Do carriers of POLG mutation W748S have disease manifestations?

Rantamäki, Maria; Luoma, Petri; Virta, Jyri J.; Rinne, Juha O.; Paetau, Anders; Suomalainen, Anu; Udd, Bjarne

doi:10.1111/j.1399-0004.2007.00908.x

Cited by 8 publications

(6 citation statements)

References 24 publications

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“…Homozygosity or compound heterozygosity of this mutation leads to the mitochondrial recessive ataxia syndrome or MIRAS (Hakonen et al, 2005). Carriers of the heterozygous p.Trp748Ser mutation have been shown to have decreased cerebral glucose metabolism without overt neurologic symptoms (Rantam€ aki et al, 2007).…”

Section: S056mentioning

confidence: 99%

Dravet syndrome: New potential genetic modifiers, imaging abnormalities, and ictal findings

et al. 2013

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Summary Purpose Dravet syndrome is an autosomal dominant epileptic encephalopathy of childhood, which is caused mainly by SCN1A and PCHD19 mutations. Although Dravet syndrome is well recognized, the causes of acute encephalopathy are still elusive, and reported data on ictal electroencephalography (EEG) and structural brain abnormalities are scarce. Methods We studied 30 children who fulfilled the clinical criteria for Dravet syndrome. All patients were screened for SCN1A mutations and 25 for POLG mutations with bidirectional sequencing. Clinical data, including etiologic studies done as part of the clinical workup, were collected from hospital charts. Ictal video‐EEG recordings and magnetic resonance (MR) images were reanalyzed by the authors. Key Findings SCN1A mutations were found in 25 patients (83%). Two SCN1A mutation–negative patients had chromosomal translocations involving chromosomes 9 and X, and one had a mutation in PCDH19. Prolonged seizures were associated with acute encephalopathy in three SCN1A mutation–positive patients. One showed evidence of a significant hypoxic–ischemic event during status epilepticus. The other two demonstrated new persistent neurologic deficits postictally; they both carried heterozygous POLG variants (p.Trp748Ser or p.Gly517Val). Hippocampal sclerosis or loss of gray–white matter definition in the temporal lobe was observed in 7 of 18 patients who had MRI after age 3 years (39%). Motor seizures were recorded on video‐EEG for 15 patients, of whom 12 were younger than 6 years at recording; 11 patients (73%) showed posterior onsets. Significance Our data imply that a heterozygous X;9 translocation and rare POLG variants may modify the clinical features of Dravet syndrome. The latter may increase susceptibility for acute encephalopathy. Temporal lobe abnormalities are common in patients imaged after 3 years of age. Focal seizures seem to localize predominantly in the posterior regions in young children with Dravet syndrome.

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Section: S056mentioning

confidence: 99%

Dravet syndrome: New potential genetic modifiers, imaging abnormalities, and ictal findings

et al. 2013

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“…Mitochondrial autosomal recessive ataxia syndrome is a common cause of AR juvenile-or adult-onset ataxia 74 . MIRAS is caused by homozygous or compound heterozygous mutations in the POLG1 gene resulting in multiple mtDNA deletions and to a lesser degree than in IOSCA also to mtDNA depletion 72 .…”

Section: Mitochondrial Autosomal Recessive Ataxia Syndrome (Miras)mentioning

confidence: 99%

Mitochondrial Ataxias

Finsterer

2009

Can. j. neurol. sci.

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Mitochondrial disorders (MIDs) are an increasingly recognized condition. The second most frequently affected organ in MIDs is the central nervous system. One of the most prevalent clinical CNS manifestations of MIDs is ataxia. Ataxia may be even the dominant manifestation of a MID. This is why certain MIDs should be included in the classification of heredoataxias or at least considered as differentials of classical heredoataxias. MIDs due to mutations of the mitochondrial DNA, which develop ataxia include the MERRF, NARP, MILS, or KSS syndrome. More rarely, ataxia may be a feature of MELAS, LHON, PS, MIDD, or MSL. MIDs due to mutations of the nuclear DNA, which develop ataxia include LS, SANDO, SCAE, AHS, XSLA/A, IOSCA, MIRAS, MEMSA, or LBSL syndrome. More rarely ataxia can be found in AD-CPEO, AR-CPEO, MNGIE, DIDMOAD, CoQ-deficiency, ADOAD, DCMA, or PDC-deficiency. MIDs most frequently associated with ataxia are the non-syndromic MIDs. Syndromic and non-syndromic MIDs with ataxia should be delineated from classical heredoataxias to initiate appropriate symptomatic or supportive treatment.

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“…The mutation is localized within a block of 6 amino acids forming beta-sheet in the spacer region of mitochondrial polymerase gamma. Carriers of the mutation are asymptomatic [32]. …”

Section: Discussionmentioning

confidence: 99%

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene

et al. 2011

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SummaryBackgroundPOLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion.Material/MethodsA cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations.ResultsThe p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion).ConclusionsOur results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.

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Do carriers of POLG mutation W748S have disease manifestations?

Cited by 8 publications

References 24 publications

Dravet syndrome: New potential genetic modifiers, imaging abnormalities, and ictal findings

Dravet syndrome: New potential genetic modifiers, imaging abnormalities, and ictal findings

Mitochondrial Ataxias

Drug-resistant epilepsia and fulminant valproate liver toxicity. Alpers-Huttenlocher syndrome in two children confirmed post mortem by identification of p.W748S mutation in POLG gene

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