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Supplemental material, sj-docx-1-tan-10.1177_17562864211035543 for Progressive multifocal leukoencephalopathy and immune reconstitution inflammatory syndrome in seven patients with sarcoidosis: a critical discussion of treatment and prognosis by Maike F. Dohrn, Gisa Ellrichmann, Rastislav Pjontek, Carsten Lukas, Jens Panse, Ralf Gold, Jörg B. Schulz, Burkhard Gess and Simone C. Tauber in Therapeutic Advances in Neurological Disorders

This editorial highlights a study by Rodriguez, Sanchez‐Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A> G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3‐ubiquitin ligase cofactor CDH1. A functional characterization of mutant APC/CCDH1 confirms an aberrant division of neural progenitor cells, a condition known to determine the mouse brain cortex size. These data suggest that APC/CCDH1 may contribute to the regulation of the human brain size., This editorial highlights a study by Rodriguez, Sanchez‐Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A>G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3‐ubiquitin ligase cofactor CDH1. The mutation causes a substantial loss of anaphase‐promoting complex/cyclosome (APC/C) activity resulting in replicative stress of neural progenitor cells (NPCs) leading to impaired neurogenesis during the embryonic stage. Based on the patient’s phenotype, one can further hypothesize that this mutation leads to an antenatally reduced size of brain cortex (microcephaly).

This editorial highlights a study by Rodriguez, Sanchez-Moran et al. (2019) in the current issue of the Journal of Neurochemistry, in which the authors describe a microcephalic boy carrying the novel heterozygous de novo missense mutation c.560A> G; p.Asp187Gly in Cdh1/Fzr1 encoding the APC/C E3-ubiquitin ligase cofactor CDH1. A functional characterization of mutant APC/C confirms an aberrant division of neural progenitor cells, a condition known to determine the mouse brain cortex size. These data suggest that APC/C may contribute to the regulation of the human brain size. (Figure presented.)., JPB is funded by MINECO (SAF2016-78114-R), Instituto de Salud Carlos III (CIBERFES CB16/10/00282), Junta de Castilla y Leon (Escalera de Excelencia CLU-2017-03), Ayudas Equipos Investigacion Biomedicina 2017 Fundacion BBVA, and Fundacion Ramon Areces.

