RARE DISEASE
Hereditary hyperekplexia
Hereditary hyperekplexia
Hereditary hyperekplexia
Synonyms: Congenital stiff man syndrome, Familial startle disease, Hereditary hyperexplexia, Kok disease, Stiff baby syndrome
Synonyms: Congenital stiff man syndrome, Familial startle disease, Hereditary hyperexplexia, Kok disease, Stiff baby syndrome
Synonyms: Congenital stiff man syndrome, Familial startle disease, Hereditary hyperexplexia, Kok disease, Stiff baby syndrome
Drug discovery
1
drug
With orphan designation
Overview
Hereditary hyperekplexia is a rare genetic channelopathy characterized by neonatal hypertonia, exaggerated startle reflexes to sensory stimuli (auditory, tactile, or visual), and transient apnea-inducing rigidity. Caused by mutations in glycinergic neurotransmission genes (GLRA1, SLC6A5, GLRB, GPHN, ARHGEF9), it exhibits autosomal dominant or recessive inheritance. Symptoms often improve by age 1, but startle-induced falls, gait instability, and anxiety in crowded environments may persist. Diagnosis relies on clinical assessment and genetic testing. First-line treatment with clonazepam effectively reduces symptom severity [1][4][6][12].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
93 drug discovery papers about Hereditary hyperekplexia, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
93 drug discovery papers about Hereditary hyperekplexia, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-04-22 | From Misdiagnosis to Treatment: Genetic Landscape and Genotype-Phenotype Correlations of Hyperekplexia.
Hyperekplexia (hereditary startle disease) is a rare, treatable neurogenetic disorder often misdiagnosed as epilepsy, leading to unnecessary interventions. This study aims to characterize the clinical and genetic features of Turkish patients with hyperekplexia and highlight genotype-phenotype correlations. We retrospectively analyzed 16 patients diagnosed with hyperekplexia across five tertiary centers in southern Turkey from 2011 to 2025. All patients underwent genetic testing via Next-Generation Sequencing. Clinical features, treatment responses, and neurodevelopmental outcomes were evaluated according to specific gene mutations (GLRA1, SLC6A5, and GLRB). All patients (100%) presented with exaggerated startle responses and nonepileptic tonic attacks but were initially misdiagnosed with epilepsy. The median delay in diagnosis was 26 months. The misdiagnosis periods for the patients were as follows: one-6 months (n = 4, 25%); 6-12 months (n = 3, 18%); 12-24 months (n = 2, 12%); 24-36 months (n = 4, 25%); and more than 36 months (n = 3, 18%). Genetic analysis revealed GLRA1mutations in 56% (n = 9), SLC6A5 in 25% (n = 4), and GLRB in 19% (n = 3). We identified a homozygous nonsense mutation in the GLRB gene (c.995 G > A; p.Trp332Ter) in three patients from the same family. Genotype-phenotype correlation revealed distinct patterns: while patients with GLRA1 and SLC6A5 mutations generally responded well to clonazepam, those with the GLRB mutation exhibited severe global neurodevelopmental delay, autism spectrum features, and required levetiracetam due to poor response to benzodiazepines. Hyperekplexia should be strongly considered in infants with exaggerated startle reflexes to prevent potential developmental consequences of delayed diagnosis. Furthermore, this study confirms that GLRB variants may be associated with a more complex phenotype, including autism and resistance to standard benzodiazepine therapy.
2025-05-08 | A novel GLRB mutation in neonatal hyperekplexia with divergent EEG findings: a case series.
Hereditary hyperekplexia (HKPX) is a rare neurogenetic disorder caused by mutations in glycine signaling genes, such as GLRB. We report two neonates with autosomal recessive HKPX2 due to a novel GLRB mutation (c.1414C>T, p.Arg472*). Case 1, a 1-month-old female, presented with severe startle responses and tonic episodes, normal EEG, and no developmental delays. Case 2, a 2-week-old male, showed similar symptoms but with generalized rhythmic ictal fast activity on EEG. Both had consanguineous parents and unremarkable brain MRIs. Whole exome sequencing identified the same homozygous GLRB mutation in both cases. Treatment with Clonazepam and Levetiracetam significantly improved symptoms. This is the first report of the c.1414C>T (p.Arg472*) mutation in GLRB, expanding the genetic spectrum of HKPX2. The differing EEG findings highlight the disorder's phenotypic variability. Early diagnosis and treatment are crucial to prevent complications like hypoxia and SIDS. This article reports a novel GLRB mutation in two neonates with autosomal recessive HKPX2, presenting with divergent EEG findings.
2025-03-26 | The implications of hyperekplexia on children's quality of life: a report on two cases.
To report two pediatric cases of hyperekplexia in a small city of São Paulo state, Brazil. Two female patients, one aged three years and six months and one aged five months, receiving care from an APAE (Association of Parents and Friends of People with Disabilities) unit, were diagnosed with hyperekplexia 1, a neurological disorder characterized by an excessive startle response. Hyperekplexia cases can be divided into three subgroups: hereditary, sporadic, and symptomatic. Several specialists have examined patient 1 since she was three weeks old, leading to two initial diagnostic hypotheses (childhood chronic non-progressive encephalopathy and spastic cerebral palsy). She was diagnosed with hyperekplexia 1 at eleven months when a genetic test revealed changes in the GLRA1 gene. Patient 2, at birth, presented hyperextension of both legs, low-set ears, cranial asymmetry, prominent occiput, and tremors in the lower limbs. After several tests and evaluations, the final diagnosis was confirmed at three months old. Her family history indicates the possibility of hereditary hyperekplexia. The cases were compared with information obtained through a bibliographical review. Both patients presented several symptoms associated with hyperekplexia, including neurological symptoms such as increased startle response, convulsions, and hypertonia, which were alleviated with appropriate treatment. So far, combining multidisciplinary assistance with drug treatment, particularly anxiolytics and anticonvulsants, with clonazepam being the most used, has significantly contributed to both patients' improved quality of life. However, physical symptoms, such as hip dislocation and clubfoot, require future surgical intervention.
2020-04-01 | C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia
Abstract Introduction: Hyperekplexia is a rare hereditary neurological disorder; only 5 glycine receptor alpha 1 subunit gene ( GLRA1 ) mutations have been reported in 5 Chinese patients. We report a Chinese infant with hyperekplexia and a novel mutation at c.292G > A. Patient concerns: A Chinese infant with hyperekplexia and a novel mutation at c.292G > A. Diagnosis: All exons of GLRA1 were sequenced in her parents and her, which revealed a mutation at c.1030C > T and another novel mutation at c.292G > A. Her diagnosis was confirmed as hereditary hyperekplexia with GlRA1 hybrid gene mutations based on the sequencing results. Interventions: She was treated with clonazepam. Outcomes: Her muscle hypertonia recovered rapidly and the excessive startle reflex to unexpected stimuli was significantly reduced. Conclusion: Genetic DNA sequencing is a crucial method for diagnosing hyperekplexia-related gene mutation.
