RARE DISEASE
Rare dystonia
Rare dystonia
Rare dystonia
Synonyms: Rare dystonic disorder
Synonyms: Rare dystonic disorder
Synonyms: Rare dystonic disorder
Drug discovery
1
drug
With orphan designation
Overview
Rare dystonias encompass genetically inherited and idiopathic movement disorders characterized by sustained or intermittent involuntary muscle contractions causing abnormal postures, tremors, and functional impairment. These disorders exhibit phenotypic variability, with focal (e.g., cervical dystonia, writer's cramp) and generalized forms, often presenting with pain, psychiatric comorbidities, and progressive disability [1][6][12].
Population
Prevalence ranges from 16.43/100,000 for primary dystonia to 1/200,000–330,000 for early-onset generalized forms in Europe [4][14]
Higher incidence in Ashkenazi Jewish populations (1/3,000–9,000) due to TOR1A founder mutations [4][16]
Adult-onset focal dystonia (e.g., cervical dystonia, blepharospasm) is most common, accounting for ~70% of cases [12][17]
Burden
Functional impact: 28.3% of focal dystonia patients experience symptom spread, worsening disability [1][12]
Psychiatric comorbidity: 42.5% report depression/anxiety, correlating with symptom severity [8][11][19]
Economic: High costs from repeated botulinum toxin regimens ($1,800–$3,800 annual) and DBS surgery ($50,000–$100,000) [8][10]
Therapies
First-line: Botulinum toxin injections for focal/segmental dystonia [3][8][13]
Oral agents: Trihexyphenidyl (anticholinergic) and levodopa (for dopa-responsive dystonia) [6][18][19]
Advanced: Deep brain stimulation (GPi target) for medically refractory generalized dystonia, particularly in DYT1 carriers [4][8][11]
Categories: rare neurological diseases
Research Papers
378 drug discovery papers about Rare dystonia, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
378 drug discovery papers about Rare dystonia, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-07-16 | Laryngeal dystonia: a comprehensive review of aetiology, clinical presentation, diagnosis, and treatment approaches.
Laryngeal dystonia (LD), also known as spasmodic dysphonia, is a rare voice production pathology manifested as focal muscle dystonia. The aim of this review is to synthesize current evidence on its aetiology, clinical presentation, diagnostic approach, and available treatment options, while identifying existing knowledge gaps to guide clinical decision-making and future research. A structured literature review was conducted using peer-reviewed articles from medical databases (e.g., PubMed, Google Scholars). Inclusion criteria comprised studies published in English within the last 20 years, focusing on LD aetiology, clinical features, diagnosis, or treatment. Both observational studies and clinical trials were included. Exclusion criteria involved case reports with limited applicability, non-English publications, and studies lacking clear diagnostic criteria or therapeutic outcomes. Primarily an idiopathic disorder, there is evidence suggesting a neurogenic origin involving basal ganglia dysfunction in LD. Clinically, LD manifests as task-specific voice disturbances, affecting most commonly the adductor muscles (strained voice) or the abductor muscles (breathy voice). Diagnosis is mainly clinical, but supported by laryngoscopic findings and other multidisciplinary evaluation. The gold standard treatment remains botulinum toxin injection, providing symptomatic relief, while voice therapy and, in selected cases, surgical interventions offer adjunctive benefits. LD is a neurological voice disorder which requires a high index of suspicion for diagnosis. Individualized treatment, particularly with botulinum toxin, and early recognition, significantly improve patient outcomes. Further research is needed to clarify pathophysiological mechanisms and optimize long-term management strategies.
2026-06-25 | Botulinum Toxin Treatment for Uncommon Phenotypes of Laryngeal Adductor Breathing Dystonia.
Laryngeal adductor breathing dystonia (LABD) is a rare form of focal, task-specific respiratory dystonia affecting the laryngeal muscles of unknown aetiology. Unlike classical laryngeal dystonia (spasmodic dysphonia), LABD is not primarily characterised by impaired speech, but rather by dysfunction of respiratory laryngeal control. The hallmark pathophysiological alteration consists of involuntary, action-induced adductor spasms of the laryngeal muscles during respiration, particularly during inspiration. LABD must be distinguished from inducible laryngeal obstruction (ILO), a broader, heterogeneous condition encompassing episodic, stimulus-triggered supraglottic or glottic closure, associated with asthma, reflux, or psychological triggers, that is generally not task-specific and lacks the neurological substrate characteristic of dystonia. In contrast, LABD is a persistent, effort-dependent, neurologically driven dystonia, demonstrable by paradoxical adductor spasms on fibreoptic laryngoscopy during normal inspiration and confirmed electromyographically by paradoxical thyroarytenoid muscle activation instead of the expected inspiratory relaxation. Traditional treatments, including respiratory retraining, speech therapy, biofeedback, psychotherapy, benzodiazepines, dopamine-blocking agents, and anticholinergic drugs, have proved largely ineffective. Tracheostomy may be required in cases of severe respiratory compromise. Botulinum toxin type A (BoNT/A) injections have been reported to successfully reduce inspiratory stridor in selected patients. Here, we present three cases of LABD displaying distinct phenotypes, in which typical features were associated with involvement of extra-laryngeal cranial districts, further expanding the known phenotypic spectrum of this condition.
2026-04-06 | A plastic surgery approach to Meige syndrome: Botulinum toxin for rebalancing facial dystonia and aesthetics - A case report.
Meige syndrome is a rare segmental dystonia characterized by blepharospasm and oromandibular dystonia, often leading to significant functional and aesthetic impairment. This report details a 59-year-old female patient with a 16-year history whose symptoms were refractory to prior drug therapies. An individualized botulinum toxin type A (BTX-A) injection protocol was devised based on detailed facial muscle mapping and plastic surgery principles of muscle balance. Following treatment, the patient showed marked improvement in facial spasms within 1 week, with resolution of nocturnal headaches and notable correction of aesthetic concerns arising from dystonia, including facial asymmetry and the involuntary "gummy smile". The gingival exposure during dystonic contraction was reduced from >4 mm (classified as severe gingival smile) to 1 mm. Social and eating functions were restored. This case suggests that a BTX-A treatment strategy guided by plastic surgery principles, which addresses both functional symptoms and aesthetic disharmony, may provide an effective and safe office-based treatment option for Meige syndrome. Further studies with larger cohorts are warranted to validate this protocol.
2026-02-02 | Assessing the effects of botulinum toxin therapy for spasmodic dysphonia: An Austria-Germany registry.
Injection of Botulinum neurotoxin (BoNT) is regarded as standard treatment for spasmodic dysphonia (SD), reducing the overactivity of the affected muscles. Due to the lack of standardized outcome parameters for diagnosing SD or assessing its treatment over time, the evaluation of systematic clinical evidence on the effects of BoNT therapy on SD symptom control is difficult. The registry presented in this article aimed to evaluate outcomes after BoNT treatment in SD patients in Austria and Germany, based on selected subjective and objective voice parameters. 41 patients with SD were included in this multicentric registry, after drop-out of 2 patients the results of 39/41 (95.1%) patients could be analyzed per protocol. Demographic and treatment characteristics as well as the occurrence of therapy-related side effects were recorded. Perceptual voice sound evaluation (RBH scale), voice range profile measurements (VRP), number of spasms, and severity of voice strain were assessed. Patients were asked to complete the Voice Handicap Index (VHI-9i), the Communicative Participation Item Bank (CPIB), and indicate their perceived phonation effort on a VAS scale. The parameters were compared between baseline and 1-month post-BoNT treatment. The patients received all BoNT type A (Xeomin®/Merz, Allergan®/Allergan or Dysport®/Ipsen). SD symptoms did not affect the frequency or dynamic range of the singing voice nor did they affect MPT; in contrast all the other parameters assessed were aberrant at baseline. BoNT treatment improved Jitter-%, Dysphonia Severity Index (DSI), degrees of roughness and hoarseness, but failed to restore them to normal. BoNT significantly reduced the voice spasm and strain. Phonation effort improved by approximately 50%. VHI-9i classification was reduced from moderate to mild after treatment, and CPIB from moderate to mild. The VHI-9i results were significantly positively correlated with the CPIB results. The results of this registry showed that BoNT injection, the current off-label treatment of SD symptoms, failed to restore normal voice quality. This registry's outcomes also indicate that the choice of the applied BoNT brand is site-specific and does not appear to be associated with differences in efficacy. We also showed that the effects of the BoNT on the SD symptoms are best described by semi-quantitative outcome measures such as spasm counts and voice strain, and by patients-reported outcome measures (PROMs), such as CPIB and VHI-9i than by more objective parameters such as frequency and dynamic range of the singing voice.
