Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation.

OBJECTIVE: IRF2BPL mutation has been associated with a rare neurodevelopmental disorder with abnormal movements, including dystonia. However, the role of IRF2BPL in dystonia remains elusive. We aimed to investigate IRF2BPL mutations in a Taiwanese dystonia cohort. METHODS: A total of 300 unrelated patients with molecularly unassigned isolated (n = 256) or combined dystonia (n = 44) were enrolled between January 2015 and July 2023. The IRF2BPL variants were analyzed based on whole exome sequencing. The in silico prediction of the identified potential pathogenic variant was performed to predict its pathogenicity. We also compared the clinical and genetic features to previous literature reports. RESULTS: We identified one adolescent patient carrying a de novo heterozygous pathogenic variant of IRF2BPL, c.379C>T (p.Gln127Ter), who presented with generalized dystonia, developmental regression, and epilepsy (0.33% of our dystonia cohort). This variant resides within the polyglutamine (poly Q) domain before the first PEST sequence block of the IRF2BPL protein, remarkably truncating the protein structure. Combined with other patients with IRF2BPL mutations in the literature (n = 60), patients with variants in the poly Q domain have a higher rate of nonsense mutations (p < 0.001) and epilepsy (p = 0.008) than patients with variants in other domains. Furthermore, as our index patient, carriers with substitutions before the first PEST sequence block have significantly older age of onset (p < 0.01) and higher non-epilepsy symptoms, including generalized dystonia (p = 0.003), and ataxia (p = 0.003). INTERPRETATION: IRF2BPL mutation is a rare cause of dystonia in our population. Mutations in different domains of IRF2BPL exhibit different phenotypes.

Advanced brain aging in Parkinson's disease with cognitive impairment.

Patients with Parkinson's disease and cognitive impairment (PD-CI) deteriorate faster than those without cognitive impairment (PD-NCI), suggesting an underlying difference in the neurodegeneration process. We aimed to verify brain age differences in PD-CI and PD-NCI and their clinical significance. A total of 94 participants (PD-CI, n = 27; PD-NCI, n = 34; controls, n = 33) were recruited. Predicted age difference (PAD) based on gray matter (GM) and white matter (WM) features were estimated to represent the degree of brain aging. Patients with PD-CI showed greater GM-PAD (7.08 ± 6.64 years) and WM-PAD (8.82 ± 7.69 years) than those with PD-NCI (GM: 1.97 ± 7.13, Padjusted = 0.011; WM: 4.87 ± 7.88, Padjusted = 0.049) and controls (GM: -0.58 ± 7.04, Padjusted = 0.004; WM: 0.88 ± 7.45, Padjusted = 0.002) after adjusting demographic factors. In patients with PD, GM-PAD was negatively correlated with MMSE (Padjusted = 0.011) and MoCA (Padjusted = 0.013) and positively correlated with UPDRS Part II (Padjusted = 0.036). WM-PAD was negatively correlated with logical memory of immediate and delayed recalls (Padjusted = 0.003 and Padjusted < 0.001). Also, altered brain regions in PD-CI were identified and significantly correlated with brain age measures, implicating the neuroanatomical underpinning of neurodegeneration in PD-CI. Moreover, the brain age metrics can improve the classification between PD-CI and PD-NCI. The findings suggest that patients with PD-CI had advanced brain aging that was associated with poor cognitive functions. The identified neuroimaging features and brain age measures can serve as potential biomarkers of PD-CI.

Influence of Verbal Instruction on Gait Training in Parkinson Disease: A Randomized Controlled Trial.

OBJECTIVE: Verbal instruction is one of the most commonly used methods that therapists use to correct walking pattern for people with Parkinson disease. This study aimed to compare the long-term training effects of two different verbal instructions that either asked the participants to "take big steps" or "strike the ground with the heel" on walking ability in individuals with Parkinson disease. DESIGN: Forty-five participants with Parkinson disease were randomized into the big-step or heel strike group. The participants underwent 12 sessions of treadmill and overground gait training. Throughout the interventions, the big-step group received an instruction to "take big steps," while the heel strike group received an instruction to "strike the ground with your heel." The primary outcome was gait performance, including velocity, stride length, cadence, and heel strike angle. The participants were assessed before, immediately after, and 1 mo after training. RESULTS: Both groups showed significant improvements in gait performance after training. The heel strike group showed continuous improvements in velocity and stride length during the follow-up period; however, the big-step group showed slightly decreased performance. CONCLUSIONS: A verbal instruction emphasizing heel strike can facilitate long-term retention of walking performance in people with Parkinson disease.

