RESUMO
Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes.
Assuntos
Colina O-Acetiltransferase/genética , Estudos de Associação Genética , Mutação , Síndromes Miastênicas Congênitas/genética , Adolescente , Alelos , Substituição de Aminoácidos , Sítios de Ligação , Domínio Catalítico , Pré-Escolar , Colina O-Acetiltransferase/química , Colina O-Acetiltransferase/metabolismo , Análise Mutacional de DNA , Ativação Enzimática , Feminino , Expressão Gênica , Genótipo , Células HEK293 , Humanos , Ligação de Hidrogênio , Masculino , Modelos Moleculares , Síndromes Miastênicas Congênitas/diagnóstico , Fosforilação , Conformação Proteica , Especificidade por SubstratoRESUMO
INTRODUCTION: Pathologic alterations in neuromuscular transmission, known as Myasthenia Gravis (MG), comprise combinations (forms) of pre- and post-synaptic changes whose age at onset and clinical manifestations are dissimilar. Some forms have autoimmune features, while others have a defect due to functional or structural plaque alternations. The purpose of this work is to describe the clinical forms of MG seen in childhood, to facilitate proper diagnosis and treatment. MATERIAL AND METHODS: Retrospective data from 87 patients studied at the Ricardo Gutierrez Children's Hospital from 1990 to 2002 are presented. They were evaluated by clinical, pharmacological, electrophysiological, laboratory and radiological exams. RESULTS: Three distinct groups of patients were found: Group 1, Transient Neonatal Myasthenia Gravis (TNMG) represented 6.8% 9 (n=6) of the total number of patients. None of these six patients had ocular involvement. Group 2, Congenital Myasthenia (CMG) represented 17.2% of cases 9 (n=15). These patients had an onset of symptoms from 1 to 12 months of age. Eight cases were sporadic and the remainder familial. The most frequent symptom in this group was bilateral blepharoptosis in 13 patients. Group 3, Juvenile Myasthenia (JMG) comprised 76% of the patients (n=66). The onset of symptoms in this group ranged from 13 months to 14 years (mean 3.6 years). Thirty-nine of these children presented purely with ocular symptoms. CONCLUSIONS: Children with myasthenia gravis may present to the ophthalmologist first, with symptoms such as unilateral or bilateral blepharoptosis, diplopia, strabismus or ophthalmoplegia. Therefore, it is essential that the ophthalmologist be aware of the varied features of this disorder in children in order to diagnosis it correctly and make appropriate treatment referrals.
Assuntos
Miastenia Gravis/diagnóstico , Adulto , Idade de Início , Blefaroptose/diagnóstico , Criança , Pré-Escolar , Inibidores da Colinesterase , Técnicas de Diagnóstico Oftalmológico , Diplopia/diagnóstico , Edrofônio , Eletrofisiologia/métodos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Lactente , Recém-Nascido , Masculino , Miastenia Gravis/classificação , Miastenia Gravis/terapia , Oftalmoplegia/diagnóstico , Estudos Retrospectivos , Estrabismo/diagnósticoRESUMO
We describe a case of poliomyelitis in a 3-year-old Argentinean boy with X-linked hypogammaglobulinemia. The child had no history of polio vaccination, but a poliovirus isolated from a stool sample had 97.2% genetic similarity to the Sabin 1 vaccine strain. According to the WHO definition, this is the first case reported of a vaccine-derived poliovirus infection recorded in continental Latin America.
Assuntos
Agamaglobulinemia/imunologia , Hospedeiro Imunocomprometido , Poliomielite/etiologia , Vacina Antipólio Oral/efeitos adversos , Poliovirus/isolamento & purificação , Pré-Escolar , Fezes/virologia , Seguimentos , Humanos , América Latina , Masculino , Paralisia/diagnóstico , Paralisia/etiologia , Poliomielite/diagnóstico , Vacina Antipólio Oral/administração & dosagem , Medição de Risco , Vacinação/efeitos adversosRESUMO
Se presenta a un paciente con deficiencia de hexosaminidasa A (Hx A), que conduce a la gangliosidosis GM2, que desarrolla un cuadro neurológico progresivo cuyo comienzo pudo fijarse a los 10 años y que se caracterizó por deterioro intelectual, compromiso cerebeloso, alteración de neuromas motoras superior e inferior y neuropatía sensitiva sin aparente compromiso de las fibras motoras que integran el nervio mixto. La biopsia del nervio safeno externo mostró pérdida de fibras mielínicas, en especial de aquellas de mayor y menor diámetro, agrupamiento axonal, axones con cubiertas mielínicas anormalmente finas en relación con su diámetro, degeneración axonal, desmielinización segmentaria y paranodal y remielinización. La microscopia electrónica reveló cuerpos de inclusión electrodensos no específicos e incusiones laminares concéntricas dentro del citoplasma de las células de Schwann. Los hallazgos hechos señalan que la neuropatía sensitiva pura puede formar parte del espectroclínico de la deficiencia de HxA
Assuntos
Humanos , Masculino , Adulto , beta-N-Acetil-Hexosaminidases/deficiência , Neuropatias Hereditárias Sensoriais e Autônomas/etiologia , beta-N-Acetil-Hexosaminidases/sangue , Células de Schwann , Doença Crônica , Neuropatias Hereditárias Sensoriais e Autônomas/diagnóstico , Músculos , Veia Safena , Nervo Sural/patologiaRESUMO
Veintidós pacientes con IRC terminal, en plan de hemodiálisis periódica trisemanal, fueron estudiados para evaluar la función total de la unidad motora en el segmento proximal y distal de los miembros superiores. Se estimuló el nervio cubital a nivel de muñeca y axila con registro con electrodo de superficie en hipotenar, determinándose amplitud de la onda M y sus respectivas latencias, obteniéndose la velocidad de conducción en el segmento axila-muñeca. Con el estímulo en el mismo nervio se obtuvieron 10 respuestas F en muñeca analizando latencia y amplitud de cada una de ellas y la velocidad de conducción de la onda F total (VCMFT) según fórmula de Kimura y la velocidad de conducción de dicha onda en el segmento proximal (C7-axila) (VCMFP). Asimismo se determinó en el nervio medicano la latencia residual motora y las velocidades de conducción motora (VCM) y sensitiva (VCS) y en el nervio ciático poplíteo externo la latencia distal y la VCM. Se dosaron valores sanguíneos de urea, creatinina y K++. Los resultados fueron comparados con un grupo de sujetos controles. En el grupo de probandos se halló una disminución significativa de la amplitud de la onda M en hipotenar (p<0,0005). A medida que se producía la lentificación de la conducción en el segmento axila-muñeca se evidenciaba una paralela reducción de la amplitud de la onda M (r = 0,44, p<0,05). La VCS del nervio mediano estuvo reducida significativamente con respecto a los controles (p<0,0005). La VCMFT fue en los probandos significativamente inferior a los controles (p<0,0005), mientras que en la VCMFP hubo diferencia de menor significación entre ambos (p<0,050). No se halló relación entre los valores de amplitud y latencia de la onda M en el nervio cubital, tampoco entre VCM y VCS en el nervio mediano ni entre los valores de urea, creatinina y K+ y los parámetros electrofisiológicos estudiados. Los resultados obtenidos señalan que en este grupo de pacientes la neuropatía es de tipo axonal y a predominio distal (ASU)