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: 4.57). 07/2008; 49(6):1038-45. DOI: 10.1111/j.1528-1167.2008.01544.x
Source: PubMed


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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Available from: Heidi K Soini, Oct 14, 2014
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    • "Multiple mtDNA deletions affecting between ∼20 and 50% of mtDNA molecules have been identified,12–15 but whether this level of mtDNA deletion alone is sufficient to cause respiratory dysfunction and neuronal death remains unclear.17 Both normal and mildly decreased (70–75% of control) mtDNA copy number have been found in brain homogenate,12,13,16,18 and 1 study in neurons from the dorsal root ganglia of a single patient15 has reported clear mtDNA depletion (∼50% of controls). Accumulation of mtDNA point mutations has been shown in skeletal muscle of patients with POLG disease using an ultradeep resequencing-by-synthesis (UDS) assay,19,20 whereas no increase in mtDNA point mutations was detected in another study in brain.12 "
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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
    Full-text · Article · May 2014 · Annals of Neurology
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    • "Early in the course of epilepsy, seizures are often controlled with conventional medications. However, as the disease progresses, the seizures become increasingly resistant to valproic acid and other medications that trigger liver failure (Bicknese et al. 1992; Engelsen et al. 2008; Uusimaa et al. 2008; Wolf et al. 2009; Saneto et al. 2010). Even without "
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    ABSTRACT: The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
    Full-text · Article · Apr 2013 · Cold Spring Harbor perspectives in biology
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    • "EEG findings for POLG disease include early predominance of epileptiform discharges over the occipital region (Engelsen et al., 2008; Wolf et al., 2009), but the EEG findings can vary as we found. Acute liver failure after the administration of VPA is common among patients with Alpers disease, but liver dysfunction has also been described in POLG patients without VPA administration (Ferrari et al., 2005; Uusimaa et al., 2008), as was the case in two of our patients (patients 1 and 8). A recent review described four POLG patients (age range 3 to 18 years) given VPA for intractable partial seizures followed by liver failure where the time from VPA exposure to liver failure was 2–3 months, posing the question of whether POLG sequencing should be considered prior to VPA treatment (Saneto et al., 2010). "
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    ABSTRACT: Purpose To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. Methods Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon–intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records. Key Findings We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged. Significance Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2-weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.
    Full-text · Article · Feb 2013 · Epilepsia
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