TY - JOUR A1 - Ioakeimidis, Fotis A1 - Ott, Christine A1 - Kozjak-Pavlovic, Vera A1 - Violitzi, Foteini A1 - Rinotas, Vagelis A1 - Makrinou, Eleni A1 - Eliopoulos, Elias A1 - Fasseas, Costas A1 - Kollias, George A1 - Douni, Eleni T1 - A Splicing Mutation in the Novel Mitochondrial Protein DNAJC11 Causes Motor Neuron Pathology Associated with Cristae Disorganization, and Lymphoid Abnormalities in Mice JF - PLOS ONE N2 - Mitochondrial structure and function is emerging as a major contributor to neuromuscular disease, highlighting the need for the complete elucidation of the underlying molecular and pathophysiological mechanisms. Following a forward genetics approach with N-ethyl-N-nitrosourea (ENU)-mediated random mutagenesis, we identified a novel mouse model of autosomal recessive neuromuscular disease caused by a splice-site hypomorphic mutation in a novel gene of unknown function, DnaJC11. Recent findings have demonstrated that DNAJC11 protein co-immunoprecipitates with proteins of the mitochondrial contact site (MICOS) complex involved in the formation of mitochondrial cristae and cristae junctions. Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. The causal role of the identified mutation in DnaJC11 was verified in rescue experiments by overexpressing the human ortholog. The full length 63 kDa isoform of human DNAJC11 was shown to localize in the periphery of the mitochondrial outer membrane whereas putative additional isoforms displayed differential submitochondrial localization. Moreover, we showed that DNAJC11 is assembled in a high molecular weight complex, similarly to mitofilin and that downregulation of mitofilin or SAM50 affected the levels of DNAJC11 in HeLa cells. Our findings provide the first mouse mutant for a putative MICOS protein and establish a link between DNAJC11 and neuromuscular diseases. KW - dominant optic atrophy KW - amyotrophic-lateral-sclerosis KW - nervous system KW - membrane organization KW - mitofilin KW - data-bank KW - model KW - biogenesis KW - morphology KW - reveals Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115581 VL - 9 IS - 8 ER - TY - JOUR A1 - Martens, Suzanne A1 - Bensch, Michael A1 - Halder, Sebastian A1 - Hill, Jeremy A1 - Nijboer, Femke A1 - Ramos-Murguialday, Ander A1 - Schoelkopf, Bernhard A1 - Birbaumer, Niels A1 - Gharabaghi, Alireza T1 - Epidural electrocorticography for monitoring of arousal in locked-in state JF - Frontiers in Human Neuroscience N2 - Electroencephalography (EEG) often fails to assess both the level (i.e., arousal) and the content (i.e., awareness) of pathologically altered consciousness in patients without motor responsiveness. This might be related to a decline of awareness, to episodes of low arousal and disturbed sleep patterns, and/or to distorting and attenuating effects of the skull and intermediate tissue on the recorded brain signals. Novel approaches are required to overcome these limitations. We introduced epidural electrocorticography (ECoG) for monitoring of cortical physiology in a late-stage amytrophic lateral sclerosis patient in completely locked-in state (CLIS) Despite long-term application for a period of six months, no implant related complications occurred. Recordings from the left frontal cortex were sufficient to identify three arousal states. Spectral analysis of the intrinsic oscillatory activity enabled us to extract state-dependent dominant frequencies at <4, similar to 7 and similar to 20 Hz, representing sleep-like periods, and phases of low and elevated arousal, respectively. In the absence of other biomarkers, ECoG proved to be a reliable tool for monitoring circadian rhythmicity, i.e., avoiding interference with the patient when he was sleeping and exploiting time windows of responsiveness. Moreover, the effects of interventions addressing the patient's arousal, e.g., amantadine medication, could be evaluated objectively on the basis of physiological markers, even in the absence of behavioral parameters. Epidural ECoG constitutes a feasible trade-off between surgical risk and quality of recorded brain signals to gain information on the patient's present level of arousal. This approach enables us to optimize the timing of interactions and medical interventions, all of which should take place when the patient is in a phase of high arousal. Furthermore, avoiding low responsiveness periods will facilitate measures to implement alternative communication pathways involving brain-computer interfaces (BCI). KW - temporal-lobe epilepsy KW - neuroprosthetic devices KW - brain computer interface KW - event-related potentials KW - intraoperative electrocoicography KW - electrocorticography KW - epidural recording KW - locked-in state KW - coma KW - consciousness KW - paralyzed patients KW - EEG KW - sleep KW - communication KW - frequencies KW - amyotrophic-lateral-sclerosis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114863 VL - 8 ER - TY - JOUR A1 - Cruccu, Giorgio A1 - Pennisi, Elena M. A1 - Antonini, Giovanni A1 - Biasiotta, Antonella A1 - Di Stefano, Giulia A1 - La Cesa, Silvia A1 - Leone, Caterina A1 - Raffa, Salvatore A1 - Sommer, Claudia A1 - Truini, Andrea T1 - Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms? JF - BMC Neurology N2 - Background: Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. Methods: Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. Results: The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. Conclusions: Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms. KW - amyotrophic-lateral-sclerosis KW - atrophy Kennedys-disease KW - trigeminal nerve KW - neuronopathy KW - trigeminal neuropathy KW - FOSMN KW - facial pain KW - Sjorgens-syndrome KW - reflex KW - afferents KW - neuralgia KW - pathways KW - humans KW - fibers Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114249 SN - 1471-2377 VL - 14 ER - TY - JOUR A1 - Karle, Kathrin N. A1 - Schüle, Rebecca A1 - Klebe, Stephan A1 - Otto, Susanne A1 - Frischholz, Christian A1 - Liepelt-Scarfone, Inga A1 - Schöls, Ludger T1 - Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP) JF - Orphanet Journal of Rare Diseases N2 - Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials. KW - motor evoked potential (MEP) KW - amyotrophic-lateral-sclerosis KW - somatosensory-evoked-potentials KW - Silver-syndrome KW - gene mutations KW - SPG4 KW - mouse model KW - ALSIN gene KW - neuropathy KW - paraparesis KW - protein KW - electrophysiology KW - hereditary spastic paraplegia (HSP) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124763 SN - 1750-1172 VL - 8 IS - 158 ER -