Background:Despite considerableheritability, previous smaller genome-wide associationstudies (GWASs) have not identified any robustgenetic risk factors for isolated dystonia.Objective:The objective of this study was to perform alarge-scale GWAS in a well-characterized, multicenter sample of >6000 individuals to identify genetic risk fac-tors for isolated dystonia. Methods:Array-based GWASs were performed onautosomes for 4303 dystonia participants and 2362healthy control subjects of European ancestry with sub-group analysis based on age at onset, affected bodyregions, and a newly developed clinical score. Another736 individuals were used for validation. Results:This GWAS identified no common genome-wide significant loci that could be replicated despitesufficient power to detect meaningful effects. Poweranalyses imply that the effects of individual variantsare likely very small. Conclusions:Moderatesingle-nucleotidepolymor-phism-based heritability indicates that common variantsdo not contribute to isolated dystonia in this cohort.Sequence-basedGWASs(eg,bywhole-genome sequencing) might help to better understand the geneticbasis. (c) 2024 The Author(s).Movement Disorderspubli-shed by Wiley Periodicals LLC on behalf of InternationalParkinson and Movement Disorder Society.

BackgroundPathogenic variants in several genes have been linked to genetic forms of isolated or combined dystonia. The phenotypic and genetic spectrum and the frequency of pathogenic variants in these genes have not yet been fully elucidated, neither in patients with dystonia nor with other, sometimes co-occurring movement disorders such as Parkinson's disease (PD).ObjectivesTo screen >2000 patients with dystonia or PD for rare variants in known dystonia-causing genes.MethodsWe screened 1207 dystonia patients from Germany (DysTract consortium), Spain, and South Korea, and 1036 PD patients from Germany for pathogenic variants using a next-generation sequencing gene panel. The impact on DNA methylation of KMT2B variants was evaluated by analyzing the gene's characteristic episignature.ResultsWe identified 171 carriers (109 with dystonia [9.0%]; 62 with PD [6.0%]) of 131 rare variants (minor allele frequency <0.005). A total of 52 patients (48 dystonia [4.0%]; four PD [0.4%, all with GCH1 variants]) carried 33 different (likely) pathogenic variants, of which 17 were not previously reported. Pathogenic biallelic variants in PRKRA were not found. Episignature analysis of 48 KMT2B variants revealed that only two of these should be considered (likely) pathogenic.ConclusionThis study confirms pathogenic variants in GCH1, GNAL, KMT2B, SGCE, THAP1, and TOR1A as relevant causes in dystonia and expands the mutational spectrum. Of note, likely pathogenic variants only in GCH1 were also found among PD patients. For DYT-KMT2B, the recently described episignature served as a reliable readout to determine the functional effect of newly identified variants. (c) 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Acute basilar artery occlusion is a life-threatening medical emergency with a highly elevated mortality rate when left untreated. Little is known about symptoms and clinical progression of chronic occlusions. The aim of this study was to systematically analyze the clinical presentation of patients with chronic basilar artery occlusion (CBAO). Monocentric retrospective analysis of adult patients with CBAO was treated between 2015 and 2023 in the Department of Neurology, Klinikum Kassel. Inclusion criteria were basilar artery occlusion without brainstem infarction as well as patients with a basilar artery occlusion in whom revascularization could not be achieved and a follow-up period of at least 3 months. A total of 15 patients were found. In five patients basilar artery occlusion was diagnosed as an incidental finding, four patients had neurological symptoms but no proven brainstem infarction (3 × transient ischemic attack, 1 × isolated posterior artery infarct) and six patients presented with acute basilar artery occlusion and a follow-up > 3 months. The most common site of occlusion was midbasilar (80

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

A reliable assessment is expected from an expert opinion. Aspects of the reliability of neuro-, myography are presented. Their importance for the assessment is discussed with a view to diagnostics and the extent of any functional deficit that may be present.

ZusammenfassungVon einem Gutachten wird eine zuverlässige Bewertung erwartet. Aspekte der Zuverlässigkeit der Elektroneuro-, myografie werden vorgestellt. Ihre Bedeutung für die Begutachtung wird mit Blick auf Diagnostik und das Ausmaß eines ggf. vorhandenen funktionellen Defizits besprochen.

