POLG mutations and Alpers syndrome

Università di Pisa, Pisa, Tuscany, Italy
Annals of Neurology (Impact Factor: 9.98). 06/2005; 57(6):921 - 923. DOI: 10.1002/ana.20498

ABSTRACT Alpers–Huttenlocher syndrome (AHS) an autosomal recessive hepatocerebral syndrome of early onset, has been associated with mitochondrial DNA (mtDNA) depletion and mutations in polymerase gamma gene (POLG). We have identified POLG mutations in four patients with hepatocerebral syndrome and mtDNA depletion in liver, who fulfilled criteria for AHS. All were compound heterozygous for the G848S and W748S mutations, previously reported in patients with progressive external ophtalmoplegia or ataxia. We conclude that AHS should be included in the clinical spectrum of mtDNA depletion and is often associated with POLG mutations, which can cause either multiple mtDNA deletions or mtDNA depletion. Ann Neurol 2005;57:921–924

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Available from: Guido Davidzon, Sep 28, 2015
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    • "They can also result in adult onset cerebellar ataxia with mtDNA multiple deletions and Alpers syndrome, an autosomal recessive hepatocerebral disease characterized by severe developmental delay, intractable seizures, liver failure and death in childhood. Moreover, throughout the years a wide spectrum of clinical findings including parkinsonism, neuropathy, optic neuritis, psychiatric disorders has been described in POLG1 mutations carriers [12,14-19]. Deschauer et al. 2007 described a patient presenting with occipital seizures and residual homonymous hemianopsia, headache and ataxia and carrying two heterozygous POLG1 mutations [7]. "
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    ABSTRACT: Background POLG1 mutations have been associated with MELAS-like phenotypes. However given several clinical differences it is unknown whether POLG1 mutations are possible causes of MELAS or give raise to a distinct clinical and genetic entity, named POLG1-associated encephalopathy. Case presentation We describe a 74 years old man carrying POLG1 mutations presenting with strokes, myopathy and ragged red fibers with some atypical aspects for MELAS such as late onset, lack of cerebral calcification and presence of frontal and occipital MRI lesions better consistent with the POLG associated-encephalopathy spectrum. Conclusion The lack of available data hampers a definite diagnosis in our patient as well as makes it difficult to compare MELAS, which is a clearly defined clinical syndrome, with POLG1-associated encephalopathy, which is so far a purely molecularly defined syndrome with a quite heterogeneous clinical picture. However, the present report contributes to expand the phenotypic spectrum of POLG1 mutations underlining the importance of searching POLG1 mutations in patients with mitochondrial signs and MELAS like phenotypes but negative for common mtDNA mutations.
    BMC Neurology 01/2013; 13(1):8. DOI:10.1186/1471-2377-13-8 · 2.04 Impact Factor
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    • "Polymerase gamma (POLG) deficiency was established as the major cause of the disorder [31] and POLG gene mutations were identified in the majority of AHS patients [10–16]. The protein (catalytic subunit of DNA polymerase gamma) is essential for mtDNA replication and repair. "
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    ABSTRACT: POLG (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. A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations. The 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). Our 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.
    Medical science monitor: international medical journal of experimental and clinical research 04/2011; 17(4):CR203-9. DOI:10.12659/MSM.881716 · 1.43 Impact Factor
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    • "Pearson syndrome (PS) (moderate psychomotor retardation, pancytopenia and pancreatic insufficiency; MIM 557000) and Alpers-Huttenlocher syndrome (AHS) (myoclonal epilepsy, liver and brain disease; MIM 203700) are known to harbour defects of mitochondrial function [17-19], but mitochondrial mosaics in the liver have not been described. "
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    ABSTRACT: In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized. COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis. Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of POLG were subsequently found in both the 2nd and 3rd patients. Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent than observed until now. A novel pathogenic mutation in POLG is reported.Tentative explanations for the mitochondrial mosaics are, in one patient, unequal partition of mutated mitochondria during mitoses, and in two others, an interaction between products of several genes required for mtDNA maintenance.
    BMC Clinical Pathology 07/2009; 9(1):4. DOI:10.1186/1472-6890-9-4
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