Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review

<p>Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.</p

fMRI group results of the reproduction phase (computed in Lipsia).

<p>*significant at p<0.05 corrected.</p

Time-course plots of the activity in the precuneus (coordinates 4 −62 26) according to the phase and interval duration.

<p>Activity is plotted during encoding short (upper left), encoding long (lower left), reproduction short (upper right) and reproduction long (lower right) conditions. Group means ± standard error of mean (SEM) for OFF (blue) and ON (green) conditions are depicted. Time points, where at least 3 observations per subject and 6 subjects per time point were not available, were excluded. Therefore encoding of short intervals was followed up to 10 seconds, encoding of long intervals up to 14 seconds, reproduction of short intervals up to 8 seconds and reproduction of long intervals up to 12 seconds. Bars in the upper right corner of each graph represent overall contrast estimate mean ± SD for each condition. The comparison between OFF and ON conditions yielded significant differences only for the reproduction of long intervals (marked with ***, paired t-test p<0.001).</p

Time-course plot of the activity in precuneus (coordinates 4 −62 26) during the reproduction phase.

<p>Each dot represents mean activity in a time point for all trials of one subject in OFF (blue) and ON (green) conditions. Lines connect group means for all subjects. For better clarity, dots are jittered.</p

Area activated in the reproduction phase, ON>OFF.

<p>On the left, results of the second-level group analysis (p<0.05 corrected) are rendered to a structural MRI image using vlrender function from Lipsia package. On the right, the mean contrast estimate plots ± SD in the right precuneus (coordinates 4 −62 26) during encoding (left) and reproduction (right) phases. There was deactivation of the precuneus found in all four conditions (encoding ON, encoding OFF, reproduction ON, reproduction OFF). Comparison between OFF (blue) and ON (green) conditions was significant only during the reproduction phase (paired t-test, p<0.001), when deactivation was more marked in the OFF condition.</p

Mean interval reproductions.

<p>Mean reproduced durations ± SD for all subjects in the OFF (blue) and ON (green) conditions. Direct comparison between the ON and OFF condition was significant only for the 16.8 s interval (paired t-test, p<0.05). Dots inside of the bars represent missed responses for each interval and condition.</p

The Subthalamic Microlesion Story in Parkinson's Disease: Electrode Insertion-Related Motor Improvement with Relative Cortico-Subcortical Hypoactivation in fMRI

<div><p>Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinson's disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinson's Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9–15 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.8±8.7 before to 23.3±4.8 after the surgery (<em>p</em><0.001), correlating with the postoperative oedema score (<em>p</em><0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (<em>p</em><0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (<em>p</em><0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.8±7.0, <em>p</em> = 0.4).</p> <p>In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.</p> </div

Description of the PD patient's group (N = 12).

<p>Mean ± SD and variance range is reported for each parameter. MMSE – Mini Mental State Examination. The UPDRS-III was assessed in OFF condition (medication OFF in session 1; medication OFF and STN DBS OFF in sessions 2 and 3) and in mON condition (after administration of 250 mg of levodopa/carbidopa) in session 1 and in sON condition (medication OFF and bilateral STN DBS ON) in sessions 2, 3, 4. DBS parameters – mean amplitude, variance in pulse duration, frequency and mode of stimulation in both hemispheres. Medtronic electrode (type 3389) positions were measured in native space according to methodology <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049056#pone.0049056-Ruzicka1" target="_blank">[37]</a> on T1-MRI obtained one year after surgery: The x-coordinate of each contact 0 and 3 was measured from the wall of the third ventricle (+ towards right; − towards left), whereas the y-coordinate (+ towards anterior; − towards posterior) and z-coordinate (+ towards vertex; − towards brainstem) were measured from the mid-commissural point.</p

Native <i>T2</i>-weighted images of collateral oedema surrounding implanted electrode 3 days after surgery in PD patients.

<p>Left – Example of bilateral oedema (score 2) involving frontal cortical regions in patient 4. Right – subcortical oedema (score 2) around contacts of the right electrode involving subthalamus and globus pallidus in patient 3. While the susceptibility artifacts from the electrodes are hypointense, the oedema appears hyperintense (white arrows).</p

UPDRS-III in ON condition in PD patients (N = 12) during the study.

<p>The UPDRS-III score before implantation (mON) in session 1 after administration of 250 mg levodopa/carbidopa; in session 2 within 1–3 days after implantation of the electrode bilaterally to STN; in session 3 one month after implantation; and in session 4 one year after implantation examined each time with STN DBS ON (sON state) always with antiparkinsonian medication withdrawn; UPDRS-III – error bars (mean and SD); * (<i>p</i><0.05), *** (<i>p</i><0.001).</p