Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase γ (POLG1)
ABSTRACT We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase gamma gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease.
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- "Valproic acid, although seemingly beneficial for SE, should be avoided, as patients with POLG1 mutations are at high risk of acute liver failure, which can manifest several weeks after starting therapy. Transient liver failure with recovery after stopping valproic acid is possible (Patient 5) and has been reported (McFarland et al., 2008). In case of irreversible organ failure, transplantation rescues liver function, but neurologic outcome remains grim. "
ABSTRACT: Refractory convulsive status epilepticus in infancy and childhood is a rare emergency situation. Metabolic disorders frequently underlie this condition, in particular Alpers' disease caused by POLG1 mutations. Status epilepticus may be the first symptom. A pathognomonic electroencephalography (EEG) signature may facilitate diagnosis of Alpers' disease and allow timely avoidance of valproic acid, which is contraindicated in this disorder because it may trigger fatal liver failure. We present five patients with Alpers' disease caused by mutations in POLG1. Age of onset ranged from 7 months to 10 years. Three of the five children died after 3 to 12 months after onset of status epilepticus. Two of these had liver failure associated with use of valproic acid; liver transplantation in one child did not prevent a fatal neurologic outcome. Convulsive status epilepticus was the first obvious sign of Alpers' disease in all children. All had focal clonic and complex-focal seizures; four of them developed epilepsia partialis continua. In four children, initial EEG showed unilateral occipital rhythmic high-amplitude delta with superimposed (poly)spikes (RHADS). Magnetic resonance imaging (MRI) revealed cortical and thalamic involvement in all, although there were only discrete abnormalities in one child. Metabolic investigations remained normal in three children. Alpers' disease is an important differential diagnosis in childhood refractory convulsive status epilepticus. Its EEG hallmark of RHADS is important for timely diagnosis, management, and counseling.Epilepsia 12/2008; 50(6):1596-607. DOI:10.1111/j.1528-1167.2008.01877.x · 4.58 Impact Factor
Article: Disorders of mitochondrial function[Show abstract] [Hide abstract]
ABSTRACT: Mitochondrial diseases are a major category of childhood illness that produce a wide variety of symptoms and multisystemic disorders. This review highlights recent clinically important developments in diagnostic evaluation and treatment of mitochondrial diseases. Major advances have been made in understanding the genetic bases of mitochondrial diseases. Molecular defects have recently been reported in mitochondrial DNA maintenance, RNA translation and protein import and in mitochondrial fusion and fission, opening new areas of cell disorder. Diagnostic testing is struggling to keep pace with these fundamental discoveries. The diagnostic approach to children suspected of mitochondrial disease is rapidly evolving but few patients have a molecular diagnosis. A better notion of the prognosis of affected children is emerging from studies of long-term outcome. Some therapeutic successes are reported, such as in coenzyme Q deficiency conditions. Mitochondrial diseases can present with signs in almost any organ. Well planned clinical evaluation is the key to successful diagnostic work-up of mitochondrial diseases. An approach is presented for further testing in specialized laboratories. Mitochondrial diseases can be caused by mutations in mitochondrial DNA or, more commonly in children, in nuclear genes. Mitochondrial DNA mutations pose special challenges for genetic counseling and prenatal diagnosis. Supportive treatment and avoidance of environmental stresses are important aspects of patient care. Specific treatment of mitochondrial diseases is in its infancy and is a major challenge for pediatric medicine.Current opinion in pediatrics 09/2008; 20(4):471-82. DOI:10.1097/MOP.0b013e328306ebb6 · 2.74 Impact Factor