2026-02-02 | Adductor Respiratory Laryngeal Dystonia (Dystonic Respiratory Stridor): Clinical Characterization and Response to Botulinum Toxin Therapy: A Single Centre Experience.
Adductor respiratory laryngeal dystonia (ARLD) is a rare focal dystonia with vocal fold closure during inspiration leading to stridor and dyspnoea. To characterize clinical features and outcomes of patients with ARLD at a tertiary movement disorders center. A retrospective cohort study was conducted of patients with adductor respiratory laryngeal dystonia attending a botulinum toxin injection clinic. Nineteen patients were identified. Most were female (94.7%). Mean age of onset was 51.9 years (range 39-89). Comorbid movement disorders included laryngeal dystonia, cervical dystonia, blepharospasm, dystonic tremor, and Parkinson's disease. Median time from symptom onset to diagnosis was 3.0 years (IQR 2.0-15.0). 92.8% of injections with botulinum toxin were effective, although 46.2% were associated with adverse events. ARLD is associated with diagnostic delay. Symptoms of stridor alongside other movement disorders may provide clues. Treatment with botulinum toxin is effective, though careful dosing is required.
small molecules
2026-07-21 | Isolated Lingual Dystonia: A Rare Tardive Manifestation of Amisulpride
Aims: To describe a rare case of isolated lingual tardive dyskinesia associated with prolonged low-dose amisulpride therapy and to emphasise the importance of early recognition and treatment. Presentation of Case: A 72-year-old woman with bipolar I disorder developed progressive dysarthria, dysphagia, and involuntary choreiform tongue movements after approximately 13 months of amisulpride therapy, initiated at 50 mg/day and titrated to 150 mg/day. Neurological examination showed continuous lingual movements with intermittent dystonic posturing, without limb involvement or other focal neurological abnormalities. Brain magnetic resonance imaging demonstrated only mild age-related cerebral atrophy, and routine laboratory investigations were within normal limits. Alternative structural, metabolic, seizure-related, and neurodegenerative causes were considered and excluded clinically. The Naranjo score was 6, and the WHO-UMC assessment classified the reaction as probable/likely. Amisulpride was discontinued, and tetrabenazine was initiated at 12.5 mg each morning and 25 mg each night. After six weeks, tongue movements and speech improved markedly, permitting dose reduction to 12.5 mg twice daily. Psychiatric stability was maintained with clozapine and sodium valproate/valproic acid. Discussion: The delayed onset, temporal relationship to prolonged dopamine receptor blockade, absence of an alternative cause, and improvement after withdrawal supported a tardive drug-induced movement disorder. Conclusion: Isolated lingual dystonia may occur during long-term low-dose amisulpride therapy. Regular movement assessment and prompt treatment modification may reduce functional impairment.
2026-07-09 | Relative Efficacy of Self-Managed Caffeine Supplementation in Maintaining Daily Activity in a Patient with ADCY5-Related Dyskinesia: A Case Report.
ADCY5-related dyskinesia is an autosomal dominant movement disorder with limited treatment options because many standard medications are ineffective. Caffeine has shown efficacy in ADCY5-related dyskinesia as an adenosine A2A receptor antagonist, but optimal dosing remains uncertain. We report a 24-year-old woman with paroxysmal dyskinesia since early childhood, consisting of chorea, dystonia, and myoclonus upon waking. More than 15 medications failed. Whole-exome sequencing identified a mosaic ADCY5 variant (p.R418Q, 7% variant allele frequency). Caffeine escalation from 100 to 600 mg worsened symptoms. Four months later, she found that unsweetened canned coffee containing approximately 100 mg of caffeine per can, taken 1-3 times daily, reduced her symptoms and helped her maintain daily employment. In a self-controlled analysis of 39 coffee-intake events, dyskinesia episodes during the 6 h after coffee intake were significantly fewer than during the preceding 6 h (p = 0.002). This case demonstrates successful symptom control in ADCY5-related dyskinesia using patient-directed, low-dose caffeine therapy. The striking response suggests a narrow therapeutic window for caffeine in this condition and that patient self-titration may be valuable in optimizing treatment response.
2026-07-02 | Central precocious puberty as the initial manifestation of multisystem involvement caused by de novo heterozygous KMT2B mutation and STS hemizygous deletion: a case report.
Pathogenic loss-of-function variants in the KMT2B gene cause a rare autosomal dominant disorder with two major phenotypes: KMT2B-related dystonia (DYT-KMT2B) and KMT2B-related neurodevelopmental disorder (KMT2B-NDD). Central precocious puberty (CPP) has been documented as a comorbidity in patients with DYT-KMT2B, but has not been reported as the primary clinical manifestation of the disorder in patients without dystonia. Deletions or pathogenic variants in the STS gene cause X-linked ichthyosis (XLI). Concurrent KMT2B and STS alterations have not been well characterised, and GnRH analogue therapy for CPP in KMT2B-related disorders has not been previously described. An 8-year-10-month-old male presented with a 1-2-year history of progressive increase in penile length and girth. Physical examination revealed distinctive craniofacial dysmorphism, classic ichthyotic scaling, pubertal changes consistent with precocious puberty, and normal muscle tone without dystonic features. Biochemical testing confirmed markedly elevated serum total testosterone, a positive gonadotropin-releasing hormone (GnRH) stimulation test consistent with CPP, and bone age advanced by 1.2 years relative to chronological age. Neurocognitive assessment identified mild intellectual disability. Family-based whole-exome sequencing and copy number variation (CNV) analysis identified a de novo heterozygous pathogenic nonsense variant in KMT2B (NM_014727.3: c.4213del, p.Leu1405Ter) and a hemizygous pathogenic full-coding deletion of STS. The patient was treated with leuprorelin acetate for CPP and topical emollients for XLI. At 3-month follow-up, physical signs of puberty remained stable. GnRHa stimulation test showed indicating but incomplete suppression of the hypothalamic-pituitary-gonadal axis. The ichthyotic skin lesions improved markedly with topical therapy. The leuprorelin acetate dose was subsequently increased. The patient is continuing on the current regimen with close monitoring. Precocious puberty has been reported in eleven patients with KMT2B-related dystonia. This case documents the co-occurrence of a KMT2B-related disorder and XLI in a patient, and provides documentation of GnRH analogue therapy and structured endocrine follow-up for CPP in this population. KMT2B haploinsufficiency may contribute to premature activation of the hypothalamic-pituitary-gonadal axis through disruption of ERα-mediated transcriptional regulation and altered epigenetic programming at key hypothalamic developmental genes. Clinically, children with KMT2B-related disorders should undergo comprehensive endocrine assessment to facilitate early diagnosis and timely intervention.
2026-05-14 | Diagnosis and pathogenesis of dystonia: clinical heterogeneity, shared mechanisms, and neurodevelopmental origins.
