RESUMO
BACKGROUND: Malignant hyperthermia (MH) is a potentially fatal, often autosomal dominant, disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anesthetics. In this article, the authors describe a malignant hyperthermia susceptible (MHS) kindred in which both parents of the proband are MHS and are first-degree cousins. Haplotype analysis in this kindred with chromosome 19 linked markers revealed that the proband and another sibling were homozygous for the affected RYR1 allele. METHODS: Eighteen members of this large pedigree were investigated, with a clinical examination for signs of a myopathy, a caffeine halothane contracture test, a histo-enzymologic study on the muscle biopsies, and linkage analysis on genomic DNA isolated from family blood samples. RYR1 cDNA was amplified by polymerase chain reaction and was cloned and sequenced, facilitating mutation detection. RESULTS: Linkage analysis demonstrated linkage between RYR1-linked markers and MH susceptibility in this family. DNA sequencing identified a T to C transition at nucleotide position 103, resulting in the substitution of an arginine for cysteine 35, representing the most N-terminal mutation reported to date in the RYR1 gene. This mutation segregates fully with the MHS trait, generating a lod score of 4.65 in favor of linkage to MHS at a recombination frequency of 0.0. CONCLUSIONS: The proband in this kindred is the first reported homozygote to have presented with an MH episode. The homozygotes in this pedigree do not have an overt myopathy. The sensitivity of muscle samples to caffeine clearly distinguished the two homozygotes from other heterozygous-susceptible individuals. No clear differentiation was observed with the halothane contracture results.
Assuntos
Canais de Cálcio/genética , Homozigoto , Hipertermia Maligna/genética , Proteínas Musculares/genética , Mutação , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Animais , Arginina/genética , Criança , Consanguinidade , Creatina Quinase/sangue , Cisteína/genética , DNA Complementar/genética , Suscetibilidade a Doenças , Feminino , Ligação Genética , Heterozigoto , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Canal de Liberação de Cálcio do Receptor de Rianodina , Homologia de Sequência de AminoácidosAssuntos
Procedimentos Cirúrgicos Ambulatórios , Anestesia Dentária , Anestesia Geral , Assistência Odontológica , Boca/cirurgia , Analgésicos/administração & dosagem , Anestesia Dentária/métodos , Anestesia Geral/métodos , Anestesia Local , Anestésicos Gerais/administração & dosagem , Sedação Consciente , Contraindicações , Humanos , Hipnóticos e Sedativos/administração & dosagemRESUMO
The advantage of calcium antagonist on cerebral arterial spasm during the peri-operative period has been recently demonstrated. However, the role of volemia and cardiac output in the pathogenesis of arterial spasm seems predominant. The basal hemodynamic profile of 17 patients operated for an intracranial aneurysm was investigated. The hemodynamic and neurological modifications induced by treatment with nimodipine, modification of blood volume and the use of inotropic drug was subsequently analysed. In 8 patients there was a clearcut hypovolemia with diminished cardiac index whereas in 9 other patients there were low filling pressures with an unmodified cardiac index. As early as the 48th hour of treatment, there was an improvement of Hunt and Hess score in 12 patients whereas in 5 others the score remained unchanged. Two death occurred due to the extension of secondary ischemic lesions. This study seems to confirm the aggravating role of hypovolemia in the occurrence of vasospasm and the neurological improvement due to the association of a calcium antagonist, restoration of blood volume with or without a vasoconstrictor.