Juvenile Alpers Disease

Wiltshire, Esko; Davidzon, Guido; DiMauro, Salvatore; Akman, Hasan O.; Sadleir, Lynette G.; Haas, Lindsey R.; Zuccollo, Jane; McEwen, Alison; Thorburn, David R.

doi:10.1001/archneurol.2007.14

Cited by 42 publications

(38 citation statements)

References 20 publications

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“…Several reports have shown that patients with POLG mutations and Alpers–Huttenlocher syndrome present with syndromic epilepsy with occipital lobe predilection. 5,21,23–25 In addition, our patient population (Table 1) and recent literature demonstrates seizure semiology consistent with occipital lobe epileptic discharges; focal clonic motor seizures, secondarily generalized tonic–clonic seizures, hallucinations and nystagmus. 23–25,28 However, early studies have not consistently shown occipital lobe discharges, with some describing generalized discharges, hypsarrhythmia or multifocal discharges.…”

Section: Discussionsupporting

confidence: 74%

“…5,21,23–25 In addition, our patient population (Table 1) and recent literature demonstrates seizure semiology consistent with occipital lobe epileptic discharges; focal clonic motor seizures, secondarily generalized tonic–clonic seizures, hallucinations and nystagmus. 23–25,28 However, early studies have not consistently shown occipital lobe discharges, with some describing generalized discharges, hypsarrhythmia or multifocal discharges. 28,29 Tulinius and Hagne 28 suggested that timing of the disease progression was likely responsible for EEG variation.…”

Section: Discussionsupporting

confidence: 74%

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POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders

Saneto

Lee

Koenig

et al. 2010

Seizure

134

128

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Purpose To review our clinical experience and determine if there are appropriate signs and symptoms to consider POLG sequencing prior to valproic acid (VPA) dosing in patients with seizures. Methods Four patients who developed VPA-induced hepatotoxicity were examined for POLG sequence variations. A subsequent chart review was used to describe clinical course prior to and after VPA dosing. Results Four patients of multiple different ethnicities, age 3–18 years, developed VPA-induced hepatotoxicity. All were given VPA due to intrac partial seizures. Three of the patients had developed epilepsia partialis continua. The time from VPA exposure to liver failure was between 2 and 3 months. Liver failure was reversible in one patient. Molecular studies revealed homozygous p.R597W or p.A467T mutations in two patients. The other two patients showed compound heterozygous mutations, p.A467T/p.Q68X and p.L83P/p.G888S. Clinical findings and POLG mutations were diagnostic of Alpers–Huttenlocher syndrome. Conclusion Our cases underscore several important findings: POLG mutations have been observed in every ethnic group studied to date; early predominance of epileptiform discharges over the occipital region is common in POLG-induced epilepsy; the EEG and MRI findings varying between patients and stages of the disease; and VPA dosing at any stage of Alpers–Huttenlocher syndrome can precipitate liver failure. Our data support an emerging proposal that POLG gene testing should be considered in any child or adolescent who presents or develops intractable seizures with or without status epilepticus or epilepsia partialis continua, particularly when there is a history of psychomotor regression.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 74%

POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders

Saneto

Lee

Koenig

et al. 2010

Seizure

134

128

View full text Add to dashboard Cite

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“…The function of these mutations remains unclear, while the p.A862T mutation affects the polymerase domain. Another polymerase domain mutation, c.3139C>T/p.R1047W, has recently been described in juvenile Alpers syndrome,17 while a sixth novel substitution, c.32G>A/p.G11D, is located in the leader sequence involved in directing the protein to the mitochondrion and warranted further investigation. Multiple conservation alignments show that all of the substitutions affect amino acids which are highly conserved across species (fig 2).…”

Section: Resultsmentioning

confidence: 99%

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

Stewart

Tennant

Powell

et al. 2008

Journal of Medical Genetics

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“…The side chain substitutions G848S, T851A, R852C, and R853Q are located in a conserved region of the thumb domain, and all are associated with Alpers syndrome [50,66,74,75]. In each case, the mutations were shown to nearly eliminate polymerase activity [76].…”

Section: Pol γ and Mtdna Replication Proteins In Diseasementioning

confidence: 99%

Mitochondrial genome maintenance in health and disease

2014

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Human mitochondria harbor an essential, high copy number, 16,569 base pair, circular DNA genome that encodes 13 gene products required for electron transport and oxidative phosphorylation. Mutation of this genome can compromise cellular respiration, ultimately resulting in a variety of progressive metabolic diseases collectively known as ‘mitochondrial diseases’. Mutagenesis of mtDNA and the persistence of mtDNA mutations in cells and tissues is a complex topic, involving the interplay of DNA replication, DNA damage and repair, purifying selection, organelle dynamics, mitophagy, and aging. We briefly review these general elements that affect maintenance of mtDNA, and we focus on nuclear genes encoding the mtDNA replication machinery that can perturb the genetic integrity of the mitochondrial genome.

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Juvenile Alpers Disease

Abstract: Background: Alpers disease is commonly associated with polymerase ␥ deficiency and usually affects infants or young children. Objective: To report a juvenile case of Alpers disease due to mutations in the polymerase ␥ gene (POLG1).

Cited by 42 publications

References 20 publications

POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders

POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders

Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children

Mitochondrial genome maintenance in health and disease

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