The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.

/pdf/polg-related-disorders-and-their-neurological-manifestations-jvntp4hljn.pdf

POLG-related disorders and their neurological manifestations.

http://www.for926.uni-bonn.de/kunden/for926/content/e229/e1379/e1382/2014_Bilkei_PharmacolTher.pdf

Genetic mouse models of brain ageing and Alzheimer's disease.

Mitochondrial respiratory chain disorders are relatively common inborn errors of energy metabolism, with a combined prevalence of one in 5000. These disorders typically affect tissues with high energy requirements, and cerebral involvement occurs frequently in childhood, often manifesting in seizures. Mitochondrial diseases are genetically heterogeneous; to date, mutations have been reported in all 37 mitochondrially encoded genes and more than 80 nuclear genes. The major genetic causes of mitochondrial epilepsy are mitochondrial DNA mutations (including those typically associated with the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS] and myoclonic epilepsy with ragged red fibres [MERRF] syndromes); mutations in POLG (classically associated with Alpers syndrome but also presenting as the mitochondrial recessive ataxia syndrome [MIRAS], spinocerebellar ataxia with epilepsy [SCAE], and myoclonus, epilepsy, myopathy, sensory ataxia [MEMSA] syndromes in older individuals) and other disorders of mitochondrial DNA maintenance; complex I deficiency; disorders of coenzyme Q(10) biosynthesis; and disorders of mitochondrial translation such as RARS2 mutations. It is not clear why some genetic defects, but not others, are particularly associated with seizures. Epilepsy may be the presenting feature of mitochondrial disease but is often part of a multisystem clinical presentation. Mitochondrial epilepsy may be very difficult to manage, and is often a poor prognostic feature. At present there are no curative treatments for mitochondrial disease. Individuals with mitochondrial epilepsy are frequently prescribed multiple anticonvulsants, and the role of vitamins and other nutritional supplements and the ketogenic diet remain unproven.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2011.04214.x

Mitochondrial disease and epilepsy.

Cerebral folate transport deficiency is an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 gene coding for folate receptor alpha (FRα) This genetic defect gives rise to a progressive neurological disorder with late infantile onset We screened 72 children with low 5-methyltetrahydrofolate concentrations in the cerebrospinal fluid and neurological symptoms that developed after infancy We identified nucleotide alterations in the folate receptor 1 gene in 10 individuals who shared developmental regression, ataxia, profound cerebral hypomyelination and cerebellar atrophy We found four novel pathogenic alleles, one splice mutation and three missense mutations Heterologous expression of the missense mutations, including previously described mutants, revealed minor decrease in protein expression but loss of cell surface localization, mistargeting to intracellular compartments and thus absence of cellular binding of folic acid These results explain the functional loss of folate receptor alpha for all detected folate receptor 1 mutations Three individuals presenting a milder clinical phenotype revealed very similar biochemical and brain imaging data but partially shared pathogenic alleles with more severely affected patients Thus, our studies suggest that different clinical severities do not necessarily correlate with residual function of folate receptor alpha mutants and indicate that additional factors contribute to the clinical phenotype in cerebral folate transport deficiency

Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.

ad=
: autosomal dominant; 
ANT1=
: adenine nucleotide translocator; 
ar=
: autosomal recessive; 
ATP=
: adenosine triphosphate; 
COX=
: cytochrome c oxidase; 
MELAS=
: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; 
MNGIE=
: mitochondrial neurogastrointestinal encephalomyopathy; 
mtDNA=
: mitochondrial DNA; 
mtSSB=
: mitochondrial single stranded binding protein; 
PEO=
: progressive external ophthalmoplegia; 
POLG=
: mitochondrial DNA polymerase γ-catalytic subunit; 
POLG=
: polymerase γ gene-catalytic subunit; 
POLG2=
: polymerase γ gene-accessory subunit; 
RHADS=
: rhythmic high-amplitude delta with superimposed spikes and polyspikes

Mitochondria are ubiquitous and play a crucial role in many vital functions, including oxidative phosphorylation and generation of adenosine triphosphate (ATP), calcium homeostasis, and apoptosis. Mitochondrial dysfunction results in neurologic and non-neurologic disorders manifesting with a broad spectrum of clinical phenotypes. In 1988, Holt and colleagues1 reported the first pathogenic mitochondrial DNA (mtDNA) mutation in mitochondrial myopathies. Since then, numerous mtDNA mutations have been identified as the cause of various disorders. Among the most prototypical of these mitochondrial disorders, linked to primary defects in the mitochondrial genome, are mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS); myoclonic epilepsy and ragged red fibers; and neuropathy, ataxia, and retinitis pigmentosa. More than a decade after the initial reports, Van Goethem and colleagues2 discovered, in patients with progressive external ophthalmoplegia (PEO), mutations in the nuclear gene polymerase γ ( POLG ), which were associated with mtDNA deletions. It is now well-established that primary defects in some nuclear genes are a common cause of mitochondrial diseases and that POLG is one of those nuclear genes.3,4

Mitochondria contain their own DNA that encodes for 22 tRNA, 2 rRNA, and 13 respiratory chain protein subunits of complexes I, III, IV, and V.5 Human mtDNA is continuously replicated by DNA polymerase γ. The mtDNA polymerase γ, in combination with the mitochondrial DNA helicase Twinkle and the mitochondrial single-stranded binding protein, forms the core replication apparatus in the mitochondria (figure 1).6 The mitochondrial DNA polymerase γ is believed to be the sole polymerase responsible for mtDNA replication and repair in the mitochondria of eukaryotic cells.7 The holoenzyme is a heterotrimer consisting of a catalytic subunit and 2 smaller accessory subunits.6 The catalytic subunit (POLG) is encoded by POLG and has both polymerase and proofreading exonuclease activity resulting in high fidelity. …

POLG-related disorders Defects of the nuclear and mitochondrial genome interaction

Objective: Mitochondrial DNA polymerase γ (POLG1) mutations in children often manifest as Alpers syndrome, whereas in adults, a common manifestation is mitochondrial recessive ataxia syndrome (MIRAS) with severe epilepsy Because some patients with MIRAS have presented with ataxia or epilepsy already in childhood, we searched for POLG1 mutations in neurologic manifestations in childhood Methods: We investigated POLG1 in 136 children, all clinically suspected to have mitochondrial disease, with one or more of the following: ataxia, axonal neuropathy, severe epilepsy without known epilepsy syndrome, epileptic encephalopathy, encephalohepatopathy, or neuropathologically verified Alpers syndrome Results: Seven patients had POLG1 mutations, and all of them had severe encephalopathy with intractable epilepsy Four patients had died after exposure to sodium valproate Brain MRI showed parieto-occipital or thalamic hyperintense lesions, white matter abnormality, and atrophy Muscle histology and mitochondrial biochemistry results were normal in all Conclusions: POLG1 analysis should belong to the first-line DNA diagnostic tests for children with an encephalitis-like presentation evolving into epileptic encephalopathy with liver involvement (Alpers syndrome), even if brain MRI and morphology, respiratory chain activities, and the amount of mitochondrial DNA in the skeletal muscle are normal POLG1 analysis should precede valproate therapy in pediatric patients with a typical phenotype However, POLG1 is not a common cause of isolated epilepsy or ataxia in childhood

POLG1 manifestations in childhood

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POLG1 manifestations in childhood