2019-08-07 | Impaired glycinergic transmission in hyperekplexia: a model of parasomnia overlap disorder
Abstract We report sleep phenotypes and polysomnographic findings in two siblings with a novel homozygous variant of the GLRA1 gene causing hereditary hyperekplexia (HH). Both sisters had startles during wakefulness and sleep, sleep terrors, and one had symptoms of REM sleep behavior disorder (RBD). Frequent startles were found in NREM sleep associated with NREM parasomnias in deep sleep. In REM sleep, both had motor behaviors and increased phasic/tonic muscle activities confirming RBD. Clonazepam improved startles, motor behaviors, and muscle activities in REM sleep. Impaired glycinergic transmission in human HH could be involved in the pathophysiology of RBD and NREM parasomnias.
antibodies
2025-12-15 | Standing Still: A Case of Stiff Person Syndrome and Common Variable Immunodeficiency.
Stiff-person syndrome (SPS) is a rare autoimmune neurologic disorder characterized by progressive rigidity and spasms, while common variable immunodeficiency (CVID) features hypogammaglobulinemia and recurrent infections. Their coexistence complicates management by requiring autoimmune suppression without further compromising host defense. A 54-year-old man with CVID, diagnosed based on hypogammaglobulinemia (IgG 386 mg/dL) and recurrent sinopulmonary infections, subsequently developed SPS with progressive truncal and limb stiffness, causing gait impairment and dyspnea. He experienced a severe aspergillus pneumonia, and examination showed finger clubbing and resting hypoxemia. Pulmonary function testing demonstrated moderate airflow obstruction with distal airway involvement. Chest radiography later revealed an elevated left hemidiaphragm, consistent with respiratory muscle dysfunction in SPS. Combined therapy with intravenous immunoglobulin (IVIG) and rituximab was initiated, yielding meaningful improvement in stiffness and a reduction in respiratory infections. After a motor vehicle accident with spinal fusion, the patient reported worsening exertional dyspnea and variable IgG troughs; treatment was transitioned to subcutaneous immunoglobulin (SCIG) 10% with rHuPH20 to maintain steadier IgG levels. This case emphasizes the importance of immunologic evaluation in refractory SPS and demonstrates that combined IVIG and rituximab can provide functional benefit while addressing CVID. Transition to SCIG may stabilize IgG exposure and sustain clinical gains. A timeline of diagnoses and treatments highlights the interplay between autoimmunity and hypogammaglobulinemia and supports a tailored, multidisciplinary strategy.
2024-02-06 | Glycine Receptor β-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.
Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.
2023-02-03 | Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.
Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.
2021-04-05 | Use of subcutaneous immunoglobulin in stiff person syndrome: Case series.
Intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of stiff person syndrome (SPS). However, some patients might not tolerate it. We report the tolerability profile of subcutaneous immunoglobulin (SCIg) in patients with SPS who did not tolerate IVIG. To our knowledge, the use of SCIg in SPS has not been reported before in a case series. The five patients included in this case series presented with various combinations of symptoms of spasms, axial and limb stiffness, and exaggerated responses to outside stimuli. These symptoms often lead to gait and functional impairment. Patients were diagnosed with classic SPS as they met the clinical criteria, which require the presence of spasms, axial rigidity, and hyperexcitability. Subcutaneous immunoglobulin infusion. Five patients were identified that were treated with SCIg. Three tested positive for serum anti-glutamic acid decarboxylase 65 antibodies prior to any treatment. The mean age at SCIg initiation was 33 years (range: 22-47). The mean duration of SPS prior to SCIg initiation was 5.9 years (range: 2.5-7). All patients used IVIG for at least two months (up to 18 months) but switched to SCIg due to IVIG side effects. Duration of SCIg use ranged from 4 months to 6 years (mean, 19.2 months). Upon switching to SCIg, the SPS symptoms remained stable. SCIg was well-tolerated in most as only one patient discontinued SCIg due to side effects. This case series highlights that SCIg could be a treatment option for patients with SPS, especially when IVIG is not feasible. Injection site reactions might be a limiting factor in some patients treated with SCIg. Prospective controlled studies are needed to confirm SCIg treatment durability and efficacy.
2021-01-06 | Stiff-person syndrome coexisting with critical illness polyneuropathy: A case report.
Stiff-person syndrome (SPS) is an uncommon neurological disorder with autoimmune features. Here, we report a 60-year-old man with SPS associated with critical illness polyneuropathy (CIP). CIP was diagnosed during an episode of acute respiratory failure secondary to muscular rigidity and spasms, which has rarely been reported in this condition. The overlapping of CIP and SPS complicated the case. A 60-year-old man presented with gradual onset of cramps, stiffness, and rigidity in his lower limbs 1 year before admission, which eventually led to inability to stand and walk. The persistent nature of his symptoms progressed to frequent acute episodes of dyspnea and he was admitted to intensive care unit (ICU). SPS had been diagnosed after 2 tests of electromyography (EMG) and the detection of an elevated anti-GAD65 antibody titer. During the first EMG, low or absent compound muscle action potentials (CMAP), and sensory nerve action potentials (SNAP) were shown. Therefore, the diagnosis of SPS coexisting with CIP was made. Symptomatic treatment was initiated with oral clonazepam (0.5 mg Bid) and baclofen (5 mg Bid). Intravenous immunoglobulin (IVIG) (0.4 g/kg/d) was administered for the patient for 5 days after admission. We observed a significant clinical improvement during the administration period, and the patient became ambulatory. On follow-up, the patient reported complete relief of his pain and rigidity. We report this special case to address the varied clinical features of SPS. Electrophysiological testing is an important diagnostic approach. Accurate recognition of the disease ensures that the patients can be given appropriate treatment without delay.
proteins
2022-03-17 | Profile of the single-use, multiple-pass protein A adsorber column in immunoadsorption.
