Molecular and clinical genetics of mitochondrial diseases due to POLG mutations

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Human Mutation (Impact Factor: 5.14). 09/2008; 29(9):E150-72. DOI: 10.1002/humu.20824
Source: PubMed


Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.

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Available from: Georgianne L Arnold, Oct 04, 2015
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    • "Impaired integrity of mtDNA with its depletion or deletion causes a broad spectrum of both non-neurological and neurological phenotypes [1]. Greater than one hundred pathogenic mutations in this enzyme have been found since it was first described [2]. These include, but are not limited to parkinsonism, chronic progressive external ophthalmoplegia (CPEO), cerebellar ataxia, sensory polyneuropathy, Alpers-Huttenlocher syndrome, which is characterized by progressive encephalopathy with seizures and hepatic failure, isolated myoclonic epilepsy or non-syndromic liver failure. "
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    ABSTRACT: Mutations in the POLG1 gene have variable phenotypic presentations and a high degree of clinical suspicion is necessary for their recognition. Parkinsonism and ataxia are the most common movement disorders associated with POLG1 mutations but no phenotype-genotype correlation has been established. Case Presentation: We identified a male patient with progressive external ophthalmoplegia who also developed a progressive bradykinesia, rigidity and camptocormia in the third decade. Parkinsonism was partially responsive to dopaminegic replacement. His father and brother had reportedly similar clinical problems. Genetic analysis identified a novel mutation p.K512M in the POLG1 gene. This report further expands the spectrum of POLG1-associated neurologic problems with the report of a novel mutation in the linker region of the gene, which are rarely associated with parkinsonism.
    BMC Neurology 07/2013; 13(1):92. DOI:10.1186/1471-2377-13-92 · 2.04 Impact Factor
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    • "Unfortunately, treatment of POLG-related diseases has been limited to symptom management and supportive care. The predominance of liver involvement in the younger child has led to liver transplantation in some patients, but the outcome has been poor and is not recommended for POLG-related disease because of neurological involvement (Tzoulis et al. 2006; Wong et al. 2008). Even though seizures in POLG patients can be resistant to anti-seizure medications, the use of valproic acid should be avoided, because of induction of liver failure (Horvath et al. 2006; Tzoulis et al. 2006; Chinnery and Zeviani 2008). "
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    ABSTRACT: The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
    Cold Spring Harbor perspectives in biology 04/2013; 5(4). DOI:10.1101/cshperspect.a011395 · 8.68 Impact Factor
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    • "Similarly, the amino acid substitution p.G1205E. A change at the same residue (p.G1205A) caused by heterozygous mutations (c.3614G>C) was associated with retinitis pigmentosa, hearing loss, and failure to thrive (Wong et al., 2008). It is likely that the POLG c.3614G>A variant is a disease-causing mutation, since (1) glycine to glutamate is a nonpolar to acidic amino acid substitution, (2) glycine at position p.1205 is highly conserved across species, and (3) this variant affects an amino acid within the functionally important polymerase domain of the protein. "
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    ABSTRACT: Purpose To assess the frequency and clinical features of childhood-onset intractable epilepsy caused by the most common mutations in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. Methods Children presenting with nonsyndromic intractable epilepsy of unknown etiology but without documented liver dysfunction at presentation were eligible for this prospective, population-based study. Blood samples were analyzed for the three most common POLG mutations. If any of the three tested mutations were found, all the exons and the exon–intron boundaries of the POLG gene were sequenced. In addition, we retrospectively reviewed the notes of patients presenting with intractable epilepsy in which we had found POLG mutations. All available clinical data were collected by questionnaire and by reviewing the medical records. Key Findings We analyzed 213 blood DNA samples from patients fulfilling the inclusion criteria of the prospective study. Among these, five patients (2.3%) were found with one of the three common POLG mutations as homozygous or compound heterozygous states. In addition, three patients were retrospectively identified. Seven of the eight patients had either raised cerebrospinal fluid (CSF) lactate (n = 3) or brain magnetic resonance imaging (MRI) changes (n = 4) at presentation with intractable epilepsy. Three patients later developed liver dysfunction, progressing to fatal liver failure in two without previous treatment with sodium valproate (VPA). Furthermore, it is worth mentioning that one patient presented first with an autism spectrum disorder before seizures emerged. Significance Mutations in POLG are an important cause of early and juvenile onset nonsyndromic intractable epilepsy with highly variable associated manifestations including autistic features. This study emphasizes that genetic testing for POLG mutations in patients with nonsyndromic intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations. We recommend POLG gene testing for patients with intractable seizures and at least one elevated CSF lactate or suggestive brain MRI changes (predominantly abnormal T2-weighted thalamic signal) with or without status epilepticus, epilepsia partialis continua, or liver manifestations typical for Alpers disease, especially when the disease course is progressive.
    Epilepsia 02/2013; 54(6). DOI:10.1111/epi.12115 · 4.57 Impact Factor
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