Search Results (174)

Background/Objectives: Dystonia, traditionally regarded as a purely motor disorder, is now increasingly recognized as involving clinically significant non-motor symptoms (NMSs) that can adversely affect patients’ health-related quality of life (HRQoL). This study aimed to assess HRQoL in Romanian patients with isolated dystonia and to evaluate the impact of two key NMSs, depression and cognitive impairment, on their HRQoL. We hypothesized that depression would have a greater adverse effect on HRQoL than cognitive impairment. Methods: A cross-sectional study was conducted involving 65 adult Romanian patients with isolated dystonia. HRQoL was measured using the Short Form-36 Health Survey (SF-36), including the physical component summary (PCS) and mental component summary (MCS). Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), and cognitive impairment was assessed using the Montreal Cognitive Assessment (MoCA). Descriptive statistics, correlation analysis, and parametric and non-parametric tests were used. Multiple regression analysis was employed to evaluate associations between NMS and HRQoL. Results: The mean (SD) age was 56.6 (14.3) years, and 80% of participants were female. Depression and cognitive function were significantly associated with PCS (0.33 and −0.51, respectively) and MCS (0.26 and −0.78, respectively). Multiple regression analysis showed that the two NMS explained 38% of the variance in PCS and 58% of the variance in MCS. Depression had a greater impact on PCS and MCS than cognitive impairment (−0.47 vs. 0.33 and −0.72 vs. 0.16, respectively). Cognitive impairment (MoCA < 26) was present in 35.4% of patients, while 46.2% had at least mild depressive symptoms (PHQ-9 ≥ 5); 23.1% met criteria for moderate-to-severe depression (PHQ-9 ≥ 10). Depressive symptoms showed strong negative correlations with all SF-36 domains, while cognitive performance correlated modestly. Conclusions: Both depression and cognitive impairment have a significant negative impact on HRQoL in dystonia, with depression having a stronger effect, as we hypothesized. Routine screening for non-motor symptoms is essential to support better clinical outcomes and enhance patients’ quality of life. Full article

Over the past decade, substantial progress has been made in understanding the pathophysiology of dystonia. The number of identified genes has surged—exceeding 400 by 2024—with approximately 76.6% linked to neurodevelopmental disorders. Despite this, the genetic diagnostic yield remains modest (12–36%), and many newly discovered genes have yet to reveal novel mechanistic insights. The limited number of studies exploring dystonia-related pathways in animal models restricts the generalizability of findings to human disease, raising concerns about their external validity. Developing experimental models remains a challenge, particularly given the importance of critical developmental windows—periods during central nervous system maturation when disruptions can have lasting effects. Some models also exhibit delayed symptom onset, prompting a shift toward faster-developing organisms such as Drosophila. There is a pressing need for standardized, scalable protocols that enable precise evaluation of specific neural tissues. Advances in neuroimaging have improved our understanding of dystonia-related brain networks at both regional and whole-brain levels. The emerging concept of “network kernels” has provided new perspectives on brain connectivity. However, future imaging studies should incorporate effective connectivity analyses to distinguish between hemodynamic and neuronal contributions and to clarify neurobiological pathways. This review synthesizes current knowledge from genetics, animal models, and neuroimaging to present an integrated view of dystonia’s neurobiological underpinnings. Full article

Kernicterus spectrum disorder is the permanent and highly disabling neurologic sequel of neonatal exposure to hyperbilirubinemia, presenting, among other symptoms, variable and untreatable motor disabilities. To search for potential biomolecular explanations, we used a Gunn rat colony exhibiting spontaneous hyperbilirubinemia and a large variability of motor deficits on a beam-walking test. Histological and microscopic analyses confirmed worsening damage in the cerebellum (Cll; hypoplasia, increased death of neurons, and disrupted astroglial structures) and parietal motor cortex (hCtx; increased cell sufferance and astrogliosis). Clustering and network analyses of transcriptomic data reveal rearrangement of the physiological expression patterns and signaling pathways associated with bilirubin neurotoxicity. Bilirubin content among hyperbilirubinemic (jj) animals is overlapped, which suggests that the amount of bilirubin challenge does not fully explain the tissue, transcriptomic, proteomic, and neurobehavioral alterations. The expression of nine genes involved in key postnatal brain development processes is permanently altered in a phenotype-dependent manner. Among them, Grm1, a metabotropic glutamatergic receptor involved in glutamate neurotoxicity, is consistently downregulated in both brain regions both at the transcriptomic and proteomic levels. Our results support the role of Grm1 and glutamate as biomolecular markers of ongoing bilirubin neurotoxicity, suggesting the possibility to improve diagnosis by ¹H-MR spectroscopy. Full article