Immunoadsorptions (IA) are used to remove autoantibodies from the plasma in autoimmune disorders. In this study, we evaluated the effects of a single-use, recombinant staphylococcal protein A-based immunoadsorber on blood composition of the patient. In a cohort of patients with myasthenia gravis or stiff-person syndrome, essential parameters of blood cell count, coagulation, clinical chemistry or plasma proteins and immunoglobulins (Ig) were measured before and after IA (n = 11). In average, IA reduced the levels of total IgG, IgG1, IgG2 and IgG4 by approximately 60%, the acetylcholine receptor autoantibody levels by more than 70%. IgG3, IgA or IgM were diminished to a lower extent. In contrast to fibrinogen or other coagulation factors, the column markedly removed vitamin K-dependent coagulation factors II, VII, IX and X by approximately 40%-70%. Accordingly, international normalized ratio and activated partial thromboplastin time were increased after IA by 59.1% and 32.7%, respectively. Coagulation tests almost returned to baseline values within 24 h. Blood cell count, electrolytes, total protein or albumin were not essentially affected. No clinical events occurred. The single-use, multiple-pass protein A adsorber column is highly efficient to remove IgG1, IgG2 and IgG4 or specific acetylcholine receptor autoantibodies from the plasma. Coagulation parameters should be monitored, since the column has the capacity to largely reduce vitamin K-dependent factors.
2021-09-20 | Different Behaviors of a Glycine Receptor Channel Pore Residue between Wild-Type-Mimicking and Disease-Type-Mimicking Formats.
The glycine receptor (GlyR) is a neurotransmitter-gated chloride channel that mediates fast inhibitory neurotransmission, predominantly in the spinal cord and brain stem. Mutations of the GlyR are the major cause of hereditary hyperekplexia. Site-specific cysteine substitution followed by labeling with a fluorophore has previously been used to explore the behaviors of the hyperekplexia-related 271 (19') residue of the GlyR. However, this manipulation dramatically compromises sensitivity toward the agonist glycine and alters the pharmacological effects of various agents in manners similar to those of the hyperekplexia-causing R19'Q/L mutations, raising the question whether what is reported by the substituted and modified residue faithfully reflects what actually happens to the wild-type (WT) residue. In this study, a mechanism-rescuing second-site mutation was introduced to create a WT-mimicking GlyR (with the 19' residue cysteine substitution and modification still in place), in which the sensitivity toward glycine and pharmacological effects of various agents were restored. Further experiments revealed stark differences in the behaviors upon the various pharmacological treatments and consequently the underlying mechanisms of the 19' residue between this WT-mimicking GlyR and the GlyR without the mechanism rescue, which is correspondingly defined as the disease-type (DT)-mimicking GlyR. The data presented in this study warn generally that caution is required when attempting to deduce the behaviors of a WT residue from data based on substituted or modified residues that alter protein structure and function. Extra measures, such as rescuing mechanisms via alternative means as presented in this study, are needed to mitigate this challenge.
2021-06-18 | Pair of Residue Substitutions at the Outer Mouth of the Channel Pore Act as Inputs for a Boolean Logic "OR" Gate Based on the Glycine Receptor.
The glycine receptor (GlyR) is a ligand-activated chloride channel, whose mutations are the major cause of hereditary hyperekplexia. The hyperekplexia-causing R271Q mutation, which is located at the extracellular outer mouth of the channel pore, dramatically impairs the GlyR function manifesting a reduced sensitivity toward glycine. This study reports that a second mutation, S273D, rescues the function of the R271Q GlyR to that of the wild-type (WT) GlyR. Surprisingly, the S273D mutation, when introduced to the WT GlyR, does not further increase the receptor function. In other words, the compromised function of the 271Q 273S GlyR (i.e., the R271Q GlyR) can be rescued to WT levels by the introduction of either, or both, of the Q271R and S273D substitutions. From the perspective of Boolean logic gates, the Q271R and S273D substitutions act as inputs for an OR gate based on the GlyR. Further experiments revealed that the negative-charge carried by the 273 residue is essential for the expression of the OR gate and that the expression of the OR gate is residue-position-specific. In addition, mechanistic investigation implied that the 273 residue influences the 271 residue, which might underpin the unique nonadditive OR gate relationship between these two residues. Such an ion-channel-based OR gate, expressing output in the form of electrical current, could potentially be developed to digitally manipulate neuronal activity.
2020-04-30 | A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition
Glycine receptors (GlyRs) are the major mediators of fast synaptic inhibition in the adult human spinal cord and brainstem. Hereditary mutations to GlyRs can lead to the rare, but potentially fatal, neuromotor disorder hyperekplexia. Most mutations located in the large intracellular domain (TM3-4 loop) of the GlyRα1 impair surface expression levels of the receptors. The novel GLRA1 mutation P366L, located in the TM3-4 loop, showed normal surface expression but reduced chloride currents, and accelerated whole-cell desensitization observed in whole-cell recordings. At the single-channel level, we observed reduced unitary conductance accompanied by spontaneous opening events in the absence of extracellular glycine. Using peptide microarrays and tandem MS-based analysis methods, we show that the proline-rich stretch surrounding P366 mediates binding to syndapin I, an F-BAR domain protein involved in membrane remodeling. The disruption of the noncanonical Src homology 3 recognition motif by P366L reduces syndapin I binding. These data suggest that the GlyRα1 subunit interacts with intracellular binding partners and may therefore play a role in receptor trafficking or synaptic anchoring, a function thus far only ascribed to the GlyRβ subunit. Hence, the P366L GlyRα1 variant exhibits a unique set of properties that cumulatively affect GlyR functionality and thus might explain the neuropathological mechanism underlying hyperekplexia in the mutant carriers. P366L is the first dominant GLRA1 mutation identified within the GlyRα1 TM3-4 loop that affects GlyR physiology without altering protein expression at the whole-cell and surface levels. SIGNIFICANCE STATEMENT We show that the intracellular domain of the inhibitory glycine receptor α1 subunit contributes to trafficking and synaptic anchoring. A proline-rich stretch in this receptor domain forms a noncanonical recognition motif important for the interaction with syndapin I (PACSIN1). The disruption of this motif, as present in a human patient with hyperekplexia led to impaired syndapin I binding. Functional analysis revealed that the altered proline-rich stretch determines several functional physiological parameters of the ion channel (e.g., faster whole-cell desensitization) reduced unitary conductance and spontaneous opening events. Thus, the proline-rich stretch from the glycine receptor α1 subunit represents a multifunctional intracellular protein motif.
2015-12-22 | Disturbances of Ligand Potency and Enhanced Degradation of the Human Glycine Receptor at Affected Positions G160 and T162 Originally Identified in Patients Suffering from Hyperekplexia
Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GlyR) undergoes direct interaction with the incoming ligand via a cation-π interaction. Recently, we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GlyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GlyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER toward the ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is delivered to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, T162 affects primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.
cell therapies
2026-01-13 | The future unfolded: CAR T cells and the transformation of treatment algorithms in autoimmune neurology.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, and its application in neuroimmunologic autoimmune diseases is now emerging as a promising therapeutic avenue. Neuroimmunologic diseases such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorder, and stiff-person syndrome have shown varying degrees of response to traditional immunomodulatory therapies, but a significant proportion of patients remain refractory to treatment. In recent studies, anti-CD19 CAR T cells have shown encouraging results in targeting B cells, a key driver of autoimmune pathogenesis. CAR T-cells can penetrate the central nervous system and overcome the limitations of conventional B-cell depleting therapies such as rituximab, particularly in accessing ectopic lymphoid follicles that maintain compartmentalized inflammation. In early clinical cases, CAR T-cell treatment has resulted in marked clinical improvements, including significant reductions in symptoms and durable disease remission, with manageable side-effects. In addition, advances in allogeneic CAR T cell constructs and chimeric autoantibody receptor T cells offer additional avenues for precision-targeted therapies. These developments underscore the potential of CAR T cells to reshape the treatment landscape for refractory neuroimmunologic autoimmune diseases and warrant further controlled trials and regulatory exploration.