The diagnosis of dystonia is often delayed because of its many different clinical manifestations and causes. Updates to the definition and classification of dystonia can assist clinicians in improving its recognition and timely diagnosis. Dystonia is characterised by sustained or intermittent abnormal movements, postures, or both. Patterned phenomenology, alleviating manoeuvres, worsening by voluntary movement, and overflow to adjacent muscles are all clinical clues of the condition. Additional non-motor manifestations are part of the clinical spectrum. In parallel to the broad heterogeneity of clinical manifestations among different types of dystonia, the biological mechanisms underlying the condition are also heterogeneous. Among these mechanisms, an alteration of the sensorimotor circuits during crucial windows of development might have a role in many forms of dystonia. Advances in the understanding of its pathogenesis indicate that targeting shared mechanisms could provide a treatment approach for multiple types of dystonia, but also suggest the possibility of personalised therapeutic approaches.
2026-05-06 | Multidisciplinary perinatal management of paroxysmal kinesigenic dyskinesia in pregnancy: a case report and a proposed structured pathway.
Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by brief dystonic or dyskinetic attacks precipitated by sudden voluntary movement or arousal. Pregnancy complicated by PKD is extremely rare, and evidence guiding perinatal decision-making, especially regarding delivery mode and anesthetic management remains scarce. We report a term pregnancy in a woman with long-standing PKD managed through a multidisciplinary team involving neurology, obstetrics, anesthesiology, and neonatology. Following individualized optimization of antiseizure medications (ASMs) and intensive antenatal surveillance, the patient showed moderate symptomatic improvement during pregnancy. Given the high risk of pain, stress, or movement-triggered dystonic attacks with transient loss of voluntary motor control during labor, elective cesarean delivery was planned. Combined spinal-epidural anesthesia (CSEA) was performed to provide effective analgesia while minimizing arousal and sensory triggers. The procedure was uneventful, with no perioperative dystonic episodes. A healthy neonate was delivered with no congenital anomalies. This case demonstrates that favorable maternal and neonatal outcomes can be achieved in pregnancies complicated by PKD through individualized antiseizure medication management, multidisciplinary care, and trigger-oriented perinatal planning. The structured clinical decision-making pathway proposed in this study may provide a practical framework for managing this rare and challenging condition.
gene therapies
2025-06-20 | Pediatric Genetic Dystonias: Current Diagnostic Approaches and Treatment Options
Genetic dystonias are a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions that cause repetitive movements and abnormal postures. Often beginning in childhood, they can significantly affect quality of life. Although individually rare, genetic causes are collectively relevant in pediatric dystonias, with over 250 associated genes. Among these, TOR1A, SGCE, and KMT2B are the most frequently reported in pediatric forms. Diagnosis is challenging due to the wide clinical and genetic variability. Recent advances in genetic testing, including whole-exome and whole-genome sequencing, have improved the early identification of causative variants. Functional data on selected mutations are helping to refine genotype–phenotype correlations. Management typically requires a multidisciplinary approach. Symptomatic treatments include anticholinergics, benzodiazepines, and botulinum toxin, while deep brain stimulation can be effective in refractory cases, especially in patients with TOR1A variants. Disease-modifying therapies are also emerging, such as gene therapy for AADC deficiency, highlighting the potential of precision medicine. This review provides an updated overview of pediatric genetic dystonias, with a focus on differential diagnosis and treatment strategies. Early and accurate diagnosis, together with personalized care, is key to improving outcomes in affected children.
2025-02-21 | AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.
Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the WDR45 gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. WDR45 encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of WDR45 can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human WDR45 transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that WDR45 gene transfer can be a promising therapeutic strategy for BPAN.
2025-01-31 | Clinical case of a patient with AADC deficiency of L-aromatic amino acid decarboxylase: diagnostic route and therapeutic options
L-aromatic amino acid decarboxylase deficiency (AADC) is a rare autosomal recessive neurometabolic disease characterized by impaired biosynthesis of neurotransmitters and manifested by disorders of movement and autonomic regulation. In the article there is discussed the diagnostic path and treatment options for a 7-year patient with severe AADC deficiency. Combination of severe neurological disorders (muscular hypotension, dystonia, hyperkinesis, oculogyric crises) and autonomic disorders (increased sweating, hypersalivation, thermoregulation disorders, nasal congestion, dyspepsia, etc.) is clearly demonstrated to require the detection of 3-O-methyldopa in dried blood spots to exclude AADC deficiency. Given the emergence of gene therapy, which is available to patients with a confirmed diagnosis of AADC deficiency in Russia within the criteria of the Circle of Kindness Foundation, it is necessary to popularize information about L-aromatic amino acid decarboxylase deficiency in the general medical community, to improve the prognosis and quality of life in AADC patients.
2024-07-18 | AAV9-Mediated Intrastriatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice.
Mutations in the GNAO1 gene, which encodes the abundant brain G-protein Gα o, result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with GNAO1 disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele (Gnao1 +/R209H) exhibit hyperactivity in open field tests but no seizures. We developed self-complementary adeno-associated virus serotype 9 (scAAV9) vectors expressing two splice variants of human GNAO1 Gα o isoforms 1 (GoA, GNAO1.1) and 2 (GoB, GNAO1.2). Bilateral intrastriatal injections of either scAAV9-GNAO1.1 or scAAV9-GNAO1.2 significantly reversed mutation-associated hyperactivity in open field tests. GNAO1 overexpression did not increase seizure susceptibility, a potential side effect of GNAO1 vector treatment. This represents the first report of successful preclinical gene therapy for GNAO1 encephalopathy applied in vivo. Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated Gα o expression and to refine the vector design. SIGNIFICANCE STATEMENT: GNAO1 mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here we show that intrastriatal delivery of scAAV9-GNAO1 to express the wild-type Gα o protein reduces the hyperactivity of the Gnao1 +/R209H mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for GNAO1 encephalopathy applied in vivo on a patient-allele model.
2024-03-06 | Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-Responsive Basal Ganglia disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene
Abstract The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is a neurological disorder characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease's rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. Despite the lack of knowledge related to genotype-phenotype correlations, the derivation of BTBGD-iPSC lines carrying a homozygous mutation in SLC19A3 constitutes a unique cell model to examine the molecular mechanisms underlying the cellular dysfunctions caused by SLC19A3 pathogenic variant and could promote the development of novel therapeutic agents.
oligonucleotides
2026-05-06 | Correction of the molecular phenotype of X-linked Dystonia-Parkinsonism reveals a non-canonical function of BRD4.
Transcription and mRNA processing are tightly coupled regulatory layers on gene expression, and their perturbations underly human disorders. X-linked Dystonia-Parkinsonism (XDP) is a unique example of a human disease connecting aberrant mRNA processing and the basal transcription machinery. XDP is a rare, monogenic fatal neurodegenerative disorder, and a limited understanding of the underlying molecular mechanisms hinders the development of effective therapies. In this study, we show that depletion of BRD4, a chromatin reader known for its role in transcriptional pausing, rescues the XDP molecular signature. Unexpectedly, this effect is independent of the canonical coactivator role of BRD4. We demonstrate that the XDP-SVA induces intronic premature cleavage and polyadenylation within the TAF1 locus, and that BRD4 depletion bypasses this premature termination checkpoint. These findings reveal new dimensions of BRD4 activity beyond transcription pause release and suggest modulation of mRNA processing as a therapeutic strategy for XDP.
2026-01-22 | Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy.
Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A (TUBB4A). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series (Tubb4aKO/KO, Tubb4aD249N/+, Tubb4aD249N/KO, and Tubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of wild-type tubulin. To further evaluate the translational potential of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a. Notably, single intracerebroventricular administration of ASO in postnatal Tubb4aD249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, treating ASO Tubb4aD249N/KO mice prevents myelin and oligodendrocyte (OL) loss and recovers visual evoked potential latencies in vivo. Furthermore, the microtubule function of Mbp mRNA transport from the OL soma to the myelin sheath is retained. A major limitation we noted is that ASOs fail to target cerebellar granule neurons even with multiple routes of administration in the brain. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.