Rare genetic movement disorders usually manifest early in life with dystonia, parkinsonism, chorea, or a combination thereof. These are often associated with neurodevelopmental delay, intellectual disability, speech problems, retinal abnormalities, seizures, ataxia, spasticity, or systemic features. Due to their vast number and pheno–genotypic heterogeneity, the diagnosis of these disorders can be challenging. However, recognising their core motor phenomenology as well as clinical, laboratory, and neuroradiological clues can expedite appropriate diagnostic workup, molecular diagnosis, and adequate treatment. In this review, we outline diagnostic clues to rare movement disorders (RMDs), focusing on those that present mainly with dystonia, parkinsonism, or paroxysmal dyskinesia due to genetic causes. Additionally, we provide a decision tree approach linking clinical, genetic, and imaging testing. Finally, we highlight selected RMDs that should not be missed, as they possess established treatments that can hinder their progression, prevent irreversible or life-threatening sequelae and, in certain cases, lead to complete symptom remission. Full article

Botulinum toxin is a neurotoxin that is used in the treatments for several medical conditions, such as dystonia, spasticity, hemifacial spasm, overactive bladder, and hyperhidrosis. This toxin can potentially treat several pain disorders through botulinum toxin’s ability to inhibit the release of pro-nociceptive neurotransmitters into the synaptic cleft and its possible action on the central nervous system. This narrative review addresses the use of botulinum toxin in treating primary and secondary headaches and facial pain disorders. The highest level of evidence supporting its use varies among the headache and facial pain disorders: chronic migraine (multicenter, double-blind, placebo-controlled studies), trigeminal neuralgia (double-blind, placebo-controlled studies), post-traumatic headache (double-blind, placebo-controlled study), cluster headache (open-label clinical trials), nummular headache (open-label clinical trial), headache attributed to craniocervical dystonia (prospective cohort study), new daily persistent headache (retrospective cohort study), hemicrania continua, and SUNCT and SUNA (case reports). The site of toxin application and the doses used vary among the studies and depending on headache type. Botulinum toxin has been shown to be safe in different studies, with generally mild adverse reactions. Full article

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. Full article

Background: Cervical dystonia (CD) is a chronic neurological disorder characterized by involuntary neck muscle contractions, leading to abnormal head postures, pain, and functional impairment. Botulinum toxin type A (BoNT-A) remains the treatment of choice, but its efficacy is highly dependent on injection accuracy. Various techniques, including palpation-guided, ultrasound-guided, and electromyography-guided (EMG), have been developed to optimize delivery, each with distinct advantages and limitations. Methods: A systematic search of PubMed and Scopus was conducted up until 30 December 2024, using defined keywords related to BoNT-A, CD, and injection techniques. Studies were included if they reported clinical outcomes of BoNT-A injection methods in adult CD patients. Data on efficacy, safety, accuracy, and muscle targeting were extracted and synthesized. Results: Seven studies comprising 239 patients were included: two randomized controlled trials, one retrospective study, one cohort study, one systematic review, one literature review, and one cadaveric study. The most common CD subtype was torticollis/torticaput (49.79%). Frequently targeted muscles included the trapezius (56.9%), levator scapulae (51.7%), and splenius capitis (48.3%). Ultrasound guidance consistently demonstrated superior injection accuracy and reduced adverse effects due to real-time anatomical visualization. EMG-guided techniques showed advantages in identifying dystonic muscles, especially when anatomy was unclear. In contrast, palpation-guided injections were less accurate and suitable only for superficial muscles. Dosing varied by product, with mean doses of 117–118 units for onabotulinumtoxinA and incobotulinumtoxinA, and 405 units for abobotulinumtoxinA. Adverse events were generally mild, including local discomfort, dysphagia, and transient muscle weakness. Conclusions: Ultrasound- and EMG-guided injections enhance the precision, safety, and efficacy of BoNT-A therapy for CD compared to anatomy-guided techniques. While ultrasound guidance improves anatomical accuracy, EMG remains valuable for functionally identifying dystonic muscles. Integration of both may offer optimal outcomes. However, further high-quality, standardized trials are needed to definitively establish best practices. Full article

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum varies from a severe classic phenotype to a variant atypical form. Material and methods: This study included 28 patients belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole-exome sequencing was performed in seven affected individuals from two unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon–intron borders of the ATM gene. Results: Twenty-four of the affected individuals were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected individuals were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of the patients the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with a splicing effect, c.3576G>A, p.Lys1192. The age at onset in our group varied between 14 days and 40 years. The main symptoms were dystonia and tremor, more prominent in the upper limbs and the neck, and dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of the patients. Conclusion: Clinical features due to mutations in the ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated α fetoprotein. Full article