2025-12-15 | CAR T-cell therapy for neurological disorders: scientific rationale and mechanistic insights.
The development and successful clinical application of engineered T cells expressing synthetic chimeric antigen receptors (CARs) represents a milestone in cancer therapy. This approach optimizes physiological in vivo T-cell activation against specific target antigens expressed on defined cell subsets with the goal of their deep and sustained depletion. Significant progress has been made in redesigning CAR T-cell constructs to improve patient safety, therapeutic efficacy, and accessibility. Efforts have also focused on streamlining manufacturing to improve availability and reduce costs, two critical challenges to widespread adoption. Beyond hematologic malignancies, CAR T-cell therapies are now increasingly being repurposed to tackle B-cell-mediated autoimmune diseases (AIDs). This is primarily achieved through broad B-cell depletion, but more targeted approaches-such as the selective elimination of autoantibody-producing B-cell subpopulations-are also being explored. Important considerations in their implementation are identifying the most pertinent patient groups, tailoring their treatment up to the point of CAR-infusion, and following up on their unique toxicity-profile. In the context of neurological AIDs-including refractory myasthenia gravis, Lambert-Eaton syndrome, multiple sclerosis, and stiff-person syndrome-early clinical experience suggests promising efficacy and tolerability, leading to a growing number of registered clinical trials. In this review, we provide an overview of the mechanism and evolution of CAR T-cell therapy, highlighting why its application in AIDs, particularly in neurology, represents a highly promising therapeutic strategy.
2025-11-17 | Promising Effects of CAR T-Cell Therapy in Refractory Stiff Person Syndrome and a Hopeful Future for All Neuroautoimmunities.
Chimeric antigen receptor (CAR) T cells are genetically modified T cells expressing CARs, initially developed to recognize tumor antigens and kill cancer cells that evade T-cell recognition. Because of their impressive success in hemato-oncologic malignancies, CAR T cells are being repurposed with redesigned constructs for safety and sustained efficacy to target refractory systemic autoimmune or neurologic diseases. The CD19 CAR T cells-targeting those CD19-positive, antibody-secreting, long-lived plasma cells, and plasmablasts-are now extensively explored in refractory neuroautoimmunities with promising benefits based on case series in patients with myasthenia gravis (MG), stiff person syndrome (SPS), neuromyelitis, myositis, and multiple sclerosis; some patients with MG and SPS with steadily progressive and disabling disease refractory to all available therapies, including rituximab and new biologics, exhibit impressive clinical improvements with long-lasting benefits. The review, triggered by these early results and ongoing trials, addresses what these cells are and why they show effectiveness not only in antibody-mediated B-cell neurologic diseases unresponsive to available anti-B-cell agents but also in patients with nonpathogenic antibodies, implying effects even beyond B cells; points out that CARs are "living cells" penetrating physiologic barriers, such as the blood-brain barrier, expanding within tissues to memory cells ensuring sustained effects; describes the process and challenges of preparing and administering CAR T cells and their safety profile stressing the differences in toxicities when treating autoimmunites vs malignancies; and highlights that CD19 CAR T cells can successfully target even 2 different autoimmune diseases in the same patient, such as SPS and MG, offering promising prospects of changing the therapeutic algorithm in all neuroautoimmunities with potential for achieving even an immune reset shifting immunity to a healthy state.
2024-08-14 | The Role of Chimeric Antigen Receptor T-Cell Therapy in Immune-Mediated Neurological Diseases.
Despite the use of 'high efficacy' disease-modifying therapies, disease activity and clinical progression of different immune-mediated neurological diseases continue for some patients, resulting in accumulating disability, deteriorating social and mental health, and high economic cost to patients and society. Although autologous hematopoietic stem cell transplant is an effective treatment modality, it is an intensive chemotherapy-based therapy with a range of short- and long-term side-effects. Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of B-cell and other hematological malignancies, conferring long-term remission for otherwise refractory diseases. However, the toxicity of this treatment, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and the complexity of production necessitate the need for a high level of specialization at treating centers. Early-phase trials of CAR-T therapies in immune-mediated B cell driven conditions, such as systemic lupus erythematosus, neuromyelitis optica spectrum disorder and myasthenia gravis, have shown dramatic clinical response with few adverse events. Based on the common physiopathology, CAR-T therapy in other immune-mediated neurological disease, including multiple sclerosis, chronic inflammatory polyradiculopathy, autoimmune encephalitis, and stiff person syndrome, might be an effective option for patients, avoiding the need for long-term immunosuppressant medications. It may prove to be a more selective immunoablative approach than autologous hematopoietic stem cell transplant, with potentially increased efficacy and lower adverse events. In this review, we present the state of the art and future directions of the use of CAR-T in such conditions. ANN NEUROL 2024;96:441-452.
2024-06-17 | Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome.
Treatment with autologous chimeric antigen receptor (CAR) T cells has emerged as a highly effective approach in neuroimmunological disorders such as myasthenia gravis. We report a case of successful anti-CD19 CAR T cell use in treatment-refractory stiff-person syndrome (SPS). To investigate clinical and immunological effects of anti-CD19 CAR T cell use in treatment-refractory SPS, a 69-y-old female with a 9-y history of treatment-refractory SPS with deteriorating episodes of stiffness received an infusion of autologous anti-CD19 CAR T cells (KYV-101) and was monitored clinically and immunologically for more than 6 mo. CAR T cell infusion resulted in reduced leg stiffness, drastic improvement in gait, walking speed increase over 100%, and daily walking distance improvement from less than 50 m to over 6 km within 3 mo. GABAergic medication (benzodiazepines) was reduced by 40%. KYV-101 CAR T cells were well tolerated with only low-grade cytokine release syndrome. This report of successful use of anti-CD19 CAR T cells in treatment-refractory SPS supports continued exploration of this approach in SPS and other B cell-related autoimmune disorders.
small molecules
2026-04-22 | From Misdiagnosis to Treatment: Genetic Landscape and Genotype-Phenotype Correlations of Hyperekplexia.