2025-11-24 | Therapeutic targeting of alternative splicing caused by a lethal noncoding structural variant in X-linked dystonia parkinsonism.
X-linked Dystonia-Parkinsonism (XDP) is a lethal adult-onset neurodegenerative disorder that exhibits features of dystonia and parkinsonism and is exclusively associated with a causal founder haplotype that is indigenous to the Philippines and affects Filipino males. Using patient-specific fibroblasts, neural stem cells (NSC), and other neuronal models, we discovered that cryptic alternative splicing caused by a novel SINE-VNTR-Alu (SVA) mobile element insertion into intron 32 of TAF1 is a mechanistic hallmark of XDP. We leveraged postmortem brain samples from an XDP-specific brain bank to demonstrate that the molecular hallmarks of XDP observed in neural stem cells (NSCs) mirror abnormalities observed in brain tissues from affected patients. Based on these findings that patient-specific NSCs reproduce mechanistic signatures found in the brain, we sought to develop a bespoke precision therapeutic for XDP and evaluate its relative efficacy in ameliorating transcriptomic signatures in neuronal models. We first used CRISPR-based excision of the SVA and demonstrated ablation of all aberrant splicing and dysregulation of TAF1 expression in NSCs across 30 independent clones. CRISPR-based correction of the XDP haplotype also restored the expression of 424 of 1,490 (30%) differentially expressed genes (DEGs) that were altered in XDP patient lines and greatly exceeded what would be expected by chance (p-value = 9.89e-87). While in vivo delivery of a gold standard CRISPR therapy is currently not feasible for XDP, we evaluated a tractable approach for Filipino patients by exploring the potential to modulate alternative splicing in XDP patients using antisense oligonucleotides (ASOs). To accomplish this, we developed a large-scale and well controlled functional genomics platform that screened eighty ASOs targeting intron 32 of XDP patients, followed by prioritization of lead ASOs based on attenuation of the alternative splicing signature. In transcriptome analyses across 1,550 libraries, we found that 8 of the 12 lead ASOs ameliorated the targeted XDP aberrant splicing. Moreover, we found that the two lead ASOs exhibited 38% and 43% rescue of XDP-specific DEGs that were also rescued by CRISPR excision of the SVA (enrichment p-values = 2.06e-13 and 2.27e-05, respectively). These rescues represented restoration of key molecular functions previously implicated in XDP, such as synaptic function, DNA-binding transcription factor activity, and gliogenesis. This study highlights a path to a potential targeted therapeutic for XDP and the capacity to exploit functional genomic signatures in patient-derived neural models to develop a scalable precision therapeutic platform for rare genetic disorders.
2025-02-12 | Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia.
Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations. By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays. This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia.
2025-02-03 | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.
GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in GNAO1, as a spectrum of neurological phenotypes, including epileptic encephalopathy, developmental delay with movement disorders, or late-onset dystonia. There are currently no effective treatments available, apart from symptomatic options. In this work, we suggest harnessing personalized RNA therapy to treat GNAO1 patients and focus specifically on a recurrent pathogenic variant (E246K). We systemically screened allele-specific antisense oligonucleotides (ASOs) targeting the mutated allele to identify a potent and specific sequence using both reporter-based platforms and a patient-derived cellular model. We show that reduction of mutated GNAO1 in vitro by knockout or by ASO has a beneficial functional outcome, which can be measured by cAMP accumulation and gene expression changes. We established a Gnao1-E246K mouse model that shows a neurological phenotype, which partially recapitulates the human condition. Due to sequence similarity, the mouse can be treated with the selected ASO to test treatment efficacy in animal models, as shown in vitro using murine neural progenitor cells. Our results demonstrate a beneficial effect for the reduction of mutated GNAO1 by ASO in patient-derived models, demonstrating its feasibility as a therapeutic approach.
other
2026-06-26 | Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort.
Background: Variants in anoctamin 3 (ANO3) are linked to autosomal dominant dystonia, commonly known as DYT-ANO3 (OMIM: #615034). While craniocervical dystonia constitutes the most frequently observed phenotype, its clinical manifestations display significant heterogeneity. Nevertheless, the data concerning the genetic characteristics, clinical features, and therapeutic outcomes of ANO3-related dystonia within Asian populations remain scarce. Methods: Whole-exome sequencing was conducted on 661 Chinese patients, comprising 356 individuals with dystonia and 305 individuals with non-dystonic movement disorders who served as an internal disease-control cohort. Candidate ANO3 variants were evaluated based on population frequency, predicted deleteriousness, ACMG criteria, and aggregate frequency analyses. A retrospective review was performed of clinical features and treatment responses. Results: Fifteen rare ANO3 missense variants were identified in 16 patients with dystonia and one non-dystonic individual, including one pathogenic variant, six likely pathogenic variants, and nine previously unreported variants. The rare ANO3 variants were significantly enriched in the dystonia cohort compared with the controls. ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia. Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients. Conclusions: This study broadens the genetic and clinical spectrum of ANO3-related movement disorders in a Chinese cohort. The findings support substantial clinical heterogeneity in DYT-ANO3 and suggest that deep brain stimulation, especially STN-DBS, may be considered in selected refractory cases, although further studies are needed.
2026-04-27 | Phage display enabled the identification of single-domain nanobody antitoxins against botulinum neurotoxin serotype C.
Botulinum neurotoxin serotype C (BoNT/C) exhibits therapeutic efficacy and duration of action comparable to those of BoNT/A. It has been demonstrated to effectively manage movement disorders such as dystonia and blepharospasm, making it a highly promising alternative to BoNT/A. BoNT/C is also one of the primary etiological botulinum isoforms causing animal botulism and may pose a zoonotic risk. So, it is of great need to develop antidote that can treat human iatrogenic, foodborne and animal botulism caused by BoNT/C. Currently, the approved botulism antidotes primarily are polyvalent horse serum antitoxins, which are severely limited due to insufficient supply and adverse reactions. In this study, we developed a high-affinity nanobody A2, a variable domain of a heavy-chain antibody (VHH) against BoNT/C, based on phage display library screening. Our results demonstrated that A2 effectively blocked the binding of BoNT/C to its target cell. Furthermore, A2 exhibited potent neutralizing activity and rescued BoNT/C-intoxicated mice. These findings supported nanobody A2 as a promising antitoxin candidate with therapeutic efficacy against botulism.
2025-05-18 | Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.
Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.
2025-02-08 | Generation of an induced pluripotent stem cell line (UCLi026-A) from a patient with ADCY5-related disease carrying the heterozygous variant c.1253G > A; (p. Arg418Gln).
Adenylyl cyclase 5 (ADCY5)-related diseases are a rare group of genetic disorders that commonly present in childhood. Heterozygous mutations in ADCY5 lead to ADCY5-related dyskinesia, comprising a wide array of disabling hyperkinetic movement disorders including chorea, myoclonus and/or dystonia. We generated an induced pluripotent stem cell line from the fibroblasts of an affected patient with the common heterozygous pathogenic variant, c.1253G > A (p.Arg418Gln). This line was further characterised for pluripotency, differentiation potential and genomic integrity. This cell line, UCLi026-A (UCL-NG-ADCY5-001) can be utilized for in vitro disease modelling of ADCY5-related diseases, as well as for the development of novel therapeutic approaches.
proteins
2026-07-16 | Laryngeal dystonia: a comprehensive review of aetiology, clinical presentation, diagnosis, and treatment approaches.