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders. Full article

The Movement Disorders Society recommends the DYT/PARK prefix for genes where dystonia and parkinsonism are prominent in approximately half or more of patients. This systematic review explores the genotype–phenotype correlations of GLB1, SLC6A3, SLC30A10, PLA2G6, and SLC39A14—recently classified as DYT SLC39A14 and historically linked to dystonia-parkinsonism. We searched PubMed and the Human Gene Mutation Database using standardized terms, including English-language, peer-reviewed publications up to February 2024. Following the MDSGene protocol, we extracted individual-level data on patients with biallelic pathogenic variants and at least one movement disorder. Features were marked “missing” if not explicitly reported. Of 1828 articles, 128 were eligible. We identified 386 patients and 262 variants. The median age at onset was 3 years for GLB1, 3 months for SLC6A3, 2.5 years for SLC30A10, 1.5 years for SLC39A14, and 16 years for PLA2G6. Missing data may reflect underreporting of negative findings. Case reports/serie, may bias toward atypical presentations. Our analysis showed dystonia-parkinsonism predominates in SLC6A3 and PLA2G6, while GLB1, SLC30A10, and SLC39A1 show predominantly dystonic phenotypes with a low frequency of parkinsonism. Ataxia was common in GLB1 and PLA2G6. Awareness of these phenotypes is essential for early diagnosis and intervention, particularly in treatable conditions like SLC30A10 or SLC39A14. The predominantly dystonic phenotype in GLB1, SLC30A10, and SLC39A14 suggest that the DYT prefix may be more appropriate, highlighting the need to reconsider their nomenclature, and the importance of systematic reviews. Full article

Background/Objectives: The introduction of dopamine transporter scan (DaTscan) in clinical diagnostics has revolutionized the way clinicians approach movement disorders, offering valuable insights into presynaptic striatal dopaminergic deficits and revealing subjacent neurodegeneration. The aim of our study was to evaluate the impact of DaTscan on diagnostic decisions regarding movement disorders, particularly Parkinson’s disease (PD) and atypical parkinsonian syndromes, under real-world circumstances in Greece. Methods: We retrospectively analyzed data from 360 patients who underwent a DaTscan examination between 2018 and 2023 at a tertiary hospital in Greece, including referrals from both movement disorder specialists and general neurologists, either hospital-based or in private practice. Demographics, primary referral symptoms, and both pre-scan and post-scan diagnoses were collected and analyzed. Results: The mean age in our cohort was 60 ± 13.5 years, and tremor was the leading referral symptom (40.8%). The initial diagnosis changed in nearly half of the cases (48.3%) following DaTscan. Significant shifts included transitions from an “Unclear” or “Dystonia” diagnosis to “Parkinson’s disease” in 78.1% and 72.7% of patients, respectively. However, the particularly high concordance rates between pre-scan and post-scan diagnosis for “Vascular parkinsonism” (100%), “Parkinson’s disease” (89.3%), and “Essential/Dystonic Tremor” (86%) suggest that the test may have been over-utilized or ordered beyond its intended indications. Conclusions: DaTscan markedly enhances diagnostic accuracy for movement disorders, particularly for general neurologists, addressing the complexities of overlapping clinical presentations. Continuous medical training is essential to ensure the cost-effective utilization of DaTscan in routine clinical practice; ongoing technological advancements will further refine and expand their applications, benefiting both patients and the broader medical community. Full article

Manganese (Mn) is an essential trace element and a cofactor for several key enzymes, such as mitochondrial superoxide dismutase. Consequently, it plays an important defense role against reactive oxygen species. Despite this, Mn chronic overexposure can result in a neurological disorder referred to as manganism, which shares some similarities with Parkinson’s disease. Mn levels seem regulated by many transporters responsible for its uptake and efflux. These transporters play an established role in many inherited disorders of Mn metabolism and neurotoxicity. Some inherited Mn metabolism disorders, caused by mutations of SLC30A10 and SLC39A14, assume crucial importance since earlier treatment results in a better prognosis. Physicians should be familiar with the clinical presentation of these disorders as the underlying cause of dystonia/parkinsonism and look for other accompanying features, such as liver disease and polycythemia, which are typically associated with SLC30A10 mutations. This review aims to highlight the currently known Mn transporters, Mn-related neurotoxicity, and its consequences, and it provides an overview of inherited and acquired disorders of Mn metabolism. Currently available treatments are also discussed, focusing on the most frequently encountered presentations. Full article