OBJECTIVES:Percutaneous tracheostomy (PT) is common on ICUs. An increase of intracranial pressure (ICP) can be observed in patients with acute cerebral diseases. Factors determining ICP increase remain unclear. PATIENTS AND METHODS:Data for all PTs were collected prospectively. ICP, cerebral perfusion pressure (CPP), mean arterial pressure (MAP), peripheral oxygen saturation (SpO2), and heart rate (HR) were monitored continuously every minute. Primary outcome parameter was an increase of ICP during PT (ICP > 20 mmHg). Influencing factors were evaluated by the means of logistic regression analysis: Body mass index (BMI), age, gender, physician performing the procedure (neurologist vs. neurosurgeon), duration of the procedure, underlying disease, duration of mechanical ventilation, and baseline ICP value before the procedure. RESULTS:A total of 175 PTs were performed during the observation period between 2010 and 2013. Of these, 54 received ICP monitoring and were included into this study. Median initial ICP value was 10.4 mmHg and rose significantly to a median value of 18.4 mmHg (p < 0.05). In 21 patients (38,9%) an increase of median ICP above 20 mmHg was seen during at least one interval. Comparing patients with and without pathological ICP increase a significant difference between the two groups was only observed for patients with an increased baseline ICP above 15 mmHg. All other factors had no significant influence on the development of a pathological ICP peaks during PT. CONCLUSION:Percutaneous tracheostomies in patients with cerebral injury leads to a significant increase of ICP during the procedure. Patients with a baseline ICP > 15 mmHg are at risk to develop harmful ICP crises.

Hereditary neuropathies are a group of diseases of which the most prevalent is Charcot Marie Tooth disease (CMT). From the clinical point of view pes cavus is a typical yet not specific sign for CMT. Motor signs like bilateral foot drop are dominant over sensory signs. Mutations in some 80 genes can lead to CMT. Whereas clinical sign can hardly differentiate between these genotypes, there is a clear differentiation by classical neurography: median nerve conduction velocity of less or more than 38 m / s differentiates between CMT type 1 and CMT type 2. The two most common forms are CMT1A induced by duplication of the PMP22 gene and hereditary neuropathy with liability to pressure palsy (HNPP) induced by deletion of the PMP22 gene.

Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non-inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late-onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy ( GNE , LDB3 / ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy ( FKRP , DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr-caveolinopathy and of limb-girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.

Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non-inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late-onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE,LDB3/ZASP, MYOT, DES and GAA),but also in genes not regularly associated with severely altered autophagy (FKRP,DYSF, CAV3, COL6A2, GYG1 and TRIM32)and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) inGYG1and of the p.(Leu156Pro)TRIM32mutation combined with compound heterozygous deletion of exon 2 ofTRIM32and expanded the phenotype of Ala93Thr-caveolinopathy and of limb-girdle muscular dystrophy 2i caused byFKRPmutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.

Background The role of ANO3 variants as a monogenic cause of dystonia is still under debate because of its relatively high frequency also in controls. Objective To screen >1000 patients with movement disorders for rare ANO3 variants. Methods We searched for rare ANO3 variants in 729 dystonia and 294 Parkinson's disease (PD) patients using a gene panel. Variants were validated by Sanger sequencing. For one variant carrier, family members were available for segregation analysis. Results Nine carriers (seven with dystonia [1.0%], two with PD [0.7%]) of seven different rare, protein-changing variants were identified. None of these variants has been previously reported in dystonia patients. Two of the variants in dystonia patients were found recurrently: p.Arg328Cys was detected in two Korean and p.Arg969Gln in two German patients. The frequency of these two variants in our sample seemed to be higher as in ethnically matched samples from the Genome Aggregation Database (GnomAD). Further, we identified a patient with early-onset, generalized dystonia with a de-novo variant in ANO3 (p.Val561Glu). Of note, she benefitted from deep brain stimulation. Conclusion This study confirms the relatively high frequency of rare, protein-changing ANO3 variants in both dystonia and non-dystonia patients indicating that not all variants contribute to the disease. Thus, disease relevance of novel variants remains difficult to interpret and functional studies are warranted for a better understanding of the role of ANO3 variants in dystonia. In contrast, de-novo variants in childhood-onset, generalized dystonia seem to represent an as yet underestimated phenotypic expression of changes in ANO3.

According to recent statistics from the United Nations High Commissioner for Refugees (https://www.unhcr.org/figures-at-a-glance.html), there are >25 million refugees worldwide which represents the highest levels of displacement on record. Many refugees from the Middle East, especially Syria and neighbouring countries, arrive in Europe. These countries are known to have relatively high rates of consanguinity leading to growing awareness of recessive movement disorders that frequently lack a positive family history and are usually caused by biallelic mutations.