Hyperekplexia (hereditary startle disease) is a rare, treatable neurogenetic disorder often misdiagnosed as epilepsy, leading to unnecessary interventions. This study aims to characterize the clinical and genetic features of Turkish patients with hyperekplexia and highlight genotype-phenotype correlations. We retrospectively analyzed 16 patients diagnosed with hyperekplexia across five tertiary centers in southern Turkey from 2011 to 2025. All patients underwent genetic testing via Next-Generation Sequencing. Clinical features, treatment responses, and neurodevelopmental outcomes were evaluated according to specific gene mutations (GLRA1, SLC6A5, and GLRB). All patients (100%) presented with exaggerated startle responses and nonepileptic tonic attacks but were initially misdiagnosed with epilepsy. The median delay in diagnosis was 26 months. The misdiagnosis periods for the patients were as follows: one-6 months (n = 4, 25%); 6-12 months (n = 3, 18%); 12-24 months (n = 2, 12%); 24-36 months (n = 4, 25%); and more than 36 months (n = 3, 18%). Genetic analysis revealed GLRA1mutations in 56% (n = 9), SLC6A5 in 25% (n = 4), and GLRB in 19% (n = 3). We identified a homozygous nonsense mutation in the GLRB gene (c.995 G > A; p.Trp332Ter) in three patients from the same family. Genotype-phenotype correlation revealed distinct patterns: while patients with GLRA1 and SLC6A5 mutations generally responded well to clonazepam, those with the GLRB mutation exhibited severe global neurodevelopmental delay, autism spectrum features, and required levetiracetam due to poor response to benzodiazepines. Hyperekplexia should be strongly considered in infants with exaggerated startle reflexes to prevent potential developmental consequences of delayed diagnosis. Furthermore, this study confirms that GLRB variants may be associated with a more complex phenotype, including autism and resistance to standard benzodiazepine therapy.
2025-05-08 | A novel GLRB mutation in neonatal hyperekplexia with divergent EEG findings: a case series.
Hereditary hyperekplexia (HKPX) is a rare neurogenetic disorder caused by mutations in glycine signaling genes, such as GLRB. We report two neonates with autosomal recessive HKPX2 due to a novel GLRB mutation (c.1414C>T, p.Arg472*). Case 1, a 1-month-old female, presented with severe startle responses and tonic episodes, normal EEG, and no developmental delays. Case 2, a 2-week-old male, showed similar symptoms but with generalized rhythmic ictal fast activity on EEG. Both had consanguineous parents and unremarkable brain MRIs. Whole exome sequencing identified the same homozygous GLRB mutation in both cases. Treatment with Clonazepam and Levetiracetam significantly improved symptoms. This is the first report of the c.1414C>T (p.Arg472*) mutation in GLRB, expanding the genetic spectrum of HKPX2. The differing EEG findings highlight the disorder's phenotypic variability. Early diagnosis and treatment are crucial to prevent complications like hypoxia and SIDS. This article reports a novel GLRB mutation in two neonates with autosomal recessive HKPX2, presenting with divergent EEG findings.
2025-03-26 | The implications of hyperekplexia on children's quality of life: a report on two cases.
To report two pediatric cases of hyperekplexia in a small city of São Paulo state, Brazil. Two female patients, one aged three years and six months and one aged five months, receiving care from an APAE (Association of Parents and Friends of People with Disabilities) unit, were diagnosed with hyperekplexia 1, a neurological disorder characterized by an excessive startle response. Hyperekplexia cases can be divided into three subgroups: hereditary, sporadic, and symptomatic. Several specialists have examined patient 1 since she was three weeks old, leading to two initial diagnostic hypotheses (childhood chronic non-progressive encephalopathy and spastic cerebral palsy). She was diagnosed with hyperekplexia 1 at eleven months when a genetic test revealed changes in the GLRA1 gene. Patient 2, at birth, presented hyperextension of both legs, low-set ears, cranial asymmetry, prominent occiput, and tremors in the lower limbs. After several tests and evaluations, the final diagnosis was confirmed at three months old. Her family history indicates the possibility of hereditary hyperekplexia. The cases were compared with information obtained through a bibliographical review. Both patients presented several symptoms associated with hyperekplexia, including neurological symptoms such as increased startle response, convulsions, and hypertonia, which were alleviated with appropriate treatment. So far, combining multidisciplinary assistance with drug treatment, particularly anxiolytics and anticonvulsants, with clonazepam being the most used, has significantly contributed to both patients' improved quality of life. However, physical symptoms, such as hip dislocation and clubfoot, require future surgical intervention.
2020-04-01 | C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia
Abstract Introduction: Hyperekplexia is a rare hereditary neurological disorder; only 5 glycine receptor alpha 1 subunit gene ( GLRA1 ) mutations have been reported in 5 Chinese patients. We report a Chinese infant with hyperekplexia and a novel mutation at c.292G > A. Patient concerns: A Chinese infant with hyperekplexia and a novel mutation at c.292G > A. Diagnosis: All exons of GLRA1 were sequenced in her parents and her, which revealed a mutation at c.1030C > T and another novel mutation at c.292G > A. Her diagnosis was confirmed as hereditary hyperekplexia with GlRA1 hybrid gene mutations based on the sequencing results. Interventions: She was treated with clonazepam. Outcomes: Her muscle hypertonia recovered rapidly and the excessive startle reflex to unexpected stimuli was significantly reduced. Conclusion: Genetic DNA sequencing is a crucial method for diagnosing hyperekplexia-related gene mutation.
2019-08-07 | Impaired glycinergic transmission in hyperekplexia: a model of parasomnia overlap disorder
Abstract We report sleep phenotypes and polysomnographic findings in two siblings with a novel homozygous variant of the GLRA1 gene causing hereditary hyperekplexia (HH). Both sisters had startles during wakefulness and sleep, sleep terrors, and one had symptoms of REM sleep behavior disorder (RBD). Frequent startles were found in NREM sleep associated with NREM parasomnias in deep sleep. In REM sleep, both had motor behaviors and increased phasic/tonic muscle activities confirming RBD. Clonazepam improved startles, motor behaviors, and muscle activities in REM sleep. Impaired glycinergic transmission in human HH could be involved in the pathophysiology of RBD and NREM parasomnias.
antibodies
2025-12-15 | Standing Still: A Case of Stiff Person Syndrome and Common Variable Immunodeficiency.
