BACKGROUND

Perampanel is an antagonist of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. It is currently FDA-approved to treat focal and generalized tonic-clonic seizures in epilepsy, but recent evidence suggests its potential in treating severe and refractory tremors.

To determine the safety and efficacy of perampanel in treating tremors via a systematic review of existing literature. 

We performed a literature search on five large databases (PubMed, Cochrane, Google Scholar, HERDIN, and Scopus) for clinical studies within the last 10 years and screened a total of 1,539 unique articles for full assessment. We filtered out papers on epilepsy as well as hypokinetic diseases and assessed nine articles for quality assessment and review.

A total of four case reports/series, four open-label trials, and one randomized controlled trial were assessed to be of fair to good quality. All trials showed that low-dose perampanel (2-4 mg/day) was safe and well-tolerated with minor adverse events reported by participants. A net benefit from baseline was observed in patients with essential and primary orthostatic tremors. However, current evidence is weak because the trials employed a non-randomized before-after study design with a small sample size and significant dropout rates.

Low-dose perampanel at 2-4 mg/day shows promising potential in treating refractory tremors and myoclonus in recent clinical studies, but current evidence is weak or anecdotal. Additional randomized controlled trials are needed to determine the conclusive benefit of perampanel for hyperkinesia.

Objective To investigate the features of surface electromyography （sEMG） signals in patients with lower limb dystonia and hepatolenticular degeneration， also known as Wilson disease （WD）， as well as the feasibility of sEMG as an assessment tool for lower limb dystonia in WD. Methods A total of 36 WD patients with lower limb dystonia （observation group） and 20 WD patients without lower limb dystonia （control group） were enrolled， and 20 normal subjects were enrolled as healthy group. The sEMG technique was used to measure the AEMG， MF， MPF， and iEMG values of the anterior tibial muscle， the gastrocnemius muscle， and the rectus femoris muscle in the walking state， and a Spearman’s rank correlation analysis was used to investigate the correlation of the iEMG value of the rectus femoris muscle in both lower limbs with Activities of Daily Living （ADL）， the neurological subscale of Unified Wilson’s Disease Rating Scale （UWDRS-I）， the Burke-Fahn-Marsden Dystonia Rating Scale （BFMDRS）， the Modified Ashworth Scale， and 10-meter walking time. The observation group and the healthy group were compared in terms of the symmetry index （SI） of the same-named muscles on both sides， and the correlation of SI value with scale scores and walking time was analyzed for the observation group. Results There were significant differences in iEMG values and all electromyography values of the rectus femoris muscle between the three groups （P<0.05）. In the observation group， the iEMG value of the rectus femoris muscle was negatively correlated with the ADL scale and was positively correlated with dystonia-related scales and 10-meter walking time， suggesting that the iEMG value of the rectus femoris muscle could reflect the severity of lower limb dystonia in WD. Meanwhile， there were significant differences in the SI values of bilateral muscles between the observation group and the healthy group （P<0.05）， and for the observation group， the SI values of the muscles were negatively correlated with the ADL scale and were positively correlated with other variables， suggesting that lower limb dystonia in WD was asymmetric， and the degree of asymmetry was positively correlated with the degree of dystonia. Conclusion This study shows that sEMG has a certain application value in assessing lower limb dystonia in WD patients and can be used as an assessment tool for lower limb dystonia in WD.
Dystonia

BACKGROUND

Perampanel is an antagonist of the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. It is currently FDA-approved to treat focal and generalized tonic-clonic seizures in epilepsy, but recent evidence suggests its potential in treating severe and refractory tremors.

To determine the safety and efficacy of perampanel in treating tremors via a systematic review of existing literature. 

We performed a literature search on five large databases (PubMed, Cochrane, Google Scholar, HERDIN, and Scopus) for clinical studies within the last 10 years and screened a total of 1,539 unique articles for full assessment. We filtered out papers on epilepsy as well as hypokinetic diseases and assessed nine articles for quality assessment and review.

A total of four case reports/series, four open-label trials, and one randomized controlled trial were assessed to be of fair to good quality. All trials showed that low-dose perampanel (2-4 mg/day) was safe and well-tolerated with minor adverse events reported by participants. A net benefit from baseline was observed in patients with essential and primary orthostatic tremors. However, current evidence is weak because the trials employed a non-randomized before-after study design with a small sample size and significant dropout rates.

Low-dose perampanel at 2-4 mg/day shows promising potential in treating refractory tremors and myoclonus in recent clinical studies, but current evidence is weak or anecdotal. Additional randomized controlled trials are needed to determine the conclusive benefit of perampanel for hyperkinesia.

