Refine
Has Fulltext
- yes (75)
Is part of the Bibliography
- yes (75)
Year of publication
Document Type
- Journal article (75)
Language
- English (75)
Keywords
- Fabry disease (11)
- neuropathic pain (8)
- cytokines (5)
- fibromyalgia syndrome (5)
- pain (5)
- skin punch biopsy (4)
- Fabry-associated pain (3)
- Medizin (3)
- Parkinson's disease (3)
- autoantibodies (3)
- depression (3)
- enzyme replacement therapy (3)
- gene expression (3)
- mouse model (3)
- small fiber neuropathy (3)
- B7-H1 (2)
- Fibromyalgia syndrome (2)
- Langerhans cells (2)
- Neuropathy (2)
- antibodies (2)
- anxiety (2)
- autoantibody (2)
- chronic pain (2)
- diagnosis (2)
- expression (2)
- glycine receptor (2)
- inflammation (2)
- inflammatory neuropathy (2)
- microRNA (2)
- mouse models (2)
- nerve fibers (2)
- neurofascin (2)
- neurology (2)
- neuropathy (2)
- opioids (2)
- passive transfer (2)
- polyneuropathy (2)
- renal system (2)
- 65-kda isoform (1)
- A-delta fibers (1)
- Agalsidase beta therapy (1)
- Alpha galactosidase (1)
- Anderson-Fabry Disease (1)
- Antiparanodal Autoantibodies (1)
- Anxiety (1)
- Arterial Diameters (1)
- Axonal degeneration (1)
- Aδ- and C-fibers (1)
- Beta-glucocerebrosidase (1)
- CCI (1)
- CIDP (1)
- CLN3 (1)
- CNS imaging (1)
- CRPS (1)
- Charcot–Marie–Tooth disease type 1A (1)
- CholinomiRs (1)
- Clinical manifestations (1)
- Cognitive behavior (1)
- Corneal confocal microscopy (1)
- Cytokines (1)
- D313Y genotype (1)
- Delphi procedure (1)
- Demyelinating peripheral neuropathy (1)
- Diabetes mellitus (1)
- Diabetic polyneuropathy (1)
- Diagnosis (1)
- Disease (1)
- English version (1)
- Enzyme replacement therapy (1)
- Epilepsy (1)
- FOSMN (1)
- Fabry (1)
- Fabry cardiomyopathy (1)
- Fabry genotype (1)
- Fabry nephropathy (1)
- Fabry phenotype (1)
- Factor messenger-RNA (1)
- Fibromyalgie (1)
- Gene-expression (1)
- Gland (1)
- Glutamic-acid decarboxylase anxiety (1)
- Guillain-Barre-Syndrome (1)
- Guillain-Barré syndrome (1)
- Heat Hyperalgesia (1)
- IENFD (1)
- IL-15 (1)
- IL-4 (1)
- IVIg (1)
- Identification (1)
- IgG4 (1)
- Immune system (1)
- Innervation (1)
- Interleukin-6 (1)
- Interleukin-6-Deficient mice (1)
- LIMP-2 (1)
- Leukemia Inhibitory Factor (1)
- MDL-28170 (1)
- MIBG scintigraphy (1)
- MIC ligands (1)
- MMP9 (1)
- Mechanisms (1)
- Mediated Inflammatory Hyperalgesia (1)
- Merkel cell density (1)
- Mice (1)
- Migräne (1)
- Monopolar depression (1)
- Motor nerve biopsy (1)
- NF-κB (1)
- NKG2D (1)
- NKG2D ligands (1)
- NMOSD (1)
- NPSI (1)
- Necrosis-factor-Alpha (1)
- Nerve growth-factorcopy (1)
- Neuralgie (1)
- Neurotrophic factors (1)
- Nodo-parandopathy (1)
- Oncostatin-M-Receptor (1)
- Opioid receptor (1)
- Outcome survey (1)
- PD-L1 (1)
- PET (1)
- Pain (1)
- Pain questionnaire (1)
- Pain-related evoked potentials (1)
- Peripheral Inflammation (1)
- Pharmacological management (1)
- Quality of life (1)
- RECK (1)
- RNA extraction (1)
- Randomized controlled trial (1)
- Rat Sensory Neurons (1)
- Receptors (1)
- Rheumatoid-Arthritis (1)
- Rochester diabetic neuropathy (1)
- SNI (1)
- Schwann cell (1)
- Schwann-cells (1)
- Serotonin (1)
- Sjorgens-syndrome (1)
- Skin biopsy (1)
- Small fiber neuropathy (1)
- Small-fiber neuropathy (1)
- T cell activation (1)
- TNFα (1)
- Thermal Hyperalgesia (1)
- Treatment (1)
- Tryptophan hydroxylase-2 (Tph2) (1)
- X-chromosomal inactivation (1)
- adsorption (1)
- afferents (1)
- aggression (1)
- algorithm (1)
- allodynia (1)
- alpha-galactosidase A (1)
