RESUMEN
We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.
Asunto(s)
Muerte Súbita Cardíaca/etiología , Pirofosfatasa Inorgánica/deficiencia , Pirofosfatasa Inorgánica/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/deficiencia , Proteínas Mitocondriales/genética , Mutación Missense/genética , Acidosis Láctica/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Arritmias Cardíacas/genética , Cardiomiopatías/enzimología , Cardiomiopatías/genética , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Niño , Preescolar , Muerte Súbita Cardíaca/patología , Etanol/efectos adversos , Exoma/genética , Femenino , Fibroblastos/citología , Fibroblastos/patología , Fibrosis/enzimología , Fibrosis/genética , Fibrosis/patología , Humanos , Lactante , Recién Nacido , Pirofosfatasa Inorgánica/química , Pirofosfatasa Inorgánica/metabolismo , Masculino , Mitocondrias/enzimología , Mitocondrias/genética , Mitocondrias/patología , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/patología , Enfermedades Mitocondriales/fisiopatología , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Modelos Moleculares , Linaje , Fenotipo , Convulsiones , Adulto JovenRESUMEN
INTRODUCTION: Toxocariasis is a worldwide human helminthiasis, which is mostly asymptomatic and caused by toxocara canis, a roundworm in dogs. These can cause visceral larva migrans syndrome in humans who ingest contaminated soil. CNS manifestation with a focal mass lesion is very rare, seizures often being the first symptom. CASE REPORT: We describe an 11-year-old girl presenting with a generalized epileptic seizure and eosinophilia in blood. Under antibiotic therapy under the assumption of toxoplasmosis the lesion did not decrease and surgical resection was considered. We used computer-assisted surgery (CAS) for careful tissue resection. Postoperatively the diagnosis of toxocariasis was confirmed and albendozole medication was administered for 7 days. The patient developed well without neurological deficits or seizures. CONCLUSION: We conclude that although neurological involvement is rare in toxocariasis, a cerebral infection in a child with epileptic seizures and eosinophilia should be considered.