Background Clinical investigations of brain death are supposed to prove absence of cerebral perfusion. However, only limited data are available documenting intracranial pressure (ICP) and cerebral perfusion pressure (CPP) during the development of brain death. Our study presents additional data to understand the course of ICP and CPP in patients developing brain death. Material and methods: We analyzed retrospective data of 18 patients with ICP monitoring during the development of brain death due to primary brain lesions. ICP and CPP values were continuously measured between two clinically defined time points: 1. non-reactive and widened pupils, 2. brain death determination. We analyzed ICP and CPP at the above-mentioned end points. Additionally, we investigated maximum ICP and minimal CPP values between these time points. Results: Patients developed fixed and dilated pupils with a median of 38 h before brain death determination. During brain death determination median ICP and median CPP were 103.5 and 2.5 mmHg, respectively. Maximum ICP before brain death determination was significantly higher and minimal CPP values were significantly lower compared to the time point of brain death. During the investigation period all patients experienced ICP values > 95 mmHg and CPP < 10 mmHg. All but one patient had documented CPP values of 0 mmHg. This single patient had a minimum CPP of 8 mmHg with a maximum ICP of 145 mmHg. Conclusion: Cerebral perfusion pressure during brain death determination may be positive in some patients. Our results showed variable values of ICP and CPP. However, extremely elevated ICP values before or during brain death in combination with low CPP values suggest absence of cerebral perfusion. The occurrence of positive CPP values during brain death determination therefore depends on the time point at which brain death determination is performed.

ZusammenfassungDie Neurografie des N. suralis hat große Bedeutung in der Diagnose von Polyneuropathien. Dieser Artikel stellt unterschiedliche Untersuchungstechniken mit ihren Vor- und Nachteilen vor, bespricht Messergebnisse und Normalwerte und nennt Anhaltspunkte für die Unterscheidung des axonalen und demyelinisierenden Läsionstyps. Letztlich wird ein Standard für die neurografische Untersuchung und deren Bewertung vorgeschlagen.

BACKGROUND:Familial hemiplegic migraine (FHM) is a rare monogenic form of migraine with aura with three distinct genetic subtypes (FHM1-3). Imaging studies during acute FHM attacks are scarce in the literature. This is particularly true for the FHM2 subtype.PATIENTS AND METHODS:In this monocentric study, we retrospectively evaluated imaging data of four different patients with genetically confirmed FHM2. Analysis comprised a total of eight cMRI and two CT perfusion studies, which were obtained during a total of six different attacks.RESULTS:cMRI investigations at all available time-points were without evidence of cytotoxic edema. The most prominent finding (four attacks in three patients) was swelling and/or cortical hyperintensity of the affected cerebral hemisphere on T2/FLAIR-weighted MRI. Further changes, encountered only in a few patients, included increased perfusion of the affected hemisphere (as assessed by perfusion CT) as well as dilatation of the middle cerebral artery.CONCLUSION:Our data from a sizeable cohort of FHM2 patients highlight that swelling / cortical hyperintensity of the clinically affected cerebral hemisphere - which has been previously reported mainly in FHM1 - can be observed also in FHM2. Further, they suggest that these changes, which tend to be present not in the very beginning, but rather later on during attacks, may be a possible correlate of the prolonged attack duration in our patients.

Heterozygous variants in BICD cargo adapter 2 (BICD2) cause autosomal dominant spinal muscular atrophy, lower extremity-predominant 2 (SMALED2). The disease is usually characterized by a benign or slowly progressive, congenital or early onset muscle weakness and atrophy that mainly affects the lower extremities, although some affected individuals show involvement of the arms and the shoulder girdle. Here we report unusual extremes of BICD2-related diseases: A severe form of congenital muscular atrophy with arthrogryposis multiplex, respiratory insufficiency and lethality within four months. This was caused by three BICD2 variants, (c.581A>G, p.(Gln194Arg)), (c.1626C>G, p.(Cys542Trp)) and (c.2080C>T, p.(Arg694Cys)), two of which were proven to be de novo. Affected individuals showed reduced fetal movement, weak muscle tone and sparse or no spontaneous activity after birth. Despite assisted ventilation, the condition led to early death. At the other extreme, we identified an asymptomatic woman with a known BICD2 variant (c.2108C>T, p.(Thr703Met)). Radiological examination showed fatty degeneration of selected thigh and calf muscles without clinical consequences. Instead, her son carrying the same variant is affected by a mild childhood onset disease with myopathic and neurogenic features. Mechanisms leading to variable expressivity and onset of BICD2-related disease may include alterations in molecular interactions of BICD2 and suggest the presence of genetic modifiers that may act in a protective fashion to ameliorate or abrogate disease. Our data define an additional severe disease type caused by BICD2 and emphasize a possibly variable etiology of BICD2-opathies with regard to primary muscle and neuronal involvement.