RESUMO
OBJECTIVE: To determine the actual incidence of mitochondrial DNA (mtDNA) depletion syndrome in multiple respiratory chain deficiency. STUDY DESIGN: We carried out a real-time polymerase chain reaction quantification of mtDNA in liver or muscle tissue of 100 children with unexplained multiple oxidative phosphorylation enzyme deficiency. RESULTS: A reduction of mtDNA copy number to <35% of control values was found in liver and/or muscle in half of the children (50/100). Most of these patients (32/50; 64%) presented with severe neonatal onset liver involvement; 7 (14%) had Alpers syndrome, and 11 (22%) exhibited various forms of neurologic involvement. Deoxyguanosine kinase or polymerase gamma (POLG) mutations could be identified in 11 of 32 patients with liver involvement, and POLG mutations were consistently found in all 7 patients with Alpers syndrome. Homozygous thymidine kinase 2 and MPV17 gene mutations were found in 2 patients. CONCLUSIONS: Our findings show that mtDNA depletion is a prevalent cause of multiple respiratory chain deficiency in infancy.
Assuntos
DNA Mitocondrial , Doenças Mitocondriais/genética , Pré-Escolar , DNA Mitocondrial/análise , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/química , Masculino , Músculo Esquelético/químicaRESUMO
We describe the clinical, biochemical, and molecular characteristics of 31 patients with hepatic respiratory chain deficiencies to suggest possible guidelines for a liver biopsy. Initially, 67% of the children did not have any sign of hepatic dysfunction, and 35% presented exclusively with neurologic symptoms. Initial hyperlactacidemia was severe in 52%. Mortality was high (52%) and more marked in newborns; 28% never developed hepatic disease over time despite long-term follow-up. Hepatic, nonspecific multisystem initial symptoms, and constant hyperlactacidemia had significant statistical value as negative prognosis factors. We conclude that liver biopsy should be considered not only in patients with hepatic involvement, but also in patients with predominant neurologic disorders if there is a suspicion of a mitochondrial respiratory chain defect.
Assuntos
Hepatopatias/enzimologia , Hepatopatias/patologia , Fígado/enzimologia , Fígado/patologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/patologia , Pré-Escolar , Citrato (si)-Sintase/metabolismo , DNA Mitocondrial/metabolismo , Transporte de Elétrons/fisiologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos RetrospectivosRESUMO
OBJECTIVE: To review the antenatal manifestations of disorders of oxidative phosphorylation. STUDY DESIGN: A total of 300 cases of proven respiratory chain enzyme deficiency were retrospectively reviewed for fetal development, based on course and duration of pregnancy, antenatal ultrasonography and birth weight, length, and head circumference. Particular attention was given to fetal movements, oligo/hydramnios, fetal cardiac rhythm, fetal heart ultrasound, and ultrasonography/echo Doppler signs of brain, facial, trunk, limb, and organ anomalies. RESULTS: Retrospective analyses detected low birth weight (<3rd percentile for gestational age) in 22.7% of cases (68/300, P<.000001). Intrauterine growth retardation was either isolated (48/300, 16%) or associated with otherwise unexplained anomalies (20/300, 6.7%, P<.0001). Antenatal anomalies were usually multiple and involved several organs sharing no common function or embryologic origin. They included polyhydramnios (6/20), oligoamnios (2/20), arthrogryposis (1/20), decreased fetal movements (1/20), ventricular septal defects (2/20), hypertrophic cardiomyopathy (4/20), cardiac rhythm anomalies (4/20), hydronephrosis (3/20), vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula/atresia, renal agenesis and dysplasia, and limb defects (VACTERL) association (2/20), and a complex gastrointestinal malformation (1/20). CONCLUSIONS: Although a number of metabolic diseases undergo a symptom-free period, respiratory chain deficiency may have an early antenatal expression, presumably related to the time course of the disease gene expression in the embryofetal period. The mechanism triggering malformations is unknown and may include decreased ATP formation and/or an alteration of apoptotic events controlled by the mitochondria.