Exploring Potential Predictors of Treadmill Training Effects in People With Parkinson Disease.

OBJECTIVE: To explore the potential predictors of people with Parkinson disease (PD) who would benefit the most from treadmill training. DESIGN: A cohort study. SETTING: Medical university rehabilitation settings. PARTICIPANTS: Seventy participants diagnosed of idiopathic PD. INTERVENTIONS: Twelve sessions of treadmill training. MAIN OUTCOME MEASURES: Hierarchical logistic regression models were used to explore significant predictors of the treadmill training effect with respect to 3 health domains: Unified Parkinson's Disease Rating Scales part III (UPDRS III); gait speed; Parkinson's Disease Questionnaire-39 (PDQ-39). A receiver operating characteristic (ROC) curve analysis was conducted to identify proper cut-off points for clinical use. RESULTS: Male sex (adjusted odds ratio [OR]: 3.73, P=.036) significantly predicted the improvement of UPDRS III. Individuals with a slower baseline gait speed (cut-off: 0.92 m/s, adjusted OR: 14.06, P<.001) and higher baseline balance confidence measured by the Activity-specific Balance Confidence scale (cut-off: 84.5 points, adjusted OR: 4.66, P=.022) have greater potential to achieve clinically relevant improvements in gait speed. A poorer baseline PDQ-39 score (cut-off: 23.1, adjusted OR: 7.47, P<.001) predicted a greater quality of life improvement after treadmill training. CONCLUSIONS: These findings provide a guideline for clinicians to easily identify suitable candidates for treadmill training. Generalization to more advanced patients with PD warrants further investigation.

Blood neurofilament light chain as a surrogate marker for dystonia.

BACKGROUND AND PURPOSE: Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia. METHOD: We enrolled 231 unrelated dystonia patients (isolated dystonia n = 203; combined dystonia n = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single-molecule array. RESULTS: Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL; p = 0.01) or controls (p < 0.01), while the level was comparable between the focal dystonia group and controls (p = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL; p = 0.04). Notably, whole-exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in THAP1 (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in ATP1A3 (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores. CONCLUSION: Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients.

Bioactive self-healing hydrogel based on tannic acid modified gold nano-crosslinker as an injectable brain implant for treating Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is one of the most common long-term neurodegenerative diseases. Current treatments for PD are mostly based on surgery and medication because of the limitation and challenges in selecting proper biomaterials. In this study, an injectable bioactive hydrogel based on novel tannic acid crosslinker was developed to treat PD. METHODS: The oxidized tannic acid modified gold nano-crosslinker was synthesized and used to effectively crosslink chitosan for preparation of the bioactive self-healing hydrogel. The crosslinking density, conductivity, self-healing ability, and injectability of the hydrogel were characterized. Abilities of the hydrogel to promote the proliferation and differentiation of neural stem cells (NSCs) were assessed in vitro. Anti-inflammatory property was analyzed on J774A.1 macrophages. The hydrogel was injected in the PD rat model for evaluation of the motor function recovery, electrophysiological performance improvement, and histological repair. RESULTS: The hydrogel exhibited self-healing property and 34G (~ 80 µm) needle injectability. NSCs grown in the hydrogel displayed long-term proliferation and differentiation toward neurons in vitro. Besides, the hydrogel owned strong anti-inflammatory and antioxidative capabilities to rescue inflamed NSCs (~ 90%). Brain injection of the bioactive hydrogel recovered the motor function of PD rats. Electrophysiological measurements showed evident alleviation of irregular discharge of nerve cells in the subthalamic nucleus of PD rats administered with the hydrogel. Histological examination confirmed that the hydrogel alone significantly increased the density of tyrosine hydroxylase positive neurons and fibers as well as reduced inflammation, with a high efficacy similar to drug-loaded hydrogel. CONCLUSION: The new bioactive hydrogel serves as an effective brain injectable implant to treat PD and a promising biomaterial for developing novel strategies to treat brain diseases.

Influences of Aerobic Exercise on Motor Sequence Learning and Corticomotor Excitability in People With Parkinson's Disease.

