POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype

<p>Abstract</p> <p>Background</p> <p>The c.2447G>A (p.R722H) mutation in the gene <it>POLG1 </it>of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease.</p> <p>Methods</p> <p>Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the <it>POLG1, POLG2, ANT1 </it>and <it>Twinkle </it>genes were sequenced.</p> <p>Results</p> <p>An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and ¹⁸F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the <it>POLG1 </it>gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in <it>POLG2</it>, <it>ANT1 </it>and <it>Twinkle </it>genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic.</p> <p>Conclusions</p> <p>The recessive c.2447G>A (p.R722H) mutation in the linker region of the <it>POLG1 </it>gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.</p

Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations

Mutations in the gene encoding of the catalytic subunit of mtDNA polymerase gamma (POLG1) can cause typical Alpers' syndrome. Recently, a new POLG1 mutation phenotype was described, the so-called juvenile-onset Alpers' syndrome. This POLG1 mutation phenotype is characterized by refractory epilepsy with recurrent status epilepticus and episodes of epilepsia partialis continua, which often necessitate admission to the intensive care unit (ICU) and pose an important mortality risk. We describe two previously healthy unrelated teenage girls, who both were admitted with generalized tonic-clonic seizures and visual symptoms leading to a DNA-supported diagnosis of juvenile-onset Alpers' syndrome. Despite combined treatment with anti-epileptic drugs, both patients developed status epilepticus requiring admission to the ICU. Intravenous magnesium as anti-convulsant therapy was initiated, resulting in clinical and neurophysiological improvement and rapid extubation of both patients. Treating status epilepticus in juvenile-onset Alpers' syndrome with magnesium has not been described previously. Given the difficulties encountered while treating epilepsy in patients with this syndrome, magnesium therapy might be considered

Thermal bremsstrahlung probing the thermodynamical state of multifragmenting systems

Inclusive and exclusive hard-photon (E$_\gamma >$ 30 MeV) production in five different heavy-ion reactions ($^{36}$Ar+$^{197}$Au, $^{107}$Ag, $^{58}$Ni, $^{12}$C at 60{\it A} MeV and $^{129}$Xe+$^{120}$Sn at 50{\it A} MeV) has been studied coupling the TAPS photon spectrometer with several charged-particle multidetectors covering more than 80% of 4$\pi$. The measured spectra, slope parameters and source velocities as well as their target-dependence, confirm the existence of thermal bremsstrahlung emission from secondary nucleon-nucleon collisions that accounts for roughly 20% of the total hard-photon yield. The thermal slopes are a direct measure of the temperature of the excited nuclear systems produced during the reaction.Comment: 4 pages, 3 figures, Proceedings CRIS 2000, 3rd Catania Relativistic Ion Studies, "Phase Transitions in Strong Interactions: Status and Perspectives", Acicastello, Italy, May 22-26, 2000 (to be published in Nuc. Phys. A

Evidence for Thermal Equilibration in Multifragmentation Reactions probed with Bremsstrahlung Photons

The production of nuclear bremsstrahlung photons (E$_{\gamma}>$ 30 MeV) has been studied in inclusive and exclusive measurements in four heavy-ion reactions at 60{\it A} MeV. The measured photon spectra, angular distributions and multiplicities indicate that a significant part of the hard-photons are emitted in secondary nucleon-nucleon collisions from a thermally equilibrated system. The observation of the thermal component in multi-fragment $^{36}$Ar+$^{197}$Au reactions suggests that the breakup of the thermalized source produced in this system occurs on a rather long time-scale.Comment: Revised version, accepted for publication in Physical Review Letters. 4 pages, 4 fig