Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an established therapy for drug-intractable dystonia, a severe movement disorder. As shown by previous studies, short-term (three hours) DBS of the entopeduncular nucleus (EPN, the homologue of the GPi in rodents) improved dystonia in dtsz mutant hamsters, a genetic animal model of paroxysmal dystonia. However, DBS in dystonia patients is thought to alter long-term plasticity during prolonged DBS accompanied with delayed improvement of dystonia. Therefore, it is important to investigate the mechanisms of long-term stimulation. In the present study, we examined the effects of prolonged bilateral pallidal (EPN) DBS (130 Hz, 60 μs, 50 μA) over ten days on the severity of dystonia by using an innovative implantable DBS device. Electrode implantation alone reduced the severity of dystonia in mutant hamsters (post-OP vs. pre-OP). In comparison to post-OP data, the severity of dystonia remained unchanged after two days of pallidal DBS (postOp-d37-On). However, during continuous DBS the severity slowly decreased. After ten days of DBS, the severity was significantly reduced compared to both pre-DBS (postOP-d35) and postOp-d37-ON, while the severity scores did not differ in age-matched sham-stimulated dtsz hamsters. Notably, in the DBS group three out of 13 animals did not respond to pallidal DBS. Thus, the present data highlight individual variability and temporal differences in the response to DBS in this model, paralleling observations in patients. Therefore, the dtsz hamster model is highly suitable for investigating the mechanisms of DBS within the pathological network.

Multiple sclerosis (MS) presents with a wide spectrum of neurological manifestations, among which paroxysmal motor phenomena remain a diagnostic and therapeutic challenge. We report the case of a 29-year-old male diagnosed with relapsing-remitting MS (RRMS) who exhibited episodes of paroxysmal dystonia, dysarthria-ataxia, and ptosis. Brain MRI revealed multiple demyelinating plaques, including a contrast-enhancing lesion in the right midbrain, which provides an anatomical correlation with the patient's neurological manifestation. The dystonic movements resolved with corticosteroid therapy, while symptomatic management with carbamazepine was required for dysarthria-ataxia. Ocrelizumab has been proposed as a long-term disease-modifying treatment. This case highlights the importance of recognizing paroxysmal motor signs in MS for early diagnosis and tailored management, despite their elusive pathogenesis. Mitochondrial short-chain enoyl-CoA hydratase deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described. Individuals with ECHS1D can present as neonates with hypotonia, dilated cardiomyopathy, severe developmental delay, seizures, sensorineural hearing loss, and severe lactic acidosis. More commonly, individuals present in infancy with developmental delay or regression, dystonia, hypotonia, ophthalmologic manifestations, sensorineural hearing loss, epilepsy, and feeding difficulties. In the late-onset form, individuals primarily present with paroxysmal dystonia that may be exacerbated by illness or exertion, subtle axial hypotonia, sensorineural hearing loss, and learning differences or normal development. T2 hyperintensity in the basal ganglia is very common in all individuals with ECHS1D and may affect any part of the basal ganglia. Prognosis is dependent on age of onset. In the neonatal form, clinical manifestations typically progress quickly, and infants succumb to central apnea or arrhythmia often consequent to overwhelming metabolic acidosis. The diagnosis of ECHS1D is established in a proband with characteristic findings and biallelic pathogenic variants in ECHS1 identified by molecular genetic testing. Targeted therapies: Valine-restricted diet; N-acetylcysteine Supportive care: Treatment of severe metabolic acidosis with bicarbonate therapy; hyperammonemia may be addressed by treatment of metabolic acidosis and/or consideration of hemodialysis. Standard treatment for developmental delay, seizures, spasticity, cardiomyopathy, pulmonary hypertension, sensorineural hearing loss, and optic atrophy. Paroxysmal dystonia may respond to benzodiazepines, whereas chronic dystonia may require botulinum toxin injections. Treatment of dystonia with levodopa may also be considered. Inadequate nutrition may require feeding therapy; placement of a feeding tube may be considered. Management of respiratory issues and apnea per intensivist and/or pulmonologist. Transition to adult care starting by approximately age 12 years; social work and family support. Surveillance: Evaluation with metabolic specialist and biochemical dietician, including assessment of total protein and valine intake, fasting plasma amino acids, blood total and free carnitine, acylcarnitine profile, blood lactate, and urine organic acids with frequency per metabolic specialist; measure sodium bicarbonate and blood lactate concentration with all viral illnesses or