- amygdala (1)
- amyotrophic-lateral-sclerosis (1)
- analgesia (1)
- animal behavior (1)
- antagomir (1)
- anti-contactin-1 (1)
- aquaporin 4 (1)
- atrophy Kennedys-disease (1)
- autoantibody (aAb) (1)
- autoimmune nodopathy (1)
- back pain (1)
- behavioral disorders (1)
- binding (1)
- binding analysis (1)
- biomarker (1)
- biopsies (1)
- biopsy (1)
- blood CSF barrier (1)
- blood flow (1)
- blood nerve barrier (1)
- brain (1)
- burning pain (1)
- calpain (1)
- capsaicin (1)
- care (1)
- celiac disease (1)
- cell binding assay (1)
- central nervous system (1)
- cerebral arteries (1)
- cerebrospinal fluid (1)
- cholinergic system (1)
- chronic constriction nerve injury (1)
- chronic constriction nerve injury (CCI) (1)
- chronic stress (1)
- classification (1)
- claudin-1 (1)
- clinical neurology (1)
- cognitive impairment (1)
- complement deposition (1)
- complex regional pain syndrome (1)
- contactin (1)
- coping (1)
- corneal confocal microscopy (1)
- cortical activation (1)
- criteria (1)
- crossover trial (1)
- cue (1)
- cutaneous innervation (1)
- cutaneous patch (1)
- cutting edge (1)
- dermal B cells (1)
- diagnosis in Fabry disease (1)
- diagnostic markers (1)
- disability (1)
- disorder (1)
- enzyme assays (1)
- enzyme-linked immunoassays (1)
- epidermis (1)
- extracellular domain (1)
- facial pain (1)
- fear (1)
- fear memory (1)
- female Fabry patients (1)
- females (1)
- fibers (1)
- fibromyalgia (1)
- flotillin-1 lipid rafts (1)
- gene variant (1)
- gene-by-environment interaction (1)
- genetics (1)
- genotype/phenotype correlation (1)
- gephyrin (1)
- globotriaosylceramide (1)
- glycine receptor (GlyR) (1)
- glycine receptor autoantibodies (1)
- glycosylation (1)
- guidelines (1)
- hernia repair (1)
- hippocampus (1)
- human muscle-cells (1)
- humans (1)
- hyperalgesia (1)
- hyperekplexia (1)
- idiopathic inflammatory myopathies (1)
- immune system (1)
- immunofluorescence (1)
- immunomodulation (1)
- inflammatory demyelinating polyradiculoneuropathy (1)
- inherited metabolic disorders (1)
- innervation (1)
- interference (1)
- intraepidermal nerve fiber density (1)
- intraepidermal nerve fibre density (1)
- intrathecal application (1)
- intravenous immunoglobulin (1)
- ion channels (1)
- ischemic stroke (1)
- learning (1)
- lesions (1)
- long-term pain (1)
- lymphokine-activated killer (1)
- lyso-Gb3 (1)
- lysosomal storage disease (1)
- macrophages (1)
- magnetic resonance imaging (1)
- management (1)
- mast cells (1)
- metaanalysis (1)
- miR-182-5p (1)
- miR-21 (1)
- miRNA (1)
- miRNA expression patterns (1)
- miRNA polymorphisms (1)
- miRNA-based analgesic (1)
- miRNA-based diagnostics (1)
- mice (1)
- migraineur (1)
- mixed fiber neuropathy (1)
- motor proteins (1)
- movement disorders (1)
- multiple sclerosis (1)
- multiple system atrophy (1)
- musk myasthenia gravis (1)
- mutation (1)
- near-infrared spectroscopy (1)
- nerve biopsy (1)
- nerve fibres (1)
- nerve tumor (1)
- nerve ultrasonography (1)
- nerve-fibers (1)
- neuralgia (1)
- neurofilament light chain (1)
- neuroleukemiosis (1)
- neurological examination (1)
- neuronopathy (1)
- neurons (1)
- nociceptive Schwann cells (1)
- nociceptor sensitization (1)
- node of ranvier (1)
- ontactin 1 (1)
- opioid (1)
- pain questionnaire (1)
- pain sensation (1)
- pain-associated behavior (1)
- pain-related evoked potentials (1)
- paranodopathy (1)
- pathology section (1)
- pathways (1)
- periperal nerve (1)
- peripheral nerve involvement (1)
