Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.
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PMID:POLG1 mutations associated with progressive encephalopathy in childhood. 1689 9

Alpers syndrome is a fatal neurogenetic disorder caused by the mutations in POLG1 gene encoding the mitochondrial DNA polymerase gamma (polgamma). Two missense variants, c.248T > C (p.L83P), c.2662G > A (p.G888S) in POLG1 were detected in a 10-year-old Chinese girl with refractory seizures, acute liver failure after exposure to valproic acid, cortical blindness, and psychomotor regression. The pathology of left occipital lobe showed neuronal loss, spongiform degeneration, astrocytosis, and demyelination. In addition, there were prominent white matter changes in a series of brain magnetic resonance imaging (MRI) and increased immunological factors in CSF.
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PMID:Alpers syndrome with prominent white matter changes. 1792 49

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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PMID:Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase gamma (POLG1). 1820 89

The epileptic semiology of 19 patients (from 15 families) with mitochondrial disease due to mutations in the POLG1 gene is presented. The patients were either homozygous for the 1399G > A (p.A467T) or 2243G > C (p.W748S) mutations or compound heterozygotes for these two mutations. While the clinical features have been reviewed, detailed analysis of their epilepsy is presented for the first time. Irrespective of genotype, patients developed an epileptic syndrome with initial features of occipital lobe epilepsy. Occipital seizure phenomena included flickering coloured light, sometimes persisting for weeks, months or even years, ictal visual loss, horizontal/vertical nystagmus or oculoclonus, dysmorphopsia, micro-/macropsia and palinopsia. Most patients developed simple partial seizure phenomena with motor symptoms suggesting frontal lobe seizure initiation or spread. Simple and complex partial seizures, clonic- and/or myoclonic seizures with epilepsia partialis continua and frequent convulsive status epilepticus were observed in this syndrome that appears to be a symptomatic and secondary generalized or multifocal epilepsy with focal occipital predilection. The mean age of seizure presentation was 18.4 years (6-58 years). All patients developed status epilepticus and 11 patient deaths were, all related to prolonged convulsive status epilepticus, including two with liver failure apparently precipitated by treatment with sodium valproate.
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PMID:POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. 1823 97

Oxidative stress and mitochondrial dysfunction are acute consequences of status epilepticus (SE). However, the role of mitochondrial oxidative stress and genomic instability during epileptogenesis remains unknown. Using the kainate animal model of temporal lobe epilepsy, we investigated oxidative mitochondrial DNA (mtDNA) damage and changes in the mitochondrial base excision repair pathway (mtBER) in the rat hippocampus for a period of 3 months after SE. Acute seizure activity caused a time-dependent increase in mitochondrial, but not nuclear 8-hydroxy-2-deoxyguanosine (8-OHdG/2dG) levels and a greater frequency of mtDNA lesions. This was accompanied by increased mitochondrial H2O2 production and a transient decrease in mtDNA repair capacity. The mtBER proteins 8-oxoguanine glycosylase (Ogg1) and DNA polymerase gamma (Pol gamma) demonstrated elevated expression at mRNA and protein levels shortly after SE and this was followed by a gradual improvement in mtDNA repair capacity. Recurrent seizures associated with the chronic phase of epilepsy coincided with the accumulation of mtDNA damage, increased mitochondrial H2O2 levels, decreased expression of Ogg1 and Pol gamma and impaired mtDNA repair capacity. Together, increased oxidative mtDNA damage, mitochondrial H2O2 production and alterations in the mtBER pathway provide evidence for mitochondrial oxidative stress in epilepsy and suggest that mitochondrial injury may contribute to epileptogenesis.
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PMID:Mitochondrial DNA damage and impaired base excision repair during epileptogenesis. 1829 98

This case concerns a 17-year-old boy, who was given the diagnosis of Alpers syndrome only postmortem when a homozygous 1399G-->A (A467T) mutation was found in the linker-region of POLG1. Serial muscle and liver biopsies as well as brain MRI scans in our patient ranging from early childhood to postmortem analyses showed that (i) routine diagnostic procedures can be normal in the early stage of the disorder and that (ii) central nervous system and further organ affection may only develop in the time course of the disease. Consecutive diagnostic examinations clearly reflected the devastating clinical course and cerebral deterioration evolving over time in Alpers syndrome.
Seizure 2009 Apr
PMID:Proof of progression over time: finally fulminant brain, muscle, and liver affection in Alpers syndrome associated with the A467T POLG1 mutation. 1878 64