Stiff-person syndrome (SPS) is a rare autoimmune neurologic disorder characterized by progressive rigidity and spasms, while common variable immunodeficiency (CVID) features hypogammaglobulinemia and recurrent infections. Their coexistence complicates management by requiring autoimmune suppression without further compromising host defense. A 54-year-old man with CVID, diagnosed based on hypogammaglobulinemia (IgG 386 mg/dL) and recurrent sinopulmonary infections, subsequently developed SPS with progressive truncal and limb stiffness, causing gait impairment and dyspnea. He experienced a severe aspergillus pneumonia, and examination showed finger clubbing and resting hypoxemia. Pulmonary function testing demonstrated moderate airflow obstruction with distal airway involvement. Chest radiography later revealed an elevated left hemidiaphragm, consistent with respiratory muscle dysfunction in SPS. Combined therapy with intravenous immunoglobulin (IVIG) and rituximab was initiated, yielding meaningful improvement in stiffness and a reduction in respiratory infections. After a motor vehicle accident with spinal fusion, the patient reported worsening exertional dyspnea and variable IgG troughs; treatment was transitioned to subcutaneous immunoglobulin (SCIG) 10% with rHuPH20 to maintain steadier IgG levels. This case emphasizes the importance of immunologic evaluation in refractory SPS and demonstrates that combined IVIG and rituximab can provide functional benefit while addressing CVID. Transition to SCIG may stabilize IgG exposure and sustain clinical gains. A timeline of diagnoses and treatments highlights the interplay between autoimmunity and hypogammaglobulinemia and supports a tailored, multidisciplinary strategy.
2024-02-06 | Glycine Receptor β-Targeting Autoantibodies Contribute to the Pathology of Autoimmune Diseases.
Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.
2023-02-03 | Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.
Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.
2021-04-05 | Use of subcutaneous immunoglobulin in stiff person syndrome: Case series.
Intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of stiff person syndrome (SPS). However, some patients might not tolerate it. We report the tolerability profile of subcutaneous immunoglobulin (SCIg) in patients with SPS who did not tolerate IVIG. To our knowledge, the use of SCIg in SPS has not been reported before in a case series. The five patients included in this case series presented with various combinations of symptoms of spasms, axial and limb stiffness, and exaggerated responses to outside stimuli. These symptoms often lead to gait and functional impairment. Patients were diagnosed with classic SPS as they met the clinical criteria, which require the presence of spasms, axial rigidity, and hyperexcitability. Subcutaneous immunoglobulin infusion. Five patients were identified that were treated with SCIg. Three tested positive for serum anti-glutamic acid decarboxylase 65 antibodies prior to any treatment. The mean age at SCIg initiation was 33 years (range: 22-47). The mean duration of SPS prior to SCIg initiation was 5.9 years (range: 2.5-7). All patients used IVIG for at least two months (up to 18 months) but switched to SCIg due to IVIG side effects. Duration of SCIg use ranged from 4 months to 6 years (mean, 19.2 months). Upon switching to SCIg, the SPS symptoms remained stable. SCIg was well-tolerated in most as only one patient discontinued SCIg due to side effects. This case series highlights that SCIg could be a treatment option for patients with SPS, especially when IVIG is not feasible. Injection site reactions might be a limiting factor in some patients treated with SCIg. Prospective controlled studies are needed to confirm SCIg treatment durability and efficacy.
2021-01-06 | Stiff-person syndrome coexisting with critical illness polyneuropathy: A case report.
Stiff-person syndrome (SPS) is an uncommon neurological disorder with autoimmune features. Here, we report a 60-year-old man with SPS associated with critical illness polyneuropathy (CIP). CIP was diagnosed during an episode of acute respiratory failure secondary to muscular rigidity and spasms, which has rarely been reported in this condition. The overlapping of CIP and SPS complicated the case. A 60-year-old man presented with gradual onset of cramps, stiffness, and rigidity in his lower limbs 1 year before admission, which eventually led to inability to stand and walk. The persistent nature of his symptoms progressed to frequent acute episodes of dyspnea and he was admitted to intensive care unit (ICU). SPS had been diagnosed after 2 tests of electromyography (EMG) and the detection of an elevated anti-GAD65 antibody titer. During the first EMG, low or absent compound muscle action potentials (CMAP), and sensory nerve action potentials (SNAP) were shown. Therefore, the diagnosis of SPS coexisting with CIP was made. Symptomatic treatment was initiated with oral clonazepam (0.5 mg Bid) and baclofen (5 mg Bid). Intravenous immunoglobulin (IVIG) (0.4 g/kg/d) was administered for the patient for 5 days after admission. We observed a significant clinical improvement during the administration period, and the patient became ambulatory. On follow-up, the patient reported complete relief of his pain and rigidity. We report this special case to address the varied clinical features of SPS. Electrophysiological testing is an important diagnostic approach. Accurate recognition of the disease ensures that the patients can be given appropriate treatment without delay.
proteins
2022-03-17 | Profile of the single-use, multiple-pass protein A adsorber column in immunoadsorption.
Immunoadsorptions (IA) are used to remove autoantibodies from the plasma in autoimmune disorders. In this study, we evaluated the effects of a single-use, recombinant staphylococcal protein A-based immunoadsorber on blood composition of the patient. In a cohort of patients with myasthenia gravis or stiff-person syndrome, essential parameters of blood cell count, coagulation, clinical chemistry or plasma proteins and immunoglobulins (Ig) were measured before and after IA (n = 11). In average, IA reduced the levels of total IgG, IgG1, IgG2 and IgG4 by approximately 60%, the acetylcholine receptor autoantibody levels by more than 70%. IgG3, IgA or IgM were diminished to a lower extent. In contrast to fibrinogen or other coagulation factors, the column markedly removed vitamin K-dependent coagulation factors II, VII, IX and X by approximately 40%-70%. Accordingly, international normalized ratio and activated partial thromboplastin time were increased after IA by 59.1% and 32.7%, respectively. Coagulation tests almost returned to baseline values within 24 h. Blood cell count, electrolytes, total protein or albumin were not essentially affected. No clinical events occurred. The single-use, multiple-pass protein A adsorber column is highly efficient to remove IgG1, IgG2 and IgG4 or specific acetylcholine receptor autoantibodies from the plasma. Coagulation parameters should be monitored, since the column has the capacity to largely reduce vitamin K-dependent factors.
2021-09-20 | Different Behaviors of a Glycine Receptor Channel Pore Residue between Wild-Type-Mimicking and Disease-Type-Mimicking Formats.