Laryngeal dystonia (LD), also known as spasmodic dysphonia, is a rare voice production pathology manifested as focal muscle dystonia. The aim of this review is to synthesize current evidence on its aetiology, clinical presentation, diagnostic approach, and available treatment options, while identifying existing knowledge gaps to guide clinical decision-making and future research. A structured literature review was conducted using peer-reviewed articles from medical databases (e.g., PubMed, Google Scholars). Inclusion criteria comprised studies published in English within the last 20 years, focusing on LD aetiology, clinical features, diagnosis, or treatment. Both observational studies and clinical trials were included. Exclusion criteria involved case reports with limited applicability, non-English publications, and studies lacking clear diagnostic criteria or therapeutic outcomes. Primarily an idiopathic disorder, there is evidence suggesting a neurogenic origin involving basal ganglia dysfunction in LD. Clinically, LD manifests as task-specific voice disturbances, affecting most commonly the adductor muscles (strained voice) or the abductor muscles (breathy voice). Diagnosis is mainly clinical, but supported by laryngoscopic findings and other multidisciplinary evaluation. The gold standard treatment remains botulinum toxin injection, providing symptomatic relief, while voice therapy and, in selected cases, surgical interventions offer adjunctive benefits. LD is a neurological voice disorder which requires a high index of suspicion for diagnosis. Individualized treatment, particularly with botulinum toxin, and early recognition, significantly improve patient outcomes. Further research is needed to clarify pathophysiological mechanisms and optimize long-term management strategies.
2026-06-25 | Botulinum Toxin Treatment for Uncommon Phenotypes of Laryngeal Adductor Breathing Dystonia.
Laryngeal adductor breathing dystonia (LABD) is a rare form of focal, task-specific respiratory dystonia affecting the laryngeal muscles of unknown aetiology. Unlike classical laryngeal dystonia (spasmodic dysphonia), LABD is not primarily characterised by impaired speech, but rather by dysfunction of respiratory laryngeal control. The hallmark pathophysiological alteration consists of involuntary, action-induced adductor spasms of the laryngeal muscles during respiration, particularly during inspiration. LABD must be distinguished from inducible laryngeal obstruction (ILO), a broader, heterogeneous condition encompassing episodic, stimulus-triggered supraglottic or glottic closure, associated with asthma, reflux, or psychological triggers, that is generally not task-specific and lacks the neurological substrate characteristic of dystonia. In contrast, LABD is a persistent, effort-dependent, neurologically driven dystonia, demonstrable by paradoxical adductor spasms on fibreoptic laryngoscopy during normal inspiration and confirmed electromyographically by paradoxical thyroarytenoid muscle activation instead of the expected inspiratory relaxation. Traditional treatments, including respiratory retraining, speech therapy, biofeedback, psychotherapy, benzodiazepines, dopamine-blocking agents, and anticholinergic drugs, have proved largely ineffective. Tracheostomy may be required in cases of severe respiratory compromise. Botulinum toxin type A (BoNT/A) injections have been reported to successfully reduce inspiratory stridor in selected patients. Here, we present three cases of LABD displaying distinct phenotypes, in which typical features were associated with involvement of extra-laryngeal cranial districts, further expanding the known phenotypic spectrum of this condition.
2026-04-06 | A plastic surgery approach to Meige syndrome: Botulinum toxin for rebalancing facial dystonia and aesthetics - A case report.
Meige syndrome is a rare segmental dystonia characterized by blepharospasm and oromandibular dystonia, often leading to significant functional and aesthetic impairment. This report details a 59-year-old female patient with a 16-year history whose symptoms were refractory to prior drug therapies. An individualized botulinum toxin type A (BTX-A) injection protocol was devised based on detailed facial muscle mapping and plastic surgery principles of muscle balance. Following treatment, the patient showed marked improvement in facial spasms within 1 week, with resolution of nocturnal headaches and notable correction of aesthetic concerns arising from dystonia, including facial asymmetry and the involuntary "gummy smile". The gingival exposure during dystonic contraction was reduced from >4 mm (classified as severe gingival smile) to 1 mm. Social and eating functions were restored. This case suggests that a BTX-A treatment strategy guided by plastic surgery principles, which addresses both functional symptoms and aesthetic disharmony, may provide an effective and safe office-based treatment option for Meige syndrome. Further studies with larger cohorts are warranted to validate this protocol.
2026-02-02 | Assessing the effects of botulinum toxin therapy for spasmodic dysphonia: An Austria-Germany registry.
Injection of Botulinum neurotoxin (BoNT) is regarded as standard treatment for spasmodic dysphonia (SD), reducing the overactivity of the affected muscles. Due to the lack of standardized outcome parameters for diagnosing SD or assessing its treatment over time, the evaluation of systematic clinical evidence on the effects of BoNT therapy on SD symptom control is difficult. The registry presented in this article aimed to evaluate outcomes after BoNT treatment in SD patients in Austria and Germany, based on selected subjective and objective voice parameters. 41 patients with SD were included in this multicentric registry, after drop-out of 2 patients the results of 39/41 (95.1%) patients could be analyzed per protocol. Demographic and treatment characteristics as well as the occurrence of therapy-related side effects were recorded. Perceptual voice sound evaluation (RBH scale), voice range profile measurements (VRP), number of spasms, and severity of voice strain were assessed. Patients were asked to complete the Voice Handicap Index (VHI-9i), the Communicative Participation Item Bank (CPIB), and indicate their perceived phonation effort on a VAS scale. The parameters were compared between baseline and 1-month post-BoNT treatment. The patients received all BoNT type A (Xeomin®/Merz, Allergan®/Allergan or Dysport®/Ipsen). SD symptoms did not affect the frequency or dynamic range of the singing voice nor did they affect MPT; in contrast all the other parameters assessed were aberrant at baseline. BoNT treatment improved Jitter-%, Dysphonia Severity Index (DSI), degrees of roughness and hoarseness, but failed to restore them to normal. BoNT significantly reduced the voice spasm and strain. Phonation effort improved by approximately 50%. VHI-9i classification was reduced from moderate to mild after treatment, and CPIB from moderate to mild. The VHI-9i results were significantly positively correlated with the CPIB results. The results of this registry showed that BoNT injection, the current off-label treatment of SD symptoms, failed to restore normal voice quality. This registry's outcomes also indicate that the choice of the applied BoNT brand is site-specific and does not appear to be associated with differences in efficacy. We also showed that the effects of the BoNT on the SD symptoms are best described by semi-quantitative outcome measures such as spasm counts and voice strain, and by patients-reported outcome measures (PROMs), such as CPIB and VHI-9i than by more objective parameters such as frequency and dynamic range of the singing voice.
2026-02-02 | Adductor Respiratory Laryngeal Dystonia (Dystonic Respiratory Stridor): Clinical Characterization and Response to Botulinum Toxin Therapy: A Single Centre Experience.
Adductor respiratory laryngeal dystonia (ARLD) is a rare focal dystonia with vocal fold closure during inspiration leading to stridor and dyspnoea. To characterize clinical features and outcomes of patients with ARLD at a tertiary movement disorders center. A retrospective cohort study was conducted of patients with adductor respiratory laryngeal dystonia attending a botulinum toxin injection clinic. Nineteen patients were identified. Most were female (94.7%). Mean age of onset was 51.9 years (range 39-89). Comorbid movement disorders included laryngeal dystonia, cervical dystonia, blepharospasm, dystonic tremor, and Parkinson's disease. Median time from symptom onset to diagnosis was 3.0 years (IQR 2.0-15.0). 92.8% of injections with botulinum toxin were effective, although 46.2% were associated with adverse events. ARLD is associated with diagnostic delay. Symptoms of stridor alongside other movement disorders may provide clues. Treatment with botulinum toxin is effective, though careful dosing is required.
small molecules
2026-07-21 | Isolated Lingual Dystonia: A Rare Tardive Manifestation of Amisulpride
Aims: To describe a rare case of isolated lingual tardive dyskinesia associated with prolonged low-dose amisulpride therapy and to emphasise the importance of early recognition and treatment. Presentation of Case: A 72-year-old woman with bipolar I disorder developed progressive dysarthria, dysphagia, and involuntary choreiform tongue movements after approximately 13 months of amisulpride therapy, initiated at 50 mg/day and titrated to 150 mg/day. Neurological examination showed continuous lingual movements with intermittent dystonic posturing, without limb involvement or other focal neurological abnormalities. Brain magnetic resonance imaging demonstrated only mild age-related cerebral atrophy, and routine laboratory investigations were within normal limits. Alternative structural, metabolic, seizure-related, and neurodegenerative causes were considered and excluded clinically. The Naranjo score was 6, and the WHO-UMC assessment classified the reaction as probable/likely. Amisulpride was discontinued, and tetrabenazine was initiated at 12.5 mg each morning and 25 mg each night. After six weeks, tongue movements and speech improved markedly, permitting dose reduction to 12.5 mg twice daily. Psychiatric stability was maintained with clozapine and sodium valproate/valproic acid. Discussion: The delayed onset, temporal relationship to prolonged dopamine receptor blockade, absence of an alternative cause, and improvement after withdrawal supported a tardive drug-induced movement disorder. Conclusion: Isolated lingual dystonia may occur during long-term low-dose amisulpride therapy. Regular movement assessment and prompt treatment modification may reduce functional impairment.