Primary cervical dystonia (PCD), or spasmodic torticollis, is a focal dystonia characterized by involuntary and often painful muscle contractions, leading to abnormal cervical movements and postures. While botulinum toxin injections are the first-line treatment, additional therapies, such as segmental muscle vibration (SMV), remain underexplored. SMV, a non-invasive neuromodulation technique, may enhance motor cortex excitability and promote neuroplasticity, offering potential benefits in PCD management. This single-center triple-blinded randomized controlled trial evaluates SMV’s efficacy in reducing dystonic pain and improving quality of life in PCD patients undergoing standardized rehabilitation after botulinum toxin treatment. Participants with a pain level of ≥3 on the Numerical Rating Scale will be randomized into two groups. The experimental group will receive 80 Hz SMV during a 10-session rehabilitation program, while the control group will undergo sham SMV. Both groups will follow identical physiotherapy and occupational therapy protocols. The primary outcomes include changes in pain intensity and function, assessed at baseline, mid-treatment, and post-treatment using validated scales. The secondary outcomes will evaluate quality of life and patient satisfaction. This study hypothesizes that SMV will significantly reduce dystonic pain and enhance quality of life, supporting its integration into multidisciplinary rehabilitation for dystonic disorders. Trial registration number: NCT06748846. Full article

Leigh syndrome (LS) is a severe neurodegenerative condition with an early onset, typically during early childhood or infancy. The disorder exhibits substantial clinical and genetic diversity. From a clinical standpoint, Leigh syndrome showcases a broad range of irregularities, ranging from severe neurological issues to minimal or no discernible abnormalities. The central nervous system is most affected, resulting in psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also experience involvement of the peripheral nervous system, such as polyneuropathy or myopathy, as well as non-neurological anomalies, such as diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). Mutations associated with Leigh syndrome impact genes in both the mitochondrial and nuclear genomes. Presently, LS remains without a cure and shows limited response to various treatments, although certain case reports suggest potential improvement with supplements. Ongoing preclinical studies are actively exploring new treatment approaches. This review comprehensively outlines the genetic underpinnings of LS, its current treatment methods, and preclinical investigations, with a particular focus on treatment. Full article

Background: Botulinum toxin (BoNT), produced by Clostridium botulinum, has transitioned from being a lethal neurotoxin to a versatile therapeutic agent. Its ability to inhibit neurotransmitter release by targeting Soluble N-ethylmaleimide-sensitive factor Attachment Protein Receptor (SNARE) proteins underpins its applications in treating conditions such as spasticity, dystonia, chronic pain, and overactive bladder. The clinical and pharmacological properties of BoNT have been extensively studied, with significant advancements in its therapeutic use, safety profile, and understanding of associated adverse effects. Objective: This comprehensive review aims to consolidate historical developments, molecular mechanisms, clinical applications, and challenges associated with BoNT, with a focus on expanding its therapeutic scope while ensuring safety and efficacy. Method: A narrative approach was used to analyze and synthesize insights from 155 references spanning experimental studies, clinical trials, and reviews. Key topics included BoNT’s historical milestones, mechanisms of action, therapeutic applications, and adverse events. Findings: BoNT demonstrates remarkable efficacy in a wide range of medical and cosmetic applications. In movement disorders such as dystonia and spasticity, it reduces muscle overactivity and improves functional outcomes. In chronic pain management, including migraines and neuropathic pain, BoNT significantly alleviates symptoms by modulating neurotransmitter activity. Cosmetic use for conditions like glabellar lines and hyperhidrosis highlights its precision and safety when administered appropriately. For conditions like strabismus and blepharospasm, BoNT effectively restores muscle control, reducing involuntary contractions. In urological applications, BoNT has proven to be an effective therapy for overactive bladder, offering significant symptom relief in refractory cases. However, concerns about long-distance effects, where the toxin may spread beyond the injection site to affect distant muscles or systems, have been reported in certain high-dose or sensitive populations. These findings emphasize the importance of dose optimization and patient-specific approaches. Adverse effects such as localized pain, hematoma, dysphagia, and systemic effects, particularly in high-risk groups, underscore the need for careful monitoring. The development of immunogenicity, leading to neutralizing antibodies, remains a challenge that impacts long-term therapeutic efficacy. Emerging research on novel serotypes, including BoNT/X, and innovations in delivery mechanisms, offer promising avenues to address current limitations. Advances in optimizing dosing regimens and refining injection techniques have also contributed to minimizing complications and improving outcomes across diverse patient populations. Conclusions: BoNT remains a cornerstone in neurology and cosmetic medicine, with its therapeutic potential still expanding. The balance between efficacy and safety, driven by innovations in formulation and application, underscores the importance of continued research. Future directions should focus on minimizing adverse effects, reducing immunogenicity, and exploring novel indications to further enhance its clinical utility. Full article