The glycine receptor (GlyR) is a neurotransmitter-gated chloride channel that mediates fast inhibitory neurotransmission, predominantly in the spinal cord and brain stem. Mutations of the GlyR are the major cause of hereditary hyperekplexia. Site-specific cysteine substitution followed by labeling with a fluorophore has previously been used to explore the behaviors of the hyperekplexia-related 271 (19') residue of the GlyR. However, this manipulation dramatically compromises sensitivity toward the agonist glycine and alters the pharmacological effects of various agents in manners similar to those of the hyperekplexia-causing R19'Q/L mutations, raising the question whether what is reported by the substituted and modified residue faithfully reflects what actually happens to the wild-type (WT) residue. In this study, a mechanism-rescuing second-site mutation was introduced to create a WT-mimicking GlyR (with the 19' residue cysteine substitution and modification still in place), in which the sensitivity toward glycine and pharmacological effects of various agents were restored. Further experiments revealed stark differences in the behaviors upon the various pharmacological treatments and consequently the underlying mechanisms of the 19' residue between this WT-mimicking GlyR and the GlyR without the mechanism rescue, which is correspondingly defined as the disease-type (DT)-mimicking GlyR. The data presented in this study warn generally that caution is required when attempting to deduce the behaviors of a WT residue from data based on substituted or modified residues that alter protein structure and function. Extra measures, such as rescuing mechanisms via alternative means as presented in this study, are needed to mitigate this challenge.
2021-06-18 | Pair of Residue Substitutions at the Outer Mouth of the Channel Pore Act as Inputs for a Boolean Logic "OR" Gate Based on the Glycine Receptor.
The glycine receptor (GlyR) is a ligand-activated chloride channel, whose mutations are the major cause of hereditary hyperekplexia. The hyperekplexia-causing R271Q mutation, which is located at the extracellular outer mouth of the channel pore, dramatically impairs the GlyR function manifesting a reduced sensitivity toward glycine. This study reports that a second mutation, S273D, rescues the function of the R271Q GlyR to that of the wild-type (WT) GlyR. Surprisingly, the S273D mutation, when introduced to the WT GlyR, does not further increase the receptor function. In other words, the compromised function of the 271Q 273S GlyR (i.e., the R271Q GlyR) can be rescued to WT levels by the introduction of either, or both, of the Q271R and S273D substitutions. From the perspective of Boolean logic gates, the Q271R and S273D substitutions act as inputs for an OR gate based on the GlyR. Further experiments revealed that the negative-charge carried by the 273 residue is essential for the expression of the OR gate and that the expression of the OR gate is residue-position-specific. In addition, mechanistic investigation implied that the 273 residue influences the 271 residue, which might underpin the unique nonadditive OR gate relationship between these two residues. Such an ion-channel-based OR gate, expressing output in the form of electrical current, could potentially be developed to digitally manipulate neuronal activity.
2020-04-30 | A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition
Glycine receptors (GlyRs) are the major mediators of fast synaptic inhibition in the adult human spinal cord and brainstem. Hereditary mutations to GlyRs can lead to the rare, but potentially fatal, neuromotor disorder hyperekplexia. Most mutations located in the large intracellular domain (TM3-4 loop) of the GlyRα1 impair surface expression levels of the receptors. The novel GLRA1 mutation P366L, located in the TM3-4 loop, showed normal surface expression but reduced chloride currents, and accelerated whole-cell desensitization observed in whole-cell recordings. At the single-channel level, we observed reduced unitary conductance accompanied by spontaneous opening events in the absence of extracellular glycine. Using peptide microarrays and tandem MS-based analysis methods, we show that the proline-rich stretch surrounding P366 mediates binding to syndapin I, an F-BAR domain protein involved in membrane remodeling. The disruption of the noncanonical Src homology 3 recognition motif by P366L reduces syndapin I binding. These data suggest that the GlyRα1 subunit interacts with intracellular binding partners and may therefore play a role in receptor trafficking or synaptic anchoring, a function thus far only ascribed to the GlyRβ subunit. Hence, the P366L GlyRα1 variant exhibits a unique set of properties that cumulatively affect GlyR functionality and thus might explain the neuropathological mechanism underlying hyperekplexia in the mutant carriers. P366L is the first dominant GLRA1 mutation identified within the GlyRα1 TM3-4 loop that affects GlyR physiology without altering protein expression at the whole-cell and surface levels. SIGNIFICANCE STATEMENT We show that the intracellular domain of the inhibitory glycine receptor α1 subunit contributes to trafficking and synaptic anchoring. A proline-rich stretch in this receptor domain forms a noncanonical recognition motif important for the interaction with syndapin I (PACSIN1). The disruption of this motif, as present in a human patient with hyperekplexia led to impaired syndapin I binding. Functional analysis revealed that the altered proline-rich stretch determines several functional physiological parameters of the ion channel (e.g., faster whole-cell desensitization) reduced unitary conductance and spontaneous opening events. Thus, the proline-rich stretch from the glycine receptor α1 subunit represents a multifunctional intracellular protein motif.
2015-12-22 | Disturbances of Ligand Potency and Enhanced Degradation of the Human Glycine Receptor at Affected Positions G160 and T162 Originally Identified in Patients Suffering from Hyperekplexia
Ligand-binding of Cys-loop receptors is determined by N-terminal extracellular loop structures from the plus as well as from the minus side of two adjacent subunits in the pentameric receptor complex. An aromatic residue in loop B of the glycine receptor (GlyR) undergoes direct interaction with the incoming ligand via a cation-π interaction. Recently, we showed that mutated residues in loop B identified from human patients suffering from hyperekplexia disturb ligand-binding. Here, we exchanged the affected human residues by amino acids found in related members of the Cys-loop receptor family to determine the effects of side chain volume for ion channel properties. GlyR variants were characterized in vitro following transfection into cell lines in order to analyze protein expression, trafficking, degradation and ion channel function. GlyR α1 G160 mutations significantly decrease glycine potency arguing for a positional effect on neighboring aromatic residues and consequently glycine-binding within the ligand-binding pocket. Disturbed glycinergic inhibition due to T162 α1 mutations is an additive effect of affected biogenesis and structural changes within the ligand-binding site. Protein trafficking from the ER toward the ER-Golgi intermediate compartment, the secretory Golgi pathways and finally the cell surface is largely diminished, but still sufficient to deliver ion channels that are functional at least at high glycine concentrations. The majority of T162 mutant protein accumulates in the ER and is delivered to ER-associated proteasomal degradation. Hence, G160 is an important determinant during glycine binding. In contrast, T162 affects primarily receptor biogenesis whereas exchanges in functionality are secondary effects thereof.
cell therapies
2026-01-13 | The future unfolded: CAR T cells and the transformation of treatment algorithms in autoimmune neurology.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, and its application in neuroimmunologic autoimmune diseases is now emerging as a promising therapeutic avenue. Neuroimmunologic diseases such as multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorder, and stiff-person syndrome have shown varying degrees of response to traditional immunomodulatory therapies, but a significant proportion of patients remain refractory to treatment. In recent studies, anti-CD19 CAR T cells have shown encouraging results in targeting B cells, a key driver of autoimmune pathogenesis. CAR T-cells can penetrate the central nervous system and overcome the limitations of conventional B-cell depleting therapies such as rituximab, particularly in accessing ectopic lymphoid follicles that maintain compartmentalized inflammation. In early clinical cases, CAR T-cell treatment has resulted in marked clinical improvements, including significant reductions in symptoms and durable disease remission, with manageable side-effects. In addition, advances in allogeneic CAR T cell constructs and chimeric autoantibody receptor T cells offer additional avenues for precision-targeted therapies. These developments underscore the potential of CAR T cells to reshape the treatment landscape for refractory neuroimmunologic autoimmune diseases and warrant further controlled trials and regulatory exploration.