Hintergrund und Ziele Die intravenöse Thrombolyse mit rekombinantem Gewebsplasminogen-Aktivator (Actilyse, rt-PA) ist für den ischämischen Schlaganfall eine effektive Therapiemethode. Nach den Zulassungskriterien muss die Lysetherapie innerhalb von 3 Stunden nach Symptombeginn verabreicht werden und das klinische Ergebnis der Patienten fällt umso besser aus, je früher mit der Behandlung begonnen wird. Innerhalb der Krankenhäuser werden daher große Anstrengungen unternommen, Verzögerungen zu vermeiden. Die Zeit ab der Ankunft in der Notaufnahme bis zum Verabreichen der Lysetherapie soll so kurz wie möglich gehalten werden. Sie wird als Door-To-Needle Zeit, kurz DTN Zeit bezeichnet. Einige Studien berichten jedoch paradoxerweise umso längere DTN Zeiten, je früher nach Symptombeginn der Patient im Krankenhaus eintrifft („3-Stunden-Effekt“). Wir stellen die Hypothese auf, dass ein standardisiertes Thrombolyseprotokoll in einer darauf spezialisierten neurologischen Notaufnahme Verzögerungen auf ein Minimum reduzieren und den 3-Stunden-Effekt so vermeiden kann. Methoden Es wurden die Onset-To-Door (OTD) Zeiten und die Door-To-Needle (DTN) Zeiten von 246 in der Neurologischen Notaufnahme Erlangens lysierten Patienten untersucht. Durchgeführt wurde die Behandlung nach einem standardisierten Algorithmus durch das Schlaganfall-Notambulanz-Team, welches sich aus Assistenzärzten und supervisierenden Oberärzten zusammensetzt. Parallel zur Anamneseerhebung und einer kurzen neurologischen Untersuchung, wird auf ärztliche Anordnung durch das Pflegepersonal der Notaufnahme Blut für die Gerinnungsbestimmung entnommen. Bei Diagnose eines stattgehabten Schlaganfalls wird der Patient unverzüglich in den Computertomographen (CT) gebracht. Zeigt das CT-Bild keine Kontraindikation für eine Lysetherapie, wird direkt mit der Gabe von rt-PA begonnen. In dieser Arbeit wurde sowohl eine Korrelation zwischen der OTD Zeit und der DTN Zeit getestet, als auch ein Zusammenhang der DTN Zeit mit dem Behandlungszeitpunkt der Patienten (tagsüber vs. nachts und wochentags vs. Wochenende). Ergebnisse und Beobachtungen Der Median der DTN Zeit lag bei 25 Minuten. Ein Zusammenhang zwischen der OTD und der DTN Zeit konnte nicht festgestellt werden (Pearson r = -0,097; p-Wert NS). Ebenso lagen die DTN Zeiten von Patienten, die innerhalb von 90 Minuten ab dem Symptombeginn in der Notaufnahme eintrafen (mediane DTN Zeit 25 Minuten), bei vergleichbaren Werten wie die der Patienten, die innerhalb von 90 bis 180 Minuten das Krankenhaus erreichten (mediane DTN Zeit 25,5 Minuten, p-Wert NS). Das Eintreffen am Wochenende (mediane DTN Zeit 28 Minuten) oder während der Nachtstunden (mediane DTN Zeit 29,5 Minuten) führte ebenfalls zu keiner signifikanten Verzögerung (p-Wert NS) der Behandlungsabläufe innerhalb des Krankenhauses. Praktische Schlussfolgerungen Das Anwenden eines standardisierten Thrombolyseprotokolls, das durch ein spezialisiertes Schlaganfall-Team in einer neurologischen Notaufnahme durchgeführt wird, kann Verzögerungen innerhalb des Krankenhauses auf ein Minimum reduzieren. Dies erlaubt eine erhebliche Verbesserung der Door-To-Needle Zeiten, unabhängig von der Ankunftszeit des Patienten. Background and Purposes Intravenous thrombolysis for acute stroke is the more efficient the earlier treatment is initiated, even within the approved three hour time window. In-hospital delays account for a significant proportion of avoidable time loss until treatment is initiated. Paradoxically, studies have reported longer door-to-needle times the earlier patients arrive (“3-hour-effect”). We hypothesized that a standardized thrombolysis procedure carried out in a specialized neurological emergency room can minimize in-hospital delays and erase the “3-hour-effect”. Methods Onset-to-door (OTD) and door-to-needle (DTN) times of 246 consecutive thrombolysis patients were analyzed. Patients were treated CT-based within 3 hours by a resident based stroke team within a neurological emergency room. The treatment in the emergency room begins with a neurologic examination and a short recording of the medical history. A nurse from the emergency room will take blood to check up on the patient's coagulation. In case of a stroke the patient is directly taken to the computer tomography (CT) scanner. If the symptom onset is within three hours and if there is no contraindication for thrombolysis, the administration of recombinant tissue plasminogen activator (rt-PA) is started immediately. Correlation of OTD time and DTN time as well as dependence of DTN time from time of treatment (daytime vs. night hours and weekend vs. weekday) were tested. Results Median DTN time was 25 minutes. The DTN time did not correlate with OTD time (Pearson r = -0.097, p = NS) and patients arriving within 90 min from symptom onset showed comparable DTN times to patients arriving within 90 - 180 min. Neither treatment on weekends nor during night hours led to significant in-hospital treatment delays. Conclusion By applying a standardized thrombolysis protocol carried out by a specialized stroke team within a neurological emergency room, in-hospital delays can be minimized. This allows improvement of door-to-needle times irrespectively of the time of arrival and treatment during off hours.

ATP1A1 encodes the α1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.

Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord -/- , Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord -/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord -/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord -/- animals starting at ∼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding - enlarged "ballooned" myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord -/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.