- peripheral nervous system (1)
- peripheral neuropathy (1)
- polymorphism (1)
- polymyositis (1)
- postherpetic neuralgia (1)
- presynaptic inhibition (1)
- progressive encephalitis with rigidity and myoclonus (PERM) (1)
- proinflammatory cytokine (1)
- quantitative sensory testing (1)
- qutenza (1)
- receptor (1)
- recommendations (1)
- reflex (1)
- reinnervation (1)
- religiosity (1)
- reproducible outcome measure (1)
- risk factors (1)
- scale (1)
- sciatic nerves (1)
- shingles (1)
- skin biopsy (1)
- skin diseases (1)
- skin tumors (1)
- small-fiber neuropathy (1)
- spinal cord (1)
- spinal-cord-injury (1)
- startle disease (1)
- stiff-person syndrome (SPS) (1)
- stroke (1)
- substance-P (1)
- superficial peroneal nerve (1)
- sural nerve (1)
- swimming (1)
- switch (1)
- synaptic transmission (1)
- systematic review (1)
- tissue resident T cells (1)
- transient receptor potential vanilloid 1 (TRPV1) (1)
- trigeminal nerve (1)
- trigeminal neuropathy (1)
- tumor immunity (1)
- validation (1)
- vasculitis (1)
- white blood cells (1)
Institute
- Neurologische Klinik und Poliklinik (74)
- Institut für Klinische Neurobiologie (8)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (7)
- Medizinische Klinik und Poliklinik I (5)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (4)
- Institut für Klinische Epidemiologie und Biometrie (2)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (2)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (2)
- Rudolf-Virchow-Zentrum (2)
- Theodor-Boveri-Institut für Biowissenschaften (2)
Sonstige beteiligte Institutionen
Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.
Background
Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women.
Patients and Methods
We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity.
Results
43/95 (45%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25% distribution) in 6/87 (7%) mouth epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome.
Conclusions
X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.
Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.
Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome
(2022)
Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome.
Background
Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future.
Methods
This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years.
Results
Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy.
Conclusion
These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.
Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.
Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies
(2022)
Background and Objectives
Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM).
Methods
We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1–associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections.
Results The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31–6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti–contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected.
Discussion
We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.
Background and aims:
Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard.
Methods:
In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART).
Results:
Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact.
Conclusion:
We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.
Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.
Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.