2025-12-15 | CAR T-cell therapy for neurological disorders: scientific rationale and mechanistic insights.
The development and successful clinical application of engineered T cells expressing synthetic chimeric antigen receptors (CARs) represents a milestone in cancer therapy. This approach optimizes physiological in vivo T-cell activation against specific target antigens expressed on defined cell subsets with the goal of their deep and sustained depletion. Significant progress has been made in redesigning CAR T-cell constructs to improve patient safety, therapeutic efficacy, and accessibility. Efforts have also focused on streamlining manufacturing to improve availability and reduce costs, two critical challenges to widespread adoption. Beyond hematologic malignancies, CAR T-cell therapies are now increasingly being repurposed to tackle B-cell-mediated autoimmune diseases (AIDs). This is primarily achieved through broad B-cell depletion, but more targeted approaches-such as the selective elimination of autoantibody-producing B-cell subpopulations-are also being explored. Important considerations in their implementation are identifying the most pertinent patient groups, tailoring their treatment up to the point of CAR-infusion, and following up on their unique toxicity-profile. In the context of neurological AIDs-including refractory myasthenia gravis, Lambert-Eaton syndrome, multiple sclerosis, and stiff-person syndrome-early clinical experience suggests promising efficacy and tolerability, leading to a growing number of registered clinical trials. In this review, we provide an overview of the mechanism and evolution of CAR T-cell therapy, highlighting why its application in AIDs, particularly in neurology, represents a highly promising therapeutic strategy.
2025-11-17 | Promising Effects of CAR T-Cell Therapy in Refractory Stiff Person Syndrome and a Hopeful Future for All Neuroautoimmunities.
Chimeric antigen receptor (CAR) T cells are genetically modified T cells expressing CARs, initially developed to recognize tumor antigens and kill cancer cells that evade T-cell recognition. Because of their impressive success in hemato-oncologic malignancies, CAR T cells are being repurposed with redesigned constructs for safety and sustained efficacy to target refractory systemic autoimmune or neurologic diseases. The CD19 CAR T cells-targeting those CD19-positive, antibody-secreting, long-lived plasma cells, and plasmablasts-are now extensively explored in refractory neuroautoimmunities with promising benefits based on case series in patients with myasthenia gravis (MG), stiff person syndrome (SPS), neuromyelitis, myositis, and multiple sclerosis; some patients with MG and SPS with steadily progressive and disabling disease refractory to all available therapies, including rituximab and new biologics, exhibit impressive clinical improvements with long-lasting benefits. The review, triggered by these early results and ongoing trials, addresses what these cells are and why they show effectiveness not only in antibody-mediated B-cell neurologic diseases unresponsive to available anti-B-cell agents but also in patients with nonpathogenic antibodies, implying effects even beyond B cells; points out that CARs are "living cells" penetrating physiologic barriers, such as the blood-brain barrier, expanding within tissues to memory cells ensuring sustained effects; describes the process and challenges of preparing and administering CAR T cells and their safety profile stressing the differences in toxicities when treating autoimmunites vs malignancies; and highlights that CD19 CAR T cells can successfully target even 2 different autoimmune diseases in the same patient, such as SPS and MG, offering promising prospects of changing the therapeutic algorithm in all neuroautoimmunities with potential for achieving even an immune reset shifting immunity to a healthy state.
2024-08-14 | The Role of Chimeric Antigen Receptor T-Cell Therapy in Immune-Mediated Neurological Diseases.
Despite the use of 'high efficacy' disease-modifying therapies, disease activity and clinical progression of different immune-mediated neurological diseases continue for some patients, resulting in accumulating disability, deteriorating social and mental health, and high economic cost to patients and society. Although autologous hematopoietic stem cell transplant is an effective treatment modality, it is an intensive chemotherapy-based therapy with a range of short- and long-term side-effects. Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of B-cell and other hematological malignancies, conferring long-term remission for otherwise refractory diseases. However, the toxicity of this treatment, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and the complexity of production necessitate the need for a high level of specialization at treating centers. Early-phase trials of CAR-T therapies in immune-mediated B cell driven conditions, such as systemic lupus erythematosus, neuromyelitis optica spectrum disorder and myasthenia gravis, have shown dramatic clinical response with few adverse events. Based on the common physiopathology, CAR-T therapy in other immune-mediated neurological disease, including multiple sclerosis, chronic inflammatory polyradiculopathy, autoimmune encephalitis, and stiff person syndrome, might be an effective option for patients, avoiding the need for long-term immunosuppressant medications. It may prove to be a more selective immunoablative approach than autologous hematopoietic stem cell transplant, with potentially increased efficacy and lower adverse events. In this review, we present the state of the art and future directions of the use of CAR-T in such conditions. ANN NEUROL 2024;96:441-452.
2024-06-17 | Successful use of anti-CD19 CAR T cells in severe treatment-refractory stiff-person syndrome.
Treatment with autologous chimeric antigen receptor (CAR) T cells has emerged as a highly effective approach in neuroimmunological disorders such as myasthenia gravis. We report a case of successful anti-CD19 CAR T cell use in treatment-refractory stiff-person syndrome (SPS). To investigate clinical and immunological effects of anti-CD19 CAR T cell use in treatment-refractory SPS, a 69-y-old female with a 9-y history of treatment-refractory SPS with deteriorating episodes of stiffness received an infusion of autologous anti-CD19 CAR T cells (KYV-101) and was monitored clinically and immunologically for more than 6 mo. CAR T cell infusion resulted in reduced leg stiffness, drastic improvement in gait, walking speed increase over 100%, and daily walking distance improvement from less than 50 m to over 6 km within 3 mo. GABAergic medication (benzodiazepines) was reduced by 40%. KYV-101 CAR T cells were well tolerated with only low-grade cytokine release syndrome. This report of successful use of anti-CD19 CAR T cells in treatment-refractory SPS supports continued exploration of this approach in SPS and other B cell-related autoimmune disorders.
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Drug Discovery Landscape
1 orphan drug designation for Hereditary hyperekplexia.
1 orphan drug designation for Hereditary hyperekplexia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Clonazepam | small molecules | FDA | — | Hoffmann-La Roche, Inc. |
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