Polymerase Gamma 1 Mutations

Department of Neurology, Mayo Clinic, Rochester, MN 55902, USA.
The Neurologist (Impact Factor: 1.16). 03/2010; 16(2):84-91. DOI: 10.1097/NRL.0b013e3181c78a89
Source: PubMed


Mitochondrial disorders result from primary defects in the mitochondrial DNA (mtDNA) or from defects in nuclear genes which cause disease by affecting the mtDNA. POLG1 is a nuclear gene which encodes for the catalytic subunit of the mtDNA polymerase gamma, essential for mtDNA replication. Less than a decade ago, POLG1 mutations were discovered in patients with progressive external ophthalmoplegia. Since then, it has emerged that POLG1 mutations can result in a spectrum of clinical manifestations, resulting in autosomal recessive or dominant mitochondrial diseases.
Here we summarize the common clinical phenotypes associated with POLG1 mutations. Alpers syndrome, progressive external ophthalmoplegia with or without limb myopathy, ataxia-neuropathy syndrome, and epilepsy are frequent clinical manifestations of the POLG1-related disease. Childhood progressive encephalopathy, Parkinsonism, stroke-like events, and isolated exercise intolerance can occur in association with POLG1 mutations. Muscle biopsy can show signs of mitochondrial dysfunction by histologic and biochemical studies or it can be unrevealing. mtDNA analysis of affected tissues can reveal depletion, multiple deletions or point mutations, but it can be occasionally noninformative by routine analysis.
: POLG1 mutations result in extremely heterogenous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes. The lack of signs of mitochondrial dysfunction in the muscle biopsy does not exclude a POLG1-related disease. Analysis of mtDNA of clinically affected tissues is often informative, but not always. Molecular analysis of POLG1 is essential when POLG1-related disease is suspected. Sodium valproate should be avoided because of the risk of liver failure.

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    • "One of the most common mutations causing ataxia is p.A467T mutation that is also located in the linker domain but it causes neurologic disease only in a homozygous state. Furthermore, this mutation in a homozygous state is the most common cause of Alpers-Huttenlocher syndrome [17]. The reasons for this variability in phenotype-genotype correlation are unknown. "
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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.
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    • "Onset in early to mid childhood Creatine deficiency syndromes DD, sz, MRS+, AE autism SLC6A8, GAMT, GATM Oral creatine (GAMT, AGAT) Inherited: GAMT/GATM (AR), SLC6A8 (X- linked) [55] Autosomal dominant nocturnal frontal lobe epilepsy Seizures arising from sleep, prominent motor manifestations CHRNA4, CHRNB2, CHRNA2 NS Inherited (AD) [56] Alpers-Huttenlocher syndrome Progressive encephalopathy, refractory sz, hepatic failure, poliodystrophy POLG1 Avoid VPA (liver failure) Inherited (AR) [57] [58] "
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