BACKGROUND: People with Parkinson's disease (PD) are known to have motor learning difficulties. Although numerous studies have demonstrated that a single bout of aerobic exercise (AEX) can facilitate motor learning in non-disabled adults, the same beneficial effect in PD is unknown. Furthermore, associated neuroplastic changes have not been investigated. OBJECTIVES: This study aimed to determine whether a single bout of aerobic exercise (AEX) can facilitate motor sequence learning in people with PD and to investigate the associated neurophysiological changes. METHODS: Thirty individuals with PD were recruited and randomized into the exercise group (PD + AEX) and non-exercise group (PD - AEX). At the first visit, corticomotor excitability was assessed using transcranial magnetic stimulation (TMS). All participants then performed a serial reaction time task (SRTT) followed by 20 minutes of moderately-high intensity aerobic exercise (AEX) for the PD + AEX group or rest for the PD - AEX group. The SRTT and TMS were reevaluated at 3 time points: immediately after aerobic exercise (AEX) or rest, on the second day after practice (D2), and a week after practice (D7). RESULTS: Both groups showed improvement throughout practice. At retention, the PD + AEX group showed improved SRTT performance on D7 compared to D2 (P = .001), while the PD - AEX group showed no change in performance. TMS results showed that the PD + AEX group had significantly higher corticomotor excitability than the PD - AEX group on D7. CONCLUSION: A single session of aerobic exercise (AEX) could enhance motor sequence learning and induce neuroplastic changes. Clinicians can consider providing aerobic exercise (AEX) after motor task training for people with PD. CLINICAL REGISTRATION: NCT04189887 (ClinicalTrials.gov).

Genetic analysis of IMPDH2 gene in Taiwanese patients with isolated or combined dystonia.

The inosine monophosphate dehydrogenase gene (IMPDH2) was recently reported as a novel gene associated with autosomal dominantly inherited dystonia. We investigated 245 Taiwanese patients with molecularly unassigned isolated or combined dystonia without features of neurodevelopmental disorders and found none had pathogenic variants. Our findings suggest that IMPDH2 may not play a major role in dystonia.

Cerebellar deep brain stimulation for movement disorders.

Deep brain stimulation (DBS) conventionally target at basal ganglia or thalamic structures, modulating nodal points in the cortico-basal ganglia circuit, in order to effectively treat various movement disorders, including Parkinson's disease, tremor and dystonia (especially mobile type dystonia). However, there are still some other movement disorders, such as dystonia (especially fixed type dystonia), ataxia and freezing of gait, which are not responding well to the current DBS therapy. Cerebellum, similar to basal ganglia, also plays a critical role in the pathophysiology of movement disorders. Deep cerebellar structures, such as dentate nucleus or superior cerebellar peduncle, are noticed for their potential role as treatment targets in movement disorders in recent years. With increasing evidences of animal DBS experiments, recent clinical human subject studies reported that some movement disorders patients not responding to DBS with conventional targets, may benefit significantly from cerebellar DBS. These pioneer study results are invaluable for understanding the clinical use of cerebellar DBS for treatment of movement disorders. We review the recent data of cerebellar DBS performed by different groups and summarize the indications, surgical targets, programming details and outcomes in these clinical reports. We then synthesize the current pathophysiological study of cerebellum on different movement disorders and discuss the potential mechanism of action of cerebellar DBS. In addition to basal ganglia, it is important to study new DBS targets in the cerebellum for more comprehensive treatment of movement disorders.

Platelet abnormalities in patients with Parkinson's disease undergoing preoperative evaluation for deep brain stimulation.

Normal hemostatic function is important for reduction of the risk of intracranial hemorrhage during stereotactic neurosurgery including deep brain stimulation (DBS) surgery. This study investigates the hemostatic function in patients with Parkinson's disease (PD) undergoing preoperative evaluation for DBS, with emphasis on the number and function of platelets. In 107 PD patients, only one had abnormal activated partial prothrombin time and normal prothrombin time. Among the other 106 patients, six (5.7%) had only thrombocytopenia, seven (6.6%) only prolonged bleeding time (BT), and 14 (13.2%) only prolonged closure time (CT) of platelet function analyzer 100 (PFA-100). Totally, 34 of the 106 patients (32.1%) had at least one of three kinds of platelet abnormalities. No factor was found to be associated with the occurrence of platelet abnormalities except that abnormal platelet group and prolonged BT subgroup had more patients using selegiline and lower UPDRS-III motor subscore with medication off than normal platelet group (p < 0.05). The use of selegiline was significantly correlated with prolonged BT (p = 0.0041) and platelet abnormality (p = 0.0197). Therefore, it is important to have detailed evaluation of the hemostatic function for PD patients undergoing preoperative evaluation for DBS, especially the platelet number and function.

Long-Term Outcomes of Idiopathic and Acquired Dystonia After Pallidal Deep Brain Stimulation: A Case Series.

BACKGROUND: Among dystonia patients receiving globus pallidus internus (GPi) deep brain stimulation (DBS), long-term outcomes remain to be established. To report the long-term outcomes of GPi DBS in a patient cohort with idiopathic and acquired dystonia. METHODS: In this long-term follow-up cohort, there were 4 patients with idiopathic dystonia and 2 patients with acquired dystonia. The Burke-Fahn-Marsden Dystonia Rating Scale was used to evaluate 6 consecutive patients preoperatively and at 6 months, 12 months, and the last follow-up. The relationship between etiology and clinical improvement was analyzed. Stimulation parameters were evaluated for similarities and differences among these patients. RESULTS: The mean follow-up of our cohort was 65.3 months (median 40.5 months). The average improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (mean ± SEM) were 56% ± 7.6, 67% ± 6.8 and 66% ± 9.7 at 6 months, 12 months, and the last follow-up, respectively. There was greater improvement during the long-term follow-up in the 4 patients with idiopathic dystonia than in the 2 patients with acquired dystonia. The 2 most ventral electrodes (contact 0 and 1) were activated in all 11 leads in this cohort. The average stimulation intensity, pulse width and frequency were 2.0 ± 0.24 mA, 252 ± 43 µs, and 99 ± 6.0 Hz, respectively. CONCLUSIONS: Isolated dystonia, either monogenic or idiopathic, usually responds better to GPi DBS than to acquired dystonia. Selection of patients by dystonia etiology, accurate placement of DBS leads in GPi targets, and proper stimulation programming are crucial to achieve better long-term outcomes.

Long-term efficacy of bilateral subthalamic deep brain stimulation in the parkinsonism of SCA 3: A rare case report.

BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV SCA3, pure parkinsonism is the only symptom. Currently, no disease-modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3 remain unclear. METHODS: A 39-year-old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young-onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3 mutation. Excellent response to levodopa and dopamine agonists in the first 3 years was noted, but wearing-off phenomena, levodopa-induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug-induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in the absence of cerebellar signs, depression, and cognitive impairment. RESULTS: As of 2019, no impulsive control disorders, motor fluctuations, or DBS-related complications were observed during a 4-year follow-up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half. CONCLUSIONS: STN-DBS may be considered as adjunct treatment for severe dopa-related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3.

Training in Varying Environmental Contexts Facilitates Transfer of Improved Gait Performance to New Contexts for Individuals With Parkinson Disease: A Randomized Controlled Trial.

OBJECTIVE: To investigate whether varying practice context during gait training could reduce context dependency and facilitate transfer of improved gait performance to a new context. DESIGN: A single-blind, parallel-group randomized controlled trial. SETTING: Medical university rehabilitation settings. PARTICIPANTS: Forty-nine participants with Parkinson disease were recruited and randomized into the constant (CONS) or varied (VARI) context group. INTERVENTIONS: All participants received 12 sessions of treadmill and over-ground gait training. The CONS group was trained in a constant environmental context throughout the study, whereas the VARI group received training in 2 different contexts in an alternating order. MAIN OUTCOME MEASURES: The primary outcome was gait performance, including velocity, cadence, and stride length. The participants were assessed in the original training context as well as in a novel context at posttest to determine the influence of changed environmental context on gait performance. RESULTS: Though both groups improved significantly after training, the CONS group showed greater improvement in stride length than the VARI group when assessed in the original practice context. However, the CONS group showed a decreased velocity and stride length in the novel context, whereas the VARI group maintained their performance. CONCLUSIONS: Varying practice context could facilitate transfer of improved gait performance to a novel context.

COQ2 and SNCA polymorphisms interact with environmental factors to modulate the risk of multiple system atrophy and subtype disposition.

BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) has no definitive genetic or environmental (G-E) risk factors, and the integrated effect of these factors on MSA etiology remains unknown. This study was undertaken to investigate the integrated effect of G-E factors associated with MSA and its subtypes, MSA-P and MSA-C. METHODS: A consecutive case-control study was conducted at two medical centers, and the interactions between genotypes of five previously reported susceptible single nucleotide polymorphisms (SNPs; SNCA_rs3857059, SNCA_rs11931074, COQ2_rs148156462, EDN1_rs16872704, MAPT_rs9303521) and graded exposure (never, ever, current) of four environmental factors (smoking, alcohol, drinking well water, pesticide exposure) were analyzed by a stepwise logistic regression model. RESULTS: A total of 207 MSA patients and 136 healthy controls were enrolled. In addition to SNP COQ2_rs148156462 (TT), MSA risk was correlated with G-E interactions, including COQ2_rs148156462 (Tc) × pesticide nonexposure, COQ2_rs148156462 (TT) × current smokers, SNCA_rs11931074 (tt) × alcohol nonusers, and SNCA_rs11931074 (GG) × well water nondrinkers (all p < 0.01), with an area under the receiver operating characteristic curve (AUC) of 0.804 (95% confidence interval [CI] = 0.671-0.847). Modulated risk of MSA-C, with MSA-P as a control, correlated with COQ2_rs148156462 (TT) × alcohol nondrinkers, SNCA_rs11931074 (GG) × well water ever drinkers, SNCA_rs11931074 (Gt) × well water never drinkers, and SNCA_rs3857059 (gg) × pesticide nonexposure (all p < 0.05), with an AUC of 0.749 (95% CI = 0.683-0.815). CONCLUSIONS: Certain COQ2 and SNCA SNPs interact with common environmental factors to modulate MSA etiology and subtype disposition. The mechanisms underlying the observed correlation between G-E interactions and MSA etiopathogenesis warrant further investigation.

A Clinical and Integrated Genetic Study of Isolated and Combined Dystonia in Taiwan.

Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this, we applied an integrated two-step approach that included gene dosage analysis and a next-generation sequencing panel containing 72 known genes causative for dystonia and related movement disorders to 318 Taiwanese patients with isolated or combined dystonia. Whole-genome sequencing was performed for one multiplex family with no known causative variant. The panel confirmed the genetic diagnosis in 40 probands (12.6%). A genetic diagnosis was more likely with juvenile onset compared with adult onset (24.2% vs 10.8%; P = 0.03) and those with combined features, especially with myoclonus, compared with isolated dystonia (35.3% vs 10.5%; P = 0.004). The most common causative genes were SGCE followed by GCH1, TH, CACNA1B, PRRT2, MR1, CIZ1, PLA2G6, and PRKN. Genetic causes were identified from single cases in TOR1A, TUBB4A, THAP1, ATP1A3, ANO3, GNAL, KMT2B, SLC6A3, ADCY5, CYP27A1, PANK2, C19orf12, and SPG11. The whole-genome sequencing analysis identified a novel intragenic deletion in OPHN1 in a multiplex family with X-linked dystonia and intellectual delay. Our findings delineate the genetic architecture and clinical spectrum of dystonia-causing pathogenic variants in an Asian population.

Amantadine treatment and delayed onset of levodopa-induced dyskinesia in patients with early Parkinson's disease.

BACKGROUND AND PURPOSE: Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early-stage PD. METHODS: This was a hospital-based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity-score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results. RESULTS: The analyses included 807, 661, and 518 patients at 6-, 12-, and 18-month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6- and 12-month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49-0.86) and 0.64 (95% CI = 0.47-0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis. CONCLUSIONS: Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings.

Subthalamic burst firing: A pathophysiological target in Parkinson's disease.

Understanding the pathophysiological mechanism of Parkinson's disease (PD) in the subthalamic nucleus (STN) has become a critical issue since deep brain stimulation (DBS) in this region has been proven as an effective treatment for this disease. The STN possesses a special ability to switch from the spike to the burst firing mode in response to dopamine deficiency in parkinsonism, and this STN burst is considered an electrophysiological signature of the cortico-basal ganglia circuit in the brains of PD patients. This review focuses on the role of STN burst firing in the pathophysiology of PD and during DBS. Here, we review existing literature on how STN bursts originate and the specific factors affecting their formation; how STN burst firing causes motor symptoms in PD and how interventions can rescue these symptoms. Finally, the similarities and differences between the two electrophysiological hallmarks of PD, STN burst firing and beta-oscillation, are discussed. STN burst firing should be considered as a pathophysiological target in PD during treatment with DBS.

Investigating DYT1 in a Taiwanese dystonia cohort.

BACKGROUND/PURPOSE: A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort. METHODS: We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020. RESULTS: Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04). CONCLUSION: Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.

Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency.

Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adeno-associated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.