metabolic stressors. Measurement of growth parameters and assessment of nutritional status, safety of oral intake, developmental and educational needs, changes in neurologic manifestations, evidence of aspiration, respiratory insufficiency, sleep apnea, and family needs at each visit. Physical medicine and occupational and physical therapy assessment of mobility and self-help skills at each visit. Brain MRI and EEG as needed in those with new neurologic manifestations. At least annual echocardiogram and audiologic evaluation. Assess eye movements at each visit; dilated ophthalmology examination at ages six and 12 months and then annually. Agents/circumstances to avoid: Mitochondrial toxins (e.g., sodium valproate, prolonged propofol infusions); anesthesia should be used with caution; prevent catabolism; avoid lactate-containing agents; ketogenic diet may be poorly tolerated. Evaluation of relatives at risk: It is appropriate to evaluate at-risk newborns and apparently asymptomatic sibs of an affected individual to identify as early as possible those who would benefit from prompt institution of treatment. In an at-risk newborn, it is crucial to ensure metabolic stability by evaluating lactic acid concentration and blood gas. Urine organic acids and acylcarnitine profile may also be used as biochemical screening testing while waiting for ECHS1 molecular genetic testing results. ECHS1D is inherited in an autosomal recessive manner. In most instances, both parents of an affected child are heterozygous for an ECHS1 pathogenic variant. If the proband is compound heterozygous for an ECHS1 pathogenic variant and the ECHS1 c.489G>A variant, a parent may be homozygous for the c.489G>A variant (the c.489G>A variant does not cause disease when homozygous). If the proband has a chromosome 10q26 deletion involving ECHS1, a parent may carry a balanced rearrangement involving the 10q26 region. Rarely, a proband has one de novo pathogenic variant and one pathogenic variant inherited from a carrier parent. If both parents of an affected individual are known to be heterozygous for an ECHS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. If one parent is known to be heterozygous for an ECHS1 pathogenic variant and the other parent is known to be homozygous for the c.489G>A variant, each sib of an affected individual has at conception a 50% chance of inheriting biallelic variants and being affected and a 50% chance of inheriting only the c.489G>A variant and being an asymptomatic carrier. Once the ECHS1 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk and prenatal/preimplantation genetic testing are possible. Benign essential blepharospasm (BEB) is a persistent focal cranial dystonia characterized by involuntary, repeated, and frequently debilitating spasms of the orbicularis oculi muscles. Blepharospasm is a disease characterized by an increased rate of bilateral eyelid closure, mainly due to involuntary contraction of the orbicularis oculi muscles (see Image. Typical Blepharospasm). The disorder typically begins with excessive blinking, ocular discomfort, or sporadic eyelid fluttering, and may progress to persistent, powerful spasms that obstruct vision. Once regarded as a purely motor disorder, recent research indicates that BEB represents a multifaceted malfunction within central sensorimotor networks, encompassing the basal ganglia, cerebellum, thalamus, and cortical inhibitory pathways. These anomalies diminish the capacity to inhibit reflexive blinking and enhance motor reactions to sensory stimuli. Over time, the natural history typically demonstrates progressive symptom exacerbation, with several people eventually experiencing functional blindness—characterized by an inability to maintain sufficient eyelid elevation for visual tasks. Contemporary cohort studies validate the progressive and debilitating characteristics of BEB, evidencing significant declines in quality of life and social engagement. Extensive epidemiological data underscore BEB as a chronic neurological condition with considerable individual and social impact. Blepharospasm is a type of dystonia, a movement disorder characterized by sustained or intermittent muscle contractions that lead to abnormal, repetitive movements or postures, often patterned and sometimes twisting or tremulous. In most dystonias, voluntary action typically leads to exacerbation of dystonia due to overactivation of muscles. Dystonia can potentially affect any part of the body and can present at a wide range of ages. This disorder can be classified according to its distribution across the body: Focal dystonia refers to dystonia that affects only 1 isolated region of the body. Segmental dystonia refers to dystonia that affects 2 or more contiguous regions of the body. Multifocal dystonia refers to dystonia affecting 2 or more noncontiguous regions. Hemidystonia refers to a form of dystonia that affects half of the body. Generalized dystonia refers to dystonia affecting the trunk and 3 other sites. Dystonia can have a