Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus.

Department of Pediatrics, University of Oulu, Oulu, Finland.
Epilepsia (Impact Factor: 4.58). 07/2008; 49(6):1038-45. DOI: 10.1111/j.1528-1167.2008.01544.x
Source: PubMed

ABSTRACT Polymerase gamma (POLG) is the sole enzyme in the replication of mitochondrial DNA (mtDNA). Numerous mutations in the POLG1 gene have been detected recently in patients with various phenotypes including a classic infantile-onset Alpers-Huttenlocher syndrome (AHS). Here we studied the molecular etiology of juvenile-onset AHS manifesting with status epilepticus and liver disease in three teenagers.
We examined 14- and 17-year-old female siblings (patients 1 and 2) and an unrelated 15-year-old girl (patient 3) with juvenile-onset AHS, sequenced POLG1, and the entire mtDNA, examined mtDNA deletions by amplification of the full-length mtDNA with the long PCR method and used real-time PCR to quantify mtDNA in the tissue samples.
The initial manifestations were migraine-like headache and epilepsy, and the terminal manifestations status epilepticus and hepatic failure. A homozygous W748S mutation in POLG1 was detected in the three patients. No deletions or pathogenic point mutations were found in mtDNA, but all three patients had mtDNA depletion.
POLG mutations should be considered in cases of teenagers and young adults with a sudden onset of intractable seizures or status epilepticus, and acute liver failure. The W748S POLG1 mutation seems to lead to tissue-specific, partial mtDNA depletion in patients with juvenile-onset Alpers syndrome. Valproic acid should be avoided in the treatment of epileptic seizures in these patients.

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    ABSTRACT: Objective Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using post-mortem tissue from a large number of patients.Methods Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls were studied employing a combination of histopathology, immunohistochemistry and molecular studies of microdissected neurons.ResultsThe primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and which showed massive neuronal loss.InterpretationPOLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to two distinct, but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014. © 2014 American Neurological Association
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    ABSTRACT: Background and aims: Patients with mutations in the POLG1 gene encoding the mitochondrial DNA polymerase gamma have an increased risk of valproate-induced liver failure. POLG1 mutations are common among populations and these patients often suffer from intractable seizures. The role of liver transplantation in the treatment of patients with mitochondrial diseases has been controversial. We studied valproate-induced liver failure associated with POLG1 mutations and the prognosis of these patients after liver transplantation.Methods: POLG1 was analyzed in blood DNA, mitochondrial DNA (mtDNA) was quantified in liver samples and clinical data was collected.Results: Five patients with valproate-induced liver failure associated with POLG1 mutations were retrospectively identified. Three patients were previously suspected to have Wilson’s disease. Four patients with homozygous p.W748S and p.E1143G mutations had mtDNA depletion in the liver. One of these patients had died prior to anticipated transplantation, the other three patients with liver transplantation have survived from 4 to 19 years. Two patients present with occasional epileptic seizures and one patient has been seizure free for 11 years. One patient with a heterozygous p.Q1236H mutation, but without mtDNA depletion in the liver, died suddenly two years after the liver transplantation.Conclusions: The POLG1 mutation status and the age at presentation of valproate-induced liver failure can affect the prognosis after liver transplantation. A heterozygous POLG1 p.Q1236H mutation was related to valproate-induced liver failure without mtDNA depletion, whereas patients homozygous for POLG1 p.W748S and p.E1143G mutations had mtDNA depletion. Analysis of the POLG1 gene should be performed for all patients with suspected mitochondrial disease before introducing valproate therapy and treatment with valproic acid should be avoided in these patients. Liver Transpl , 2014. © 2014 AASLD.
    Liver Transplantation 11/2014; 20(11). DOI:10.1002/lt.23965 · 3.79 Impact Factor
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