2026-07-09 | Relative Efficacy of Self-Managed Caffeine Supplementation in Maintaining Daily Activity in a Patient with ADCY5-Related Dyskinesia: A Case Report.
ADCY5-related dyskinesia is an autosomal dominant movement disorder with limited treatment options because many standard medications are ineffective. Caffeine has shown efficacy in ADCY5-related dyskinesia as an adenosine A2A receptor antagonist, but optimal dosing remains uncertain. We report a 24-year-old woman with paroxysmal dyskinesia since early childhood, consisting of chorea, dystonia, and myoclonus upon waking. More than 15 medications failed. Whole-exome sequencing identified a mosaic ADCY5 variant (p.R418Q, 7% variant allele frequency). Caffeine escalation from 100 to 600 mg worsened symptoms. Four months later, she found that unsweetened canned coffee containing approximately 100 mg of caffeine per can, taken 1-3 times daily, reduced her symptoms and helped her maintain daily employment. In a self-controlled analysis of 39 coffee-intake events, dyskinesia episodes during the 6 h after coffee intake were significantly fewer than during the preceding 6 h (p = 0.002). This case demonstrates successful symptom control in ADCY5-related dyskinesia using patient-directed, low-dose caffeine therapy. The striking response suggests a narrow therapeutic window for caffeine in this condition and that patient self-titration may be valuable in optimizing treatment response.
2026-07-02 | Central precocious puberty as the initial manifestation of multisystem involvement caused by de novo heterozygous KMT2B mutation and STS hemizygous deletion: a case report.
Pathogenic loss-of-function variants in the KMT2B gene cause a rare autosomal dominant disorder with two major phenotypes: KMT2B-related dystonia (DYT-KMT2B) and KMT2B-related neurodevelopmental disorder (KMT2B-NDD). Central precocious puberty (CPP) has been documented as a comorbidity in patients with DYT-KMT2B, but has not been reported as the primary clinical manifestation of the disorder in patients without dystonia. Deletions or pathogenic variants in the STS gene cause X-linked ichthyosis (XLI). Concurrent KMT2B and STS alterations have not been well characterised, and GnRH analogue therapy for CPP in KMT2B-related disorders has not been previously described. An 8-year-10-month-old male presented with a 1-2-year history of progressive increase in penile length and girth. Physical examination revealed distinctive craniofacial dysmorphism, classic ichthyotic scaling, pubertal changes consistent with precocious puberty, and normal muscle tone without dystonic features. Biochemical testing confirmed markedly elevated serum total testosterone, a positive gonadotropin-releasing hormone (GnRH) stimulation test consistent with CPP, and bone age advanced by 1.2 years relative to chronological age. Neurocognitive assessment identified mild intellectual disability. Family-based whole-exome sequencing and copy number variation (CNV) analysis identified a de novo heterozygous pathogenic nonsense variant in KMT2B (NM_014727.3: c.4213del, p.Leu1405Ter) and a hemizygous pathogenic full-coding deletion of STS. The patient was treated with leuprorelin acetate for CPP and topical emollients for XLI. At 3-month follow-up, physical signs of puberty remained stable. GnRHa stimulation test showed indicating but incomplete suppression of the hypothalamic-pituitary-gonadal axis. The ichthyotic skin lesions improved markedly with topical therapy. The leuprorelin acetate dose was subsequently increased. The patient is continuing on the current regimen with close monitoring. Precocious puberty has been reported in eleven patients with KMT2B-related dystonia. This case documents the co-occurrence of a KMT2B-related disorder and XLI in a patient, and provides documentation of GnRH analogue therapy and structured endocrine follow-up for CPP in this population. KMT2B haploinsufficiency may contribute to premature activation of the hypothalamic-pituitary-gonadal axis through disruption of ERα-mediated transcriptional regulation and altered epigenetic programming at key hypothalamic developmental genes. Clinically, children with KMT2B-related disorders should undergo comprehensive endocrine assessment to facilitate early diagnosis and timely intervention.
2026-05-14 | Diagnosis and pathogenesis of dystonia: clinical heterogeneity, shared mechanisms, and neurodevelopmental origins.
The diagnosis of dystonia is often delayed because of its many different clinical manifestations and causes. Updates to the definition and classification of dystonia can assist clinicians in improving its recognition and timely diagnosis. Dystonia is characterised by sustained or intermittent abnormal movements, postures, or both. Patterned phenomenology, alleviating manoeuvres, worsening by voluntary movement, and overflow to adjacent muscles are all clinical clues of the condition. Additional non-motor manifestations are part of the clinical spectrum. In parallel to the broad heterogeneity of clinical manifestations among different types of dystonia, the biological mechanisms underlying the condition are also heterogeneous. Among these mechanisms, an alteration of the sensorimotor circuits during crucial windows of development might have a role in many forms of dystonia. Advances in the understanding of its pathogenesis indicate that targeting shared mechanisms could provide a treatment approach for multiple types of dystonia, but also suggest the possibility of personalised therapeutic approaches.
2026-05-06 | Multidisciplinary perinatal management of paroxysmal kinesigenic dyskinesia in pregnancy: a case report and a proposed structured pathway.
Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by brief dystonic or dyskinetic attacks precipitated by sudden voluntary movement or arousal. Pregnancy complicated by PKD is extremely rare, and evidence guiding perinatal decision-making, especially regarding delivery mode and anesthetic management remains scarce. We report a term pregnancy in a woman with long-standing PKD managed through a multidisciplinary team involving neurology, obstetrics, anesthesiology, and neonatology. Following individualized optimization of antiseizure medications (ASMs) and intensive antenatal surveillance, the patient showed moderate symptomatic improvement during pregnancy. Given the high risk of pain, stress, or movement-triggered dystonic attacks with transient loss of voluntary motor control during labor, elective cesarean delivery was planned. Combined spinal-epidural anesthesia (CSEA) was performed to provide effective analgesia while minimizing arousal and sensory triggers. The procedure was uneventful, with no perioperative dystonic episodes. A healthy neonate was delivered with no congenital anomalies. This case demonstrates that favorable maternal and neonatal outcomes can be achieved in pregnancies complicated by PKD through individualized antiseizure medication management, multidisciplinary care, and trigger-oriented perinatal planning. The structured clinical decision-making pathway proposed in this study may provide a practical framework for managing this rare and challenging condition.
gene therapies
2025-06-20 | Pediatric Genetic Dystonias: Current Diagnostic Approaches and Treatment Options
Genetic dystonias are a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions that cause repetitive movements and abnormal postures. Often beginning in childhood, they can significantly affect quality of life. Although individually rare, genetic causes are collectively relevant in pediatric dystonias, with over 250 associated genes. Among these, TOR1A, SGCE, and KMT2B are the most frequently reported in pediatric forms. Diagnosis is challenging due to the wide clinical and genetic variability. Recent advances in genetic testing, including whole-exome and whole-genome sequencing, have improved the early identification of causative variants. Functional data on selected mutations are helping to refine genotype–phenotype correlations. Management typically requires a multidisciplinary approach. Symptomatic treatments include anticholinergics, benzodiazepines, and botulinum toxin, while deep brain stimulation can be effective in refractory cases, especially in patients with TOR1A variants. Disease-modifying therapies are also emerging, such as gene therapy for AADC deficiency, highlighting the potential of precision medicine. This review provides an updated overview of pediatric genetic dystonias, with a focus on differential diagnosis and treatment strategies. Early and accurate diagnosis, together with personalized care, is key to improving outcomes in affected children.