static or progressive course. Furthermore, the variability of symptoms can be classified according to how often they occur: Persistent dystonia refers to dystonia that remains at the same level throughout the day. Action-specific dystonia refers to dystonia that occurs only when performing a specific activity. Diurnal fluctuation refers to dystonia that varies throughout the day, with circadian variation in severity. Paroxysmal dystonia refers to sudden episodes of dystonia typically induced by a trigger. Examples of focal dystonia include blepharospasm, oromandibular dystonia, writer's cramp, spasmodic dysphonia, and torticollis. Blepharospasm is a focal dystonia characterized by simultaneous contraction of agonist and antagonist muscles, resulting in involuntary eyelid closure; the first report of patients with blepharospasm was a description of 10 patients by Henri Meige in 1910. The patients reported in this study had involuntary eyelid closure associated with jaw muscle contraction. In his paper, Meige named this phenomenon Convulsions de la Face ("convulsions of the face"). BEB originates from the dysregulated function of the orbicularis oculi muscle, which is innervated by the facial nerve and modulated by brainstem and basal ganglia circuits. Pathological excitability in these circuits leads to heightened blinking responses to trivial stimuli, such as bright light, dryness, or emotional stress. Neurophysiological investigations indicate increased blink reflex sensitivity and diminished inhibitory control, suggesting that BEB disrupts normal sensorimotor gating. Furthermore, ocular surface disorders significantly contribute to symptom exacerbation. Dry eye disease is prevalent in BEB, and elevated blink frequency appears to be both a catalyst and a result of tear-film instability. Research indicates that tear hyperosmolarity, elevated levels of inflammatory cytokines, and mechanical irritation of the ocular surface may exacerbate dystonic contractions, thereby creating a positive feedback loop between sensory irritation and motor dysfunction. Alterations in the ocular surface constitute an additional aspect of the normal progression of BEB. Excessive blinking intensity and frequency lead to tear-film instability, lid wiper epitheliopathy, meibomian gland strain, and epithelial microtrauma. Research investigating the ocular surface pre- and post-botulinum toxin injections demonstrates persistent anomalies, such as diminished tear breakup time, heightened corneal staining, and mechanical damage in the lid wiper area, which frequently ameliorate following the regulation of spasms. Long-term observational data indicate that BEB is linked to significant psychological effects, including anxiety, depression, and sleep disturbances, all of which correlate with heightened dystonic severity. These non-motor manifestations further underscore the multimodal nature of BEB and its significant impact on patient well-being. 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency can be categorized into three subtypes based on age of presentation. Neonatal onset, the least frequent phenotype, is characterized by hypotonia, seizures, and feeding difficulties at birth. There is a high risk of death in childhood, and individuals that survive typically have developmental delay, seizures, poor weight gain, and growth deficiency and develop a movement disorder. Infantile onset is the most common phenotype, presenting in the first two years of life with feeding difficulties, vomiting, developmental delay with regression, hypotonia, seizures, movement disorder, microcephaly, vision impairment, and episodes of neurologic deterioration. Late onset is the second most common phenotype, presenting in childhood as a slowly progressive disease with significant movement disorder with or without paroxysmal dystonia, variable cognitive impairment, and high survivability. The diagnosis of HIBCH deficiency is established in a proband with characteristic clinical, laboratory, and brain imaging findings and biallelic pathogenic variants in HIBCH identified by molecular genetic testing. Targeted therapy: Valine-restricted diet. As seen in other metabolic disorders, treatment using special formulas (medical food) can be implemented successfully via oral route in individuals diagnosed within the first few months of life. Later on, if palatability or feeding intolerance becomes a problem, formula can be given by gastrostomy tube. A restriction in total protein intake without quantitation of valine may be necessary in individuals on an oral diet with poor adherence to medical food or formula. Supportive care: Developmental and educational support; feeding therapy with gastrostomy tube as needed; standard treatments for spasticity and epilepsy; treatment of movement disorder per movement disorder specialist; management of ocular issues per ophthalmologist with low vision services as needed; early intervention for cerebral visual impairment; hearing aids per otolaryngologist and community