Polymerase gamma deficiency (POLG): Clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh’s encephalopathy

Scalais, Emmanuel; François, B.; Schlesser, Patrick; Stevens, R. W. C.; Nuttin, C.; Martin, Jean‐Jacques; Coster, Rudy Van; Seneca, Sara; Roels, Frank; Goethem, Gert Van; Löfgren, A.; Meırleır, Linda De

doi:10.1016/j.ejpn.2012.01.013

Cited by 22 publications

(35 citation statements)

References 31 publications

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“…T 2 ‐hyperintense thalamic lesions (37%), often bilateral, are another common finding observed in cases with drug‐resistant seizures. Unusual imaging appearances such as enhancement of bilateral cranial nerves (III, V, to X) and cervical nerve roots, and T 2 ‐hyperintensity in inferior colliculus (a midbrain nucleus) have also been reported . Overall, brainstem signal abnormality is extremely uncommon.…”

Section: Resultsmentioning

confidence: 99%

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Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

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We performed a systematic review of the clinical, molecular, and biochemical features of polymerase gamma (POLG)-related epilepsy and current evidence on seizure management. Patients were identified from a combined electronic search of articles using Ovid Medline and Scopus databases, published from January 2000 to January 2015. Only patients with a confirmed genetic diagnosis of POLG mutations were considered. Seventy-two articles were included for analysis. We identified 128 pathogenic variants in 372 patients who had POLG-related epilepsy. Among these, 84% of the cases harbored at least one of these pathogenic variants: p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser. A bimodal distribution of disease onset was present in early childhood (<5 years) and adolescence; female patients had a later presentation than male patients (median age 4.00 vs. 1.83 years, p-value = 0.041). Focal-onset seizure including convulsive, myoclonus, and occipital seizures was common at the outset and was refractory to pharmacotherapy. We confirmed that homozygous pathogenic variants located in the linker region of POLG were associated with later age of onset and longer survival compared to compound heterozygous variants. In addition, biochemical and molecular heterogeneities in different tissues were frequently observed. POLG-related epilepsy is clinically heterogeneous, and the prognosis is, in part, influenced by the location of the variants in the gene and the presence of hepatic involvement. Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.

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Section: Resultsmentioning

confidence: 99%

“…Neuropathology reports were available for 28 patients, of whom 21 were infants/children (0–9 years) and seven were adolescents/young adults (12–18 years) . These samples were mainly postmortem, although three were brain biopsies …”

Section: Resultsmentioning

confidence: 99%

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

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“…Disease Genes Associated with Leigh-like Syndrome 76,77 Disease genes that predominantly underlie a Leigh-like presentation that may not fit a stringent LS diagnosis also include SERAC1, which causes 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome associated with isolated or combined OXPHOS enzyme deficiency. 78 These patients often present with atypical neuroradiology, or with unusual additional symptoms including abnormal behavior.…”

Section: 72mentioning

confidence: 98%

Leigh syndrome: One disorder, more than 75 monogenic causes

Lake

Compton

Rahman

et al. 2015

Annals of Neurology

407

382

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Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one-third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype-phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options.

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“…Interestingly the authors describe that their patient did not respond to glucagon, a response that could be consistent with GDE deficiency depending on the fasting time. Due to the many similarities between our patient and the one previously published (Roels et al 2009;Scalais et al 2012), one may speculate whether our findings are genotype specific. A search of the Human DNA Polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg) for p.…”

Section: Discussionmentioning

confidence: 57%

“…In contrast to our patient who initially presented with isolated ketotic hypoglycemia, normal lactic acid level, and normal physical exam at 10 months of age, this infant had already developed severe liver dysfunction at 3.5 months of age with jaundice, ascites, and hepatomegaly. A liver biopsy at~9 months of age showed micronodular cirrhosis and bile ductular proliferation (Scalais et al 2012). At 18 months a second liver biopsy showed Kupffer cells with PAS positive large granules and glycogen rosettes, a finding usually considered secondary to glycogen storage #2 #5 Fig.…”

Section: Discussionmentioning

confidence: 98%

Abnormalities in Glycogen Metabolism in a Patient with Alpers’ Syndrome Presenting with Hypoglycemia

et al. 2013

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Intermittent hypoglycemia has been described in association with Alpers' syndrome, a disorder caused by mutations in the mitochondrial DNA polymerase gamma gene. In some patients hypoglycemia may define the initial disease presentation well before the onset of the classical Alpers' triad of psychomotor retardation, intractable seizures, and liver failure. Correlating with the genotype, POLG pathogenicity is a result of increased mitochondrial DNA mutability, and mitochondrial DNA depletion resulting in energy deficient states. Hypoglycemia therefore could be secondary to any metabolic pathway affected by ATP deficiency. Although it has been speculated that hypoglycemia is due to secondary fatty acid oxidation defects or abnormal gluconeogenesis, the exact underlying etiology is still unclear. Here we present detailed studies on carbohydrate metabolism in an Alpers' patient who presented initially exclusively with intermittent episodes of hypoglycemia and ketosis. Our results do not support a defect in gluconeogenesis or fatty acid oxidation as the cause of hypoglycemia. In contrast, studies performed on liver biopsy suggested abnormal glycogenolysis. This is shown via decreased activities of glycogen brancher and debrancher enzymes with normal glycogen structure and increased glycogen on histology of the liver specimen. To our knowledge, this is the first report documenting abnormalities in glycogen metabolism in a patient with Alpers' syndrome.

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Polymerase gamma deficiency (POLG): Clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh’s encephalopathy

Cited by 22 publications

References 31 publications

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Leigh syndrome: One disorder, more than 75 monogenic causes

Abnormalities in Glycogen Metabolism in a Patient with Alpers’ Syndrome Presenting with Hypoglycemia

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