2025-02-21 | AAV-Mediated Gene Transfer of WDR45 Corrects Neurological Deficits in the Mouse Model of Beta-Propeller Protein-Associated Neurodegeneration.
Beta-propeller protein-associated neurodegeneration (BPAN) is an ultra-rare, X-linked dominant, neurodevelopmental, and neurodegenerative disease caused by loss-of-function mutations in the WDR45 gene. It manifests in neurodevelopmental delay and seizures followed by secondary neurological decline with dystonia/parkinsonism and dementia in adolescence and early adulthood and is characterized by progressive accumulation of iron in the basal ganglia. WDR45 encodes β-propeller-shaped scaffold protein, or WD repeat domain phosphoinositide-interacting protein 4 (WIPI4), which plays an important role in autophagosome formation. While the mechanisms of how WIPI4 loss of function results in neurological decline and brain pathology have not yet been established, findings of lower autophagic activity provide a direct link between impaired autophagy and neurological disease in BPAN. Here we performed phenotypical characterization of a novel mouse model of BPAN, Wdr45_ex9+1g>a mouse. We identified hyperactive behavior and reduction of autophagy markers in brain tissue in Wdr45_ex9+1g>a hemizygous males as early as at 2 months of age. Given the early onset and spectrum of neurological symptoms such as hyper-arousal and attention deficits in human patients, this model presents a disease-relevant phenotype and can be used in preclinical studies. We used this mouse model for a proof-of-concept study to evaluate whether adeno-associated virus (AAV)-mediated central nervous system (CNS)-targeted gene transfer of WDR45 can provide therapeutic benefit and be considered a therapeutic paradigm for BPAN. We observed successful expression of human WDR45 transcripts and WIPI4 protein in the brain tissue, rescue of hyperactive behavior, and correction of autophagy markers. These data demonstrate that WDR45 gene transfer can be a promising therapeutic strategy for BPAN.
2025-01-31 | Clinical case of a patient with AADC deficiency of L-aromatic amino acid decarboxylase: diagnostic route and therapeutic options
L-aromatic amino acid decarboxylase deficiency (AADC) is a rare autosomal recessive neurometabolic disease characterized by impaired biosynthesis of neurotransmitters and manifested by disorders of movement and autonomic regulation. In the article there is discussed the diagnostic path and treatment options for a 7-year patient with severe AADC deficiency. Combination of severe neurological disorders (muscular hypotension, dystonia, hyperkinesis, oculogyric crises) and autonomic disorders (increased sweating, hypersalivation, thermoregulation disorders, nasal congestion, dyspepsia, etc.) is clearly demonstrated to require the detection of 3-O-methyldopa in dried blood spots to exclude AADC deficiency. Given the emergence of gene therapy, which is available to patients with a confirmed diagnosis of AADC deficiency in Russia within the criteria of the Circle of Kindness Foundation, it is necessary to popularize information about L-aromatic amino acid decarboxylase deficiency in the general medical community, to improve the prognosis and quality of life in AADC patients.
2024-07-18 | AAV9-Mediated Intrastriatal Delivery of GNAO1 Reduces Hyperlocomotion in Gnao1 Heterozygous R209H Mutant Mice.
Mutations in the GNAO1 gene, which encodes the abundant brain G-protein Gα o, result in neurologic disorders characterized by developmental delay, epilepsy, and movement abnormalities. There are over 50 mutant alleles associated with GNAO1 disorders; the R209H mutation results in dystonia, choreoathetosis, and developmental delay without seizures. Mice heterozygous for the human mutant allele (Gnao1 +/R209H) exhibit hyperactivity in open field tests but no seizures. We developed self-complementary adeno-associated virus serotype 9 (scAAV9) vectors expressing two splice variants of human GNAO1 Gα o isoforms 1 (GoA, GNAO1.1) and 2 (GoB, GNAO1.2). Bilateral intrastriatal injections of either scAAV9-GNAO1.1 or scAAV9-GNAO1.2 significantly reversed mutation-associated hyperactivity in open field tests. GNAO1 overexpression did not increase seizure susceptibility, a potential side effect of GNAO1 vector treatment. This represents the first report of successful preclinical gene therapy for GNAO1 encephalopathy applied in vivo. Further studies are needed to uncover the molecular mechanism that results in behavior improvements after scAAV9-mediated Gα o expression and to refine the vector design. SIGNIFICANCE STATEMENT: GNAO1 mutations cause a spectrum of developmental, epilepsy, and movement disorders. Here we show that intrastriatal delivery of scAAV9-GNAO1 to express the wild-type Gα o protein reduces the hyperactivity of the Gnao1 +/R209H mouse model, which carries one of the most common movement disorder-associated mutations. This is the first report of a gene therapy for GNAO1 encephalopathy applied in vivo on a patient-allele model.
2024-03-06 | Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-Responsive Basal Ganglia disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene
Abstract The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is a neurological disorder characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease's rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. Despite the lack of knowledge related to genotype-phenotype correlations, the derivation of BTBGD-iPSC lines carrying a homozygous mutation in SLC19A3 constitutes a unique cell model to examine the molecular mechanisms underlying the cellular dysfunctions caused by SLC19A3 pathogenic variant and could promote the development of novel therapeutic agents.
oligonucleotides
2026-05-06 | Correction of the molecular phenotype of X-linked Dystonia-Parkinsonism reveals a non-canonical function of BRD4.
Transcription and mRNA processing are tightly coupled regulatory layers on gene expression, and their perturbations underly human disorders. X-linked Dystonia-Parkinsonism (XDP) is a unique example of a human disease connecting aberrant mRNA processing and the basal transcription machinery. XDP is a rare, monogenic fatal neurodegenerative disorder, and a limited understanding of the underlying molecular mechanisms hinders the development of effective therapies. In this study, we show that depletion of BRD4, a chromatin reader known for its role in transcriptional pausing, rescues the XDP molecular signature. Unexpectedly, this effect is independent of the canonical coactivator role of BRD4. We demonstrate that the XDP-SVA induces intronic premature cleavage and polyadenylation within the TAF1 locus, and that BRD4 depletion bypasses this premature termination checkpoint. These findings reveal new dimensions of BRD4 activity beyond transcription pause release and suggest modulation of mRNA processing as a therapeutic strategy for XDP.
2026-01-22 | Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy.
Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A (TUBB4A). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series (Tubb4aKO/KO, Tubb4aD249N/+, Tubb4aD249N/KO, and Tubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of wild-type tubulin. To further evaluate the translational potential of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a. Notably, single intracerebroventricular administration of ASO in postnatal Tubb4aD249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, treating ASO Tubb4aD249N/KO mice prevents myelin and oligodendrocyte (OL) loss and recovers visual evoked potential latencies in vivo. Furthermore, the microtubule function of Mbp mRNA transport from the OL soma to the myelin sheath is retained. A major limitation we noted is that ASOs fail to target cerebellar granule neurons even with multiple routes of administration in the brain. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.
2025-11-24 | Therapeutic targeting of alternative splicing caused by a lethal noncoding structural variant in X-linked dystonia parkinsonism.