Although inborn errors of metabolism (IEM) are a relatively rare cause of epilepsy in children, their diagnosis is important with respect to treatment, prognosis and genetic counselling. In addition to seizures and epilepsy, IEM may produce a complex clinical picture in which epilepsy is only one of the various neurologic manifestations including developmental delay/regression, mental retardation, movement disorders, micro-/macrocephaly, as well as cerebral grey and white matter changes. Dysmorphic features and cerebral dysgenesis may also be part of a metabolic epilepsy syndrome (e.g. disorders of peroxisomal biogenesis, glutaric aciduria type 2, pyruvate dehydrogenease complex deficiency). Metabolic epilepsies may dominate the clinical presentation (e.g. pyridoxine dependent epilepsy) or may precede further neurologic deterioration (e.g. neuronal ceroid lipofuscinosis) and additional organ involvement (e.g. liver failure in Alpers (POLG1) disease). Metabolic epilepsies often present with myoclonic seizures (e.g. Gaucher Disease type 3, mitochondrial syndromes) and, as a rule, patients presenting with predominantly myoclonic seizures should be carefully investigated for these types of metabolic epilepsies. Patients with very early onset of epilepsy are considered at high risk for an underlying IEM as well. In this review we present an overview of metabolic epilepsies based on various criteria such as treatability, age of onset, seizure type, and pathogenetic background. Exemplary disorders will be described in more detail including cerebral glucose transporter (GLUT1) deficiency, pyridoxine dependent epilepsy, neuronal ceroid lipofuscinosis, cathepsin D deficiency, Alpers syndrome (POLG deficiency), and guanidinoacetate methyltransferase (GAMT) deficiency.
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PMID:Metabolic epilepsies: approaches to a diagnostic challenge. 1976 Sep 6

DNA POLG is the only mitochondrial DNA polymerase and is encoded by nuclear DNA. Depending on the location and inheritance, mutations in POLG1, the catalytic subunit, can cause symptoms including severe infantile epilepsy, metabolic strokes, chronic ataxia, neuropathy, and ophthalmoplegia. We reviewed medical records and conducted extensive interviews with the family of identical twin probands with a mutation in the linker region of DNA polymerase gamma 1 (POLG1) (G517V) and discuss postmortem findings from their grandmother. Both twins developed type I diabetes, adrenal insufficiency, hypothyroidism, and psychiatric problems in addition to neurological difficulties including bilateral basal ganglia infarcts, headaches, and seizures. The maternal grandmother, now deceased, had psychosis and balance problems, and postmortem findings include lacunar infarcts in the basal ganglia (caudate nucleus, putamen, and globus pallidus) and posterior spinal column degeneration. We discuss novel aspects of their presentation and implications for practice.
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PMID:Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease. 1981 14

An 11 months old boy, developed liver failure after febrile status epilepticus while being treated with valproic acid for myoclonic epilepsy and recurrent partial and generalized seizures. The diagnosis of Alpers-Huttenlocher disease was considered. A muscle biopsy showed mitochondrial dysfunction. Mitochondrial DNA depletion was ruled out. Sequencing of the polymerase gamma gene (POLG1) did not detect any mutations. Sequencing of the alpha-1 subunit gene of the voltage-gated neuronal sodium channel (SCN1A) revealed a novel, de novo amino acid change p.Val 1637 Glu. This case expands the spectrum of clinical presentations related to mutations in SCN1A. We warn that children with SCN1A mutations may be at risk for developing liver failure following status epilepticus, due to mitochondrial dysfunction.
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PMID:Hepatic coma culminating in severe brain damage in a child with a SCN1A mutation. 2039 57

Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy with recurrent status epilepticus and episodes of epilepsia partialis continua, which often necessitate admission to the intensive care unit (ICU) and pose an important mortality risk. We describe two previously healthy unrelated teenage girls, who both were admitted with generalized tonic-clonic seizures and visual symptoms leading to a DNA-supported diagnosis of juvenile-onset Alpers' syndrome. Despite combined treatment with anti-epileptic drugs, both patients developed status epilepticus requiring admission to the ICU. Intravenous magnesium as anti-convulsant therapy was initiated, resulting in clinical and neurophysiological improvement and rapid extubation of both patients. Treating status epilepticus in juvenile-onset Alpers' syndrome with magnesium has not been described previously. Given the difficulties encountered while treating epilepsy in patients with this syndrome, magnesium therapy might be considered.
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PMID:Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations. 2080 13


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