RESUMEN
BACKGROUND: The Democratic Republic of the Congo (DRC) changed its national policy for the treatment of severe malaria in both children and adults in 2012 from intravenous quinine to injectable artesunate. The country is now planning to deploy nationwide injectable artesunate as the preferred treatment for the management of severe malaria. To support this process, the feasibility and acceptability of the use of injectable artesunate in the context of the DRC was assessed, from the perspective of both health care providers and patients/caretakers. METHODS: Questionnaires and observations were used to collect information from health care providers and patients/caretakers in eight health facilities in the Province of Kinshasa and in the Province of Bas-Congo. RESULTS: A total of 31 health care providers and 134 patients/care takers were interviewed. Seventy five percent (75%) of health care providers found it less difficult to prepare injectable artesunate compared to quinine. None of them encountered problems during preparation and administration of injectable artesunate. The large majority of care providers (93%) and patients/caretakers (93%) answered that injectable artesunate took less time than quinine to cure the symptoms of the patients. 26 (84%) health care providers reported that the personnel workload had diminished with the use of injectable artesunate. 7 (22.6%) health workers reported adverse drug reactions, of which a decrease in the haemoglobin rate was the most common (71.4%). All care providers and the vast majority of patients/caretakers (96%, N = 128) were either satisfied or very satisfied with injectable artesunate. CONCLUSIONS: These findings show that the use of injectable artesunate for the treatment of severe malaria is feasible and acceptable in the context of DRC, with appropriate training of care providers. Both care providers and patients/caretakers perceived injectable artesunate to be effective and safe, thus promoting acceptability.
Asunto(s)
Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Artemisininas/administración & dosificación , Artemisininas/uso terapéutico , Malaria/tratamiento farmacológico , Adolescente , Adulto , Artesunato , Niño , República Democrática del Congo , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.
Asunto(s)
ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Enfermedades Mitocondriales/genética , Mutación , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , ADN Polimerasa gamma , Esclerosis Cerebral Difusa de Schilder/genética , Femenino , Frecuencia de los Genes , Humanos , Lactante , Masculino , Persona de Mediana Edad , Encefalomiopatías Mitocondriales/genética , Oftalmoplejía Externa Progresiva Crónica/genética , Fenotipo , Factores SexualesRESUMEN
We studied 26 patients belonging to 20 families with a disorder caused by mutations in the POLG gene. The patients were homozygous for 1399 G/A or 2243 G/C (giving the amino acid changes A467T and W748S, respectively) or compound heterozygotes for these two mutations. Irrespective of genotype, the patients exhibited a progressive neurological disorder usually starting in their teens and characterized by epilepsy, headache, ataxia, neuropathy, myoclonus and late onset ophthalmoplegia. However, major differences in survival were seen depending on genotype, with compound heterozygotes having a significantly shorter survival time than patients homozygous either for the A467T or W748S (P = 0.006). Epilepsy occurred in 22 of the 26 patients and in the majority of these there was an occipital EEG focus. Episodes of both generalized and focal motor status epilepticus were common and highly resistant to treatment, even with generalized anaesthesia. Status epilepticus was the recorded cause of death in 9 of 11 patients. Liver failure was the sole cause of death in two patients and evolved terminally in six others, all but one of whom were being treated with sodium valproate. Two patients underwent liver transplantation, but only one survived. Delayed psychomotor development and subsequent cognitive decline also occurs. This study demonstrates the clinical spectrum of a disorder that combines features of Alpers' syndrome and a later onset mitochondrial spinocerebellar ataxia with epilepsy and headache. Patients with this disorder are at high risk of death from status epilepticus and from liver failure, if exposed to sodium valproate. Each mutation appears capable of producing a disorder that is recessively inherited, although we also find evidence in one patient suggesting that heterozygotes may manifest. Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect.
Asunto(s)
ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Enfermedades Mitocondriales/genética , Mutación , Adolescente , Adulto , Edad de Inicio , Anciano , Ataxia/genética , Niño , ADN Polimerasa gamma , Discapacidades del Desarrollo/genética , Esclerosis Cerebral Difusa de Schilder/genética , Progresión de la Enfermedad , Métodos Epidemiológicos , Epilepsia Tónico-Clónica/genética , Femenino , Genotipo , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Fallo Hepático/genética , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades Mitocondriales/patologíaRESUMEN
We studied nine infant patients with a combination of progressive neurological and hepatic failure. Eight children, including two sibling pairs and four singletons, were affected by Alpers' hepatopathic poliodystrophy. A ninth baby patient suffered of a severe floppy infant syndrome associated with liver failure. Analysis of POLG1, the gene encoding the catalytic subunit of mitochondrial DNA polymerase, revealed that all the patients carried different allelic mutations in this gene. POLG1 is a major disease gene in mitochondrial disorders. Mutations in this gene can be associated with multiple deletions, depletion or point mutations of mitochondrial DNA (mtDNA). In turn, these different molecular phenotypes dictate an extremely heterogeneous spectrum of clinical outcomes, ranging from adult-onset progressive ophthalmoplegia to juvenile ataxic syndromes with epilepsy, to rapidly fatal hepatocerebral presentations, including Alpers' syndrome.
Asunto(s)
ADN Mitocondrial/genética , ADN Polimerasa Dirigida por ADN/genética , Esclerosis Cerebral Difusa de Schilder/genética , Fallo Hepático/genética , Mutación , Encéfalo/patología , ADN Polimerasa gamma , Esclerosis Cerebral Difusa de Schilder/patología , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , MasculinoRESUMEN
Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.