X-linked Dystonia-Parkinsonism (XDP) is a lethal adult-onset neurodegenerative disorder that exhibits features of dystonia and parkinsonism and is exclusively associated with a causal founder haplotype that is indigenous to the Philippines and affects Filipino males. Using patient-specific fibroblasts, neural stem cells (NSC), and other neuronal models, we discovered that cryptic alternative splicing caused by a novel SINE-VNTR-Alu (SVA) mobile element insertion into intron 32 of TAF1 is a mechanistic hallmark of XDP. We leveraged postmortem brain samples from an XDP-specific brain bank to demonstrate that the molecular hallmarks of XDP observed in neural stem cells (NSCs) mirror abnormalities observed in brain tissues from affected patients. Based on these findings that patient-specific NSCs reproduce mechanistic signatures found in the brain, we sought to develop a bespoke precision therapeutic for XDP and evaluate its relative efficacy in ameliorating transcriptomic signatures in neuronal models. We first used CRISPR-based excision of the SVA and demonstrated ablation of all aberrant splicing and dysregulation of TAF1 expression in NSCs across 30 independent clones. CRISPR-based correction of the XDP haplotype also restored the expression of 424 of 1,490 (30%) differentially expressed genes (DEGs) that were altered in XDP patient lines and greatly exceeded what would be expected by chance (p-value = 9.89e-87). While in vivo delivery of a gold standard CRISPR therapy is currently not feasible for XDP, we evaluated a tractable approach for Filipino patients by exploring the potential to modulate alternative splicing in XDP patients using antisense oligonucleotides (ASOs). To accomplish this, we developed a large-scale and well controlled functional genomics platform that screened eighty ASOs targeting intron 32 of XDP patients, followed by prioritization of lead ASOs based on attenuation of the alternative splicing signature. In transcriptome analyses across 1,550 libraries, we found that 8 of the 12 lead ASOs ameliorated the targeted XDP aberrant splicing. Moreover, we found that the two lead ASOs exhibited 38% and 43% rescue of XDP-specific DEGs that were also rescued by CRISPR excision of the SVA (enrichment p-values = 2.06e-13 and 2.27e-05, respectively). These rescues represented restoration of key molecular functions previously implicated in XDP, such as synaptic function, DNA-binding transcription factor activity, and gliogenesis. This study highlights a path to a potential targeted therapeutic for XDP and the capacity to exploit functional genomic signatures in patient-derived neural models to develop a scalable precision therapeutic platform for rare genetic disorders.
2025-02-12 | Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia.
Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations. By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays. This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia.
2025-02-03 | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.
GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in GNAO1, as a spectrum of neurological phenotypes, including epileptic encephalopathy, developmental delay with movement disorders, or late-onset dystonia. There are currently no effective treatments available, apart from symptomatic options. In this work, we suggest harnessing personalized RNA therapy to treat GNAO1 patients and focus specifically on a recurrent pathogenic variant (E246K). We systemically screened allele-specific antisense oligonucleotides (ASOs) targeting the mutated allele to identify a potent and specific sequence using both reporter-based platforms and a patient-derived cellular model. We show that reduction of mutated GNAO1 in vitro by knockout or by ASO has a beneficial functional outcome, which can be measured by cAMP accumulation and gene expression changes. We established a Gnao1-E246K mouse model that shows a neurological phenotype, which partially recapitulates the human condition. Due to sequence similarity, the mouse can be treated with the selected ASO to test treatment efficacy in animal models, as shown in vitro using murine neural progenitor cells. Our results demonstrate a beneficial effect for the reduction of mutated GNAO1 by ASO in patient-derived models, demonstrating its feasibility as a therapeutic approach.
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2026-06-26 | Clinical and Genetic Spectrum of ANO3-Related Dystonia with Treatment Responses in a Chinese Cohort.
Background: Variants in anoctamin 3 (ANO3) are linked to autosomal dominant dystonia, commonly known as DYT-ANO3 (OMIM: #615034). While craniocervical dystonia constitutes the most frequently observed phenotype, its clinical manifestations display significant heterogeneity. Nevertheless, the data concerning the genetic characteristics, clinical features, and therapeutic outcomes of ANO3-related dystonia within Asian populations remain scarce. Methods: Whole-exome sequencing was conducted on 661 Chinese patients, comprising 356 individuals with dystonia and 305 individuals with non-dystonic movement disorders who served as an internal disease-control cohort. Candidate ANO3 variants were evaluated based on population frequency, predicted deleteriousness, ACMG criteria, and aggregate frequency analyses. A retrospective review was performed of clinical features and treatment responses. Results: Fifteen rare ANO3 missense variants were identified in 16 patients with dystonia and one non-dystonic individual, including one pathogenic variant, six likely pathogenic variants, and nine previously unreported variants. The rare ANO3 variants were significantly enriched in the dystonia cohort compared with the controls. ANO3-related dystonia exhibited broad clinical heterogeneity, with frequent cervical involvement (62.5%) and tremulous features (75%), and occasionally extended beyond classical isolated dystonia. Oral medication and botulinum toxin showed variable benefit, whereas deep brain stimulation was associated with marked improvement in selected medically refractory patients. Conclusions: This study broadens the genetic and clinical spectrum of ANO3-related movement disorders in a Chinese cohort. The findings support substantial clinical heterogeneity in DYT-ANO3 and suggest that deep brain stimulation, especially STN-DBS, may be considered in selected refractory cases, although further studies are needed.
2026-04-27 | Phage display enabled the identification of single-domain nanobody antitoxins against botulinum neurotoxin serotype C.
Botulinum neurotoxin serotype C (BoNT/C) exhibits therapeutic efficacy and duration of action comparable to those of BoNT/A. It has been demonstrated to effectively manage movement disorders such as dystonia and blepharospasm, making it a highly promising alternative to BoNT/A. BoNT/C is also one of the primary etiological botulinum isoforms causing animal botulism and may pose a zoonotic risk. So, it is of great need to develop antidote that can treat human iatrogenic, foodborne and animal botulism caused by BoNT/C. Currently, the approved botulism antidotes primarily are polyvalent horse serum antitoxins, which are severely limited due to insufficient supply and adverse reactions. In this study, we developed a high-affinity nanobody A2, a variable domain of a heavy-chain antibody (VHH) against BoNT/C, based on phage display library screening. Our results demonstrated that A2 effectively blocked the binding of BoNT/C to its target cell. Furthermore, A2 exhibited potent neutralizing activity and rescued BoNT/C-intoxicated mice. These findings supported nanobody A2 as a promising antitoxin candidate with therapeutic efficacy against botulism.
2025-05-18 | Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice.
Pathogenic variants in the neuronal Na+/K+ ATPase transmembrane ion transporter (ATP1A3) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common de novo pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the Atp1a3 gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.
2025-02-08 | Generation of an induced pluripotent stem cell line (UCLi026-A) from a patient with ADCY5-related disease carrying the heterozygous variant c.1253G > A; (p. Arg418Gln).
Adenylyl cyclase 5 (ADCY5)-related diseases are a rare group of genetic disorders that commonly present in childhood. Heterozygous mutations in ADCY5 lead to ADCY5-related dyskinesia, comprising a wide array of disabling hyperkinetic movement disorders including chorea, myoclonus and/or dystonia. We generated an induced pluripotent stem cell line from the fibroblasts of an affected patient with the common heterozygous pathogenic variant, c.1253G > A (p.Arg418Gln). This line was further characterised for pluripotency, differentiation potential and genomic integrity. This cell line, UCLi026-A (UCL-NG-ADCY5-001) can be utilized for in vitro disease modelling of ADCY5-related diseases, as well as for the development of novel therapeutic approaches.
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Drug Discovery Landscape
1 orphan drug designation for Rare dystonia.
1 orphan drug designation for Rare dystonia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
baclofen | small molecules | FDA | 2003-12-02 | — | Medtronic Neurological |
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