RESUMEN
OBJECTIVE: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. PATIENTS AND METHODS: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. RESULTS: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290â¯kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. CONCLUSION: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome.
Asunto(s)
Antígenos de Neoplasias/genética , Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/patología , Coloboma/genética , Coloboma/patología , Fibroblastos/patología , Proteínas de Neoplasias/genética , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/patología , Anomalías Múltiples/patología , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Centrosoma/metabolismo , Centrosoma/patología , Enfermedades Cerebelosas/fisiopatología , Cerebelo/anomalías , Cerebelo/patología , Cerebelo/fisiopatología , Cilios/metabolismo , Cilios/patología , Coloboma/fisiopatología , Proteínas del Citoesqueleto , Anomalías del Ojo/patología , Anomalías del Ojo/fisiopatología , Familia , Femenino , Fibroblastos/metabolismo , Humanos , Inmunohistoquímica , Enfermedades Renales Quísticas/patología , Enfermedades Renales Quísticas/fisiopatología , Microscopía Electrónica de Transmisión , Peso Molecular , Mutación , Proteínas de Neoplasias/metabolismo , Enfermedades Renales Poliquísticas/fisiopatología , Retina/anomalías , Retina/patología , Retina/fisiopatología , Secuenciación del Exoma , Adulto JovenRESUMEN
We report the case of a 4-year-old girl who presented with paroxysmal sympathetic hyperactivity (PSH), after developing severe hypoxic-ischemic-encephalopathy because of cardiopulmonary arrest. She showed dramatic paroxysmal sympathetic activity with dystonia. She was treated with wide variety of medications against PSH, which were found to be effective in previous studies. Among them, morphine, bromocriptine, propranolol, and clonidine were effective in reducing the frequency of her attacks while gabapentin, baclofen, dantrolene, and benzodiazepine were ineffective. Though the paroxysms decreased markedly after the treatment, they could not be completely controlled beyond 500 days. Following the treatment, levels of plasma catecholamines and their urinary metabolites decreased to normal during inter- paroxysms. However, once a paroxysm had recurred, these levels were again very high. This case study is considered significant for two rea- sons. One is that PSH among children have been rarely reported, and the other is that this case of prolonged PSH delineated the transition of plasma catecholamines during the treatment. The excitatory: inhibitory ratio (EIR) model proposed by Baguley was considered while dis- cussing drug sensitivity in this case. Accumulation of similar case studies will help establish more effective treatment strategies and elucidate the pathophysiology of PSH.
Asunto(s)
Hipercinesia , Preescolar , Femenino , Humanos , Hipercinesia/patología , Hipercinesia/fisiopatología , Imagen por Resonancia Magnética , Prohibitinas , Vasoconstricción , Signos VitalesRESUMEN
AIM: We have never known any epidemiological study of Arima syndrome since it was first described in 1971. To investigate the number of Arima syndrome patients and clarify the clinical differences between Arima syndrome and Joubert syndrome, we performed the first nationwide survey of Arima syndrome, and herein report its results. Furthermore, we revised the diagnostic criteria for Arima syndrome. METHODS: As a primary survey, we sent out self-administered questionnaires to most of the Japanese hospitals with a pediatric clinic, and facilities for persons with severe motor and intellectual disabilities, inquiring as to the number of patients having symptoms of Arima syndrome, including severe psychomotor delay, agenesis or hypoplasia of cerebellar vermis, renal dysfunction, visual dysfunction and with or without ptosis-like appearance. Next, as the second survey, we sent out detailed clinical questionnaires to the institutes having patients with two or more typical symptoms. RESULTS: The response rate of the primary survey was 72.7% of hospitals with pediatric clinic, 63.5% of national hospitals and 66.7% of municipal and private facilities. The number of patients with 5 typical symptoms was 13 and that with 2-4 symptoms was 32. The response rate of the secondary survey was 52% (23 patients). After reviewing clinical features of 23 patients, we identified 7 Arima syndrome patients and 16 Joubert syndrome patients. Progressive renal dysfunction was noticed in all Arima syndrome patients, but in 33% of those with Joubert syndrome. CONCLUSION: It is sometimes difficult to distinguish Arima syndrome from Joubert syndrome. Some clinicians described a patient with Joubert syndrome and its complications of visual dysfunction and renal dysfunction, whose current diagnosis was Arima syndrome. Thus, the diagnosis of the two syndromes may be confused. Here, we revised the diagnostic criteria for Arima syndrome.
Asunto(s)
Enfermedades Cerebelosas/diagnóstico , Enfermedades Cerebelosas/epidemiología , Coloboma/diagnóstico , Coloboma/epidemiología , Enfermedades Renales Poliquísticas/diagnóstico , Enfermedades Renales Poliquísticas/epidemiología , Anomalías Múltiples , Adolescente , Adulto , Cerebelo/anomalías , Niño , Preescolar , Diagnóstico Diferencial , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/epidemiología , Femenino , Humanos , Japón/epidemiología , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/epidemiología , Masculino , Retina/anomalías , Adulto JovenRESUMEN
We administered intramuscular injections of botulinum toxin type A (BTX-A) in 11 persons with cervical dystonia (CD) and muscular hypertonia (MH). All patients had severe motor and intellectual disabilities (SMID). Furthermore, in 10 patients, SMID was accompanied by respiratory problems and/or dysphagia. Three patients received night nasal intermittent positive pressure ventilation and 3 had undergone tracheotomy; 5 patients had upper respiratory problems. Because of these complications, BTX-A dose was gradually increased in those patients until the desired effect was obtained (mean last dose, 6.8 u/kg/dose). All patients were clinically assessed with the Tsui scale before treatment with BTX-A. At 1, 2, 4, and 8 weeks after BTX-A injections, responses to the injections were assessed with the Tsui scale repetitively in all patients. Significant or mild improvements in the Tsui scale scores were observed in 8 patients without any severe adverse effects. In addition, some improvements in respiration and body weight gain were observed. We observed a reduction in the number of oral medications in 10 cases. Administration of BTX-A for the treatment of SMID has numerous benefits, not all of which can be explained by Tsui scale scores. BTX-A is safe and has potential for use in the treatment of CD and MH with respiratory problems and/or dysphagia.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Fármacos Neuromusculares/uso terapéutico , Tortícolis/tratamiento farmacológico , Adolescente , Adulto , Toxinas Botulínicas Tipo A/administración & dosificación , Preescolar , Trastornos de Deglución/complicaciones , Femenino , Humanos , Inyecciones Intramusculares , Discapacidad Intelectual/complicaciones , Masculino , Persona de Mediana Edad , Hipertonía Muscular/tratamiento farmacológico , Fármacos Neuromusculares/administración & dosificación , Tortícolis/complicacionesRESUMEN
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder characterized by macrocephaly, deterioration of motor function with ataxia, spasticity and mental decline. It has been revealed that the mutations in the gene, KIAA0027, were responsible for MLC and the gene was renamed subsequently 'MLC1'. A 41-year-old Japanese male with MLC, in whom a homozygous missense mutation, TCG to TTG at codon 93 resulting in S93L, was detected in the MLC1 gene, was described. MRI revealed marked cerebral atrophy and enlargement of the ventricular system. The subject's motor function had severely deteriorated, while his cognitive function had maintained at the level of a 2-year-old for the past 10 years. The mutation in the MLC1 gene of the patient is considered to be a common mutation responsible for MLC in Japanese patients because the same mutation had been detected in two other Japanese patients with MLC.