción/genética , Niño , Preescolar , Humanos , Lactante , Masculino , Factor Nuclear Tiroideo 1RESUMEN
BACKGROUND: NKX2.1 mutations have been identified in patients displaying complete or partial brain-lung-thyroid syndrome, which can include benign hereditary chorea (BHC), hypothyroidism and/or lung disease. AIMS AND METHODS: We evaluated the recently developed Multiplex Ligation-dependent Probe Amplification (MLPA) method to assess the relative copy number of genes. The goal was to determine if MLPA could improve, in addition to direct sequencing, the detection rate of NKX2.1 mutations in a phenotype-selected cohort of 24 patients affected by neurological, thyroid and/or pulmonary disorders. RESULTS: Direct sequencing revealed two heterozygous mutations. Using MLPA, we identified two further heterozygous NKX2.1 gene deletions. MLPA increased the detection rate by 50%. All patients with gene deletions identified were affected by BHC and congenital hypothyroidism. CONCLUSION: MLPA should be considered as a complementary tool in patients with partial or total brain-lung-thyroid syndrome when direct sequencing failed to identify NKX2.1 mutations. All patients with an NKX2.1 mutation had BHC and congenital hypothyroidism, emphasizing the high prevalence of these signs associated with defective NKX2.1 alleles.
Asunto(s)
Corea/genética , Hipotiroidismo Congénito/genética , Enfermedades Pulmonares/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Niño , Preescolar , Femenino , Eliminación de Gen , Humanos , Recién Nacido , Masculino , Mutación , Técnicas de Amplificación de Ácido Nucleico/métodos , Síndrome , Factor Nuclear Tiroideo 1Asunto(s)
Ganglios Basales/patología , Corea/complicaciones , Lateralidad Funcional/fisiología , Esclerosis Tuberosa/complicaciones , Adulto , Atrofia/etiología , Ganglios Basales/diagnóstico por imagen , Corea/genética , Salud de la Familia , Femenino , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Tálamo/patología , Tomografía Computarizada por Rayos X , Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genéticaRESUMEN
Benign hereditary chorea is an autosomal dominant disease with an early onset of symptoms. In some families, symptoms tend to decrease in adulthood, suggesting that the disorder results from a developmental disturbance in the brain. Individuals with benign hereditary chorea, a nonprogressive disease, have normal or slightly below normal intelligence. The locus for benign hereditary chorea is on chromosome 14. Benign hereditary chorea is a result of mutations in the thyroid transcription factor 1 gene. Previous neuroimaging and pathological investigations of the brain showed no notable abnormalities in patients with this condition. In this study, 5 patients from 1 family with typical clinical features of benign hereditary chorea are presented. Clinical severity varied considerably in the family. Brain magnetic resonance imaging results were normal. Brain single photon emission computed tomography in 3 children, performed 1 hour after intravenous injection of 0.35 mCi/kg of body weight of technetium 99m ethyl cysteinate dimer, showed markedly decreased uptake in the right striatum and the right thalamus in 1 child. The oldest child had mildly reduced uptake in the right putamen and the left thalamus. Brain single photon emission computed tomographic findings in the youngest child were normal. Contrary to other reports of radionuclide brain imaging, notable brain single photon emission computed tomography changes were detected in 2 of 5 patients. Brain single photon emission computed tomography findings did not seem to correlate with the clinical status of the children.
Asunto(s)
Química Encefálica/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Corea/diagnóstico , Corea/genética , Predisposición Genética a la Enfermedad/genética , Adolescente , Encéfalo/metabolismo , Mapeo Encefálico , Niño , Preescolar , Corea/fisiopatología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas Nucleares/genética , Linaje , Tomografía de Emisión de Positrones , Tálamo/diagnóstico por imagen , Tálamo/metabolismo , Tálamo/patología , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: Choreic movements of patients with Huntington's disease (HD) may result from an abnormal control of sensory inputs. In order to further examine the pathophysiology of facial choreic movements (FCM), we carried out a neurophysiological study, including prepulse inhibition of the blink reflex (BR), in HD patients with and without FCM. METHODS: The study was conducted in 20 genetically proven HD patients with Unified Huntington Disease Rating Scale (UHDRS) scores of FCM ranging between 0 and 3, and in 12 age-matched healthy volunteers who served as control subjects. We counted the number of spontaneous blinks, recorded the electromyographic activity underlying FCM, and analyzed latency, amplitude, and duration of the BR responses to electrical and auditory stimuli. Prepulse inhibition was studied by comparing the responses to test trials with those to control trials. In control trials BRs were obtained to either a single supraorbital nerve electrical stimulus (EBR) or to a 90dB auditory stimulus (ABR). In test trials, the same stimuli were preceded by the prepulse, which was either a weak acoustic tone or a weak electrical stimulus to the third finger, delivered 30-150 ms before. RESULTS: Spontaneous blinking rate was abnormally low in 3 patients, and abnormally high in 9 patients. Mean duration of the BR was longer in patients than in control subjects. In prepulse trials, the percentage inhibition of the BR was abnormally reduced in 15 patients to at least one sensory modality, and significantly correlated with the score of FCM. CONCLUSIONS: Our results suggest that the severity of FCM in patients with HD might be an expression of a disturbance in motor control partly related to an abnormal processing of sensory inputs. Such abnormality involves circuits used in prepulse inhibition of the BR.
Asunto(s)
Corea/fisiopatología , Enfermedad de Huntington/fisiopatología , Neurofisiología/métodos , Estimulación Acústica , Adulto , Anciano , Anciano de 80 o más Años , Parpadeo/fisiología , Estudios de Casos y Controles , Corea/etiología , Corea/genética , Estimulación Eléctrica , Electromiografía/métodos , Cara/fisiopatología , Femenino , Humanos , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/genética , Masculino , Persona de Mediana Edad , Músculos/fisiopatología , Inhibición Neural , Examen Neurológico , Órbita/inervación , Tiempo de Reacción , Factores de Tiempo , Repeticiones de TrinucleótidosRESUMEN
We report the neuropathological data from a familial case of chorea-acanthocytosis with central and peripheral nervous system involvement. At the age of 34, the patient underwent a peripheral nerve biopsy which was analyzed by light- and electron microscopy. These studies showed a selective reduction in the large diameter myelinated fibre population, with several clusters of regeneration. Remyelinating fibers surrounded by flattened Schwann cell processes were also present. The patient died at the age of 44, and post-mortem macroscopic examination of the brain showed marked atrophy of the caudate. Histological examination of paraffin sections showed almost complete depletion of neurons in the caudate, with severe astrocytic gliosis. The putamen and pallidum were slightly less severely depleted of neurons, but with marked astrocytic gliosis. Diffuse mild gliosis was also evidenced, by immunohistochemistry with anti-GFAP, in the thalamus and subcortical white matter.
Asunto(s)
Encéfalo/patología , Corea/patología , Nervios Periféricos/patología , Adulto , Astrocitos/patología , Atrofia , Biopsia , Núcleo Caudado/patología , Corea/genética , Gliosis/patología , Humanos , Masculino , Microscopía Electrónica , Fibras Nerviosas Mielínicas/patología , Neuronas/patología , Tálamo/patologíaRESUMEN
The effect of the adenosine A(2A) receptor agonist CGS 21680 (2-carboxyethyl)phenylethylamino]-5'-N-ethylcarbonyamido-ade nosine) on severity of dystonia was examined in genetically dystonic hamsters which exhibit attacks of dystonic and choreoathetotic disturbances in response to mild stress. CGS 21680 significantly reduced the severity of dystonia (0.5, 1.0 and 2.0 mg/kg i.p.). The marked antidystonic effects of CGS 21680 in the hamster model suggest that this compound may represent an interesting candidate for the therapy of paroxysmal dystonia. Furthermore, the present data indicate that the precipitating effect of caffeine in patients with paroxysmal dystonia is probably due to its adenosine receptor antagonistic action.
Asunto(s)
Adenosina/análogos & derivados , Corea/tratamiento farmacológico , Distonía/tratamiento farmacológico , Fenetilaminas/uso terapéutico , Receptores Purinérgicos P1/uso terapéutico , Adenosina/uso terapéutico , Animales , Corea/genética , Cricetinae , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Distonía/genética , Modelos Genéticos , Agonistas del Receptor Purinérgico P1 , Estrés PsicológicoRESUMEN
Computerized EEG spectral analyses of depth electrode recordings from striatum (caudate/putamen; CPu), globus pallidus (GP), and parietal cortex (pCtx) were performed before and after dystonic attacks in freely moving mutant dt(sz) hamsters with paroxysmal dystonia. In these hamsters, sustained attacks of abnormal movements and postures can be reproducibly induced by stress, such as placing the animals in a new environment. Data recorded from mutant hamsters were compared with recordings from age-matched nondystonic control hamsters. The predominant EEG changes in CPu and GP of dystonic hamsters were significant decreases in the high-frequency beta2 range and there was a tendency to increase in delta and theta activities. These changes were seen both before and after onset of dystonic attacks, indicating a permanent disturbance of neural activities in the basal ganglia of dystonic animals. No such changes were seen in the pCtx. Furthermore, no epileptic or epileptiform activity was seen in any of the recordings, substantiating a previous notion from cortical and hippocampal recordings that paroxysmal dystonia in these mutant hamsters has no epileptogenic basis. The present finding of abnormal synchronization of neural activity in the CPu and GP of dystonic hamsters adds to the belief that the striatopallidal-thalamocortical circuit is the most likely site in which to search for the unknown defect in primary (idiopathic) dystonia. As suggested by this study, quantitative EEG analysis can increase the likelihood of detecting subtle EEG abnormalities in different types of idiopathic dystonia and thereby improves our understanding of the pathogenetic mechanisms of this movement disorder.
Asunto(s)
Ganglios Basales/fisiopatología , Distonía/fisiopatología , Electroencefalografía/instrumentación , Lóbulo Parietal/fisiopatología , Procesamiento de Señales Asistido por Computador/instrumentación , Animales , Nivel de Alerta/genética , Nivel de Alerta/fisiología , Atetosis/genética , Atetosis/fisiopatología , Mapeo Encefálico , Corea/genética , Corea/fisiopatología , Cricetinae , Ritmo Delta , Distonía/genética , Electrodos Implantados , Mutación/genética , Vías Nerviosas/fisiopatología , Tálamo/fisiopatología , Ritmo TetaRESUMEN
The value of functional neurosurgery in the treatment of motor movement disorders is emphasized. The two methods of stereotactic procedures, namely a destructive one with small lesions centered on specific targets, and a non-destructive one with chronically inserted electrodes connected with an also implanted programmable neuropacemaker are described in detail. The results in Parkinsonian tremor, essential tremor, tremor of multiple sclerosis, post-traumatic tremor and in other involuntary movement disorders are reported and demonstrate that stereotactic neurosurgical treatment of these conditions is a safe and efficacious method.