hearing services as needed; transitional care support; social work and family support. Surveillance: Evaluation with a metabolic specialist and metabolic dietitian including assessment of total protein and valine intake, fasting plasma amino acids, blood total and free carnitine and acylcarnitine profile, lactic acid in blood, and urine organic acids with frequency per metabolic specialist; measurement of growth parameters, evaluation of nutrition and oral intake, and assessment of developmental progress and educational needs at each visit; assessment for changes in tone, seizures, movement disorders, mobility, self-help skills, evidence of aspiration, respiratory insufficiency, and sleep apnea at each visit; ophthalmology evaluation at least annually; audiology evaluation as needed. Agents/circumstances to avoid: Due to secondary mitochondrial abnormalities it may be beneficial to avoid sodium valproate if possible; consider anesthesia use carefully; avoid prolonged propofol use; prevent catabolism; avoid neuromuscular blocking agents in those with muscle disease; avoid lactate-containing agents, including dialysate containing lactate; ketogenic / modified Atkins diets should be avoided due to potential side effects; triheptanoin is contraindicated due to the potential increase in propionyl-CoA; dichloroacetate, as there is no published evidence to support its use in HIBCH deficiency. Evaluation of relatives at risk: It is appropriate to evaluate at-risk newborns and older sibs of an affected individual to identify as early as possible those who would benefit from prompt initiation of targeted therapy. HIBCH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HIBCH pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the HIBCH pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Emerging preclinical evidence suggests that the cerebellum plays a critical role in paroxysmal kinesigenic dyskinesia (PKD) associated with proline-rich transmembrane protein 2 (PRRT2) mutations. This study aimed to investigate the role of cerebello-cerebral network in PKD patients with PRRT2 mutations (PKD-M) and PKD patients with no PRRT2 mutations (PKD-N). Resting-state functional magnetic resonance imaging scan was performed on 105 PKD patients (47 PKD-M and 58 PKD-N) and 62 healthy controls (HC). For seed-based functional connectivity (FC) analysis, the cerebellum was parcellated into 10 function-related regions through a functional atlas of the human cerebellum obtained by a multi-domain task battery. The cerebello-cerebral FC and regional homogeneity (ReHo) were examined using one-way analysis of covariance and two-sample t-test in PKD-M, PKD-N and HC. PKD-M had increased FC between a motor-planning related cerebellar region (region 4) and the middle cingulate gyrus, compared to HC. While PKD-M had decreased FC between this region and the lingual gyrus, compared to HC. PKD-M had increased FC between another cerebellar region (region 8) and the right inferior temporal gyrus/right superior frontal gyrus, compared to PKD-N. Additionally, PKD-M had decreased ReHo in the pons and the cerebellum anterior lobe and increased ReHo in the right inferior temporal gyrus, compared to HC. PRRT2 mutations may cause abnormalities in a motor-planning cerebello-cerebral network, which likely play a major role in the pathogenesis of PKD-M.

Paroxysmal kinesigenic dyskinesia (PKD) is a genetically heterogeneous movement disorder primarily associated with PRRT2 variants. Recently, TMEM151A and KCNJ10 have emerged as additional PKD-associated genes. However, genotype-phenotype correlations remain poorly defined. In this study, we retrospectively analyzed 41 PKD patients from a single center in Southeastern China. All patients underwent comprehensive clinical evaluation and whole-exome sequencing (WES), with variant classification based on ACMG guidelines. Additionally, we conducted a literature review of PKD cohorts published since 2021 to compare the clinical characteristics of patients carrying PRRT2, TMEM151A, KCNJ10 variants, and those without identified mutations. A genetic diagnosis was achieved in 19/41 patients (46.3%), with PRRT2 being the most frequent. We identified five novel variants, including two in KCNJ10, two in TMEM151A, and one in PNKD. Compared to other groups, PRRT2-positive patients had the earliest onset and highest treatment response. TMEM151A-positive patients tended to exhibit more frequent attacks and a lower response to carbamazepine. KCNJ10-positive patients presented with later onset and ultra-brief attacks. Genetically negative cases displayed distinct features, including fewer auras and more unilateral, ultra-brief episodes, yet responded well to carbamazepine. PKD exhibits significant genotype-dependent clinical heterogeneity. Novel variants in TMEM151A and KCNJ10 expand the mutational spectrum and suggest emerging genotype-specific phenotypic trends. Systematic genetic and phenotypic profiling may guide more precise diagnosis and management of PKD.