OBJECTIVE: To explore the clinical phenotype and genetic features of two children with MEGDEL syndrome due to variants of the SERAC1 gene. METHODS: Two children who had presented at the Fujian Medical University Union Hospital respectively on July 14, 2020 and July 28, 2018 were selected as the study subjects. Clinical features and results of genetic testing were retrospectively analyzed. RESULTS: Both children had featured developmental delay, dystonia and sensorineural deafness, along with increased urine 3-methylglutaric acid levels. Magnetic resonance imaging revealed changes similar to Leigh-like syndrome. Gene sequencing revealed that both children have harbored pathogenic compound heterozygous variants of the SERAC1 gene, including c.1159C>T and c.442C>T in child 1, and c.1168C>T and exons 4~9 deletion in child 2. CONCLUSION Children with MEGDEL syndrome due to SERAC1 gene variants have variable clinical genotypes. Delineation of its clinical characteristics and typical imaging changes can facilitate early diagnosis and treatment. Discovery of the novel variants has also enriched the spectrum of SERAC1 gene variants.
Humans ; Retrospective Studies ; Metabolism, Inborn Errors ; Hearing Loss, Sensorineural/genetics* ; Dystonia ; Carboxylic Ester Hydrolases

Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.
Female ; Humans ; Infant ; Male ; Benserazide/therapeutic use* ; Dystonia/genetics* ; Hypokinesia/drug therapy* ; Levodopa/pharmacology* ; Muscle Hypotonia ; Retrospective Studies ; Tyrosine 3-Monooxygenase/genetics*

Objective: To investigate the clinical features and genetic features of combined oxidative phosphorylation deficiency 32 (COXPD32) caused by MRPS34 gene variation. Methods: The clinical data and genetic test of a child with COXPD32 hospitalized in the Department of Neurology, Children's Hospital, Capital Institute of Pediatrics in March 2021 were extracted and analyzed. A literature search was implemented using Wanfang, China biology medicine disc, China national knowledge infrastructure, ClinVar, human gene mutation database (HGMD) and Pubmed databases with the key words "MRPS34" "MRPS34 gene" and "combined oxidative phosphorylation deficiency 32" (up to February 2023). Clinical and genetic features of COXPD32 were summarized. Results: A boy aged 1 year and 9 months was admitted due to developmental delay. He showed mental and motor retardation, and was below the 3^rd percentile for height, weight, and head circumference of children of the same age and gender. He had poor eye contact, esotropia, flat nasal bridge, limbs hypotonia, holding instability and tremors. In addition, Grade Ⅲ/6 systolic murmur were heard at left sternal border. Arterial blood gases suggested that severe metabolic acidosis with lactic acidosis. Brain magnetic resonance imaging (MRI) showed multiple symmetrical abnormal signals in the bilateral thalamus, midbrain, pons and medulla oblongata. Echocardiography showed atrial septal defect. Genetic testing identified the patient as a compound heterozygous variation of MRPS34 gene, c.580C>T (p.Gln194Ter) and c.94C>T (p.Gln32Ter), with c.580C>T being the first report and a diagnosis of COXPD32. His parents carried a heterozygous variant, respectively. The child improved after treatment with energy support, acidosis correction, and "cocktail" therapy (vitaminB₁, vitaminB₂, vitaminB₆, vitaminC and coenzyme Q10). A total of 8 cases with COXPD32 were collected through 2 English literature reviews and this study. Among the 8 patients, 7 cases had onset during infancy and 1 was unknown, all had developmental delay or regression, 7 cases had feeding difficulty or dysphagia, followed by dystonia, lactic acidosis, ocular symptoms, microcephaly, constipation and dysmorphic facies(mild coarsening of facial features, small forehead, anterior hairline extending onto forehead,high and narrow palate, thick gums, short columella, and synophrys), 2 cases died of respiratory and circulatory failure, and 6 were still alive at the time of reporting, with an age range of 2 to 34 years. Blood and (or) cerebrospinal fluid lactate were elevated in all 8 patients. MRI in 7 cases manifested symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia. Urine organic acid test were all normal but 1 patient had alanine elevation. Five patients underwent respiratory chain enzyme activity testing, and all had varying degrees of enzyme activity reduction. Six variants were identified, 6 patients were homozygous variants, with c.322-10G>A was present in 4 patients from 2 families and 2 compound heterozygous variants. Conclusions: The clinical phenotype of COXPD32 is highly heterogenous and the severity of the disease varies from development delay, feeding difficulty, dystonia, high lactic