RESUMEN
Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.
Asunto(s)
Adenosina Trifosfatasas/deficiencia , Epilepsia/genética , Proteínas de la Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Errores Innatos del Metabolismo/genética , Encefalomiopatías Mitocondriales/genética , Adenosina Trifosfatasas/genética , Proteínas Portadoras/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Proteínas de la Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , ATPasas de Translocación de Protón Mitocondriales , Mutación , Polimorfismo de Nucleótido Simple , EmbarazoRESUMEN
A peculiar non-hypertrophic myocardiopathy is described which occurred in three and possibly five generations of a single family. Clinical features included systolic murmurs, electrocardiographic abnormalities, and sudden cardiac death with a paucity of symptoms of cardiac dysfunction. Pathological studies in three generations showed a striking similarity of cardiac findings including globular and dilated ventricles, endocardial fibroelastosis, and mitral valve thickening. Myocardium in two showed basophilic degeneration and fibrosis. A retrospective genealogic analysis and a prospective clinical evaluation of living family members suggested an autosomal dominant mode of inheritance with variable penetrance. The cause of this heritable myocardiopathy is presumably a mutant gene; the biochemical defect to which the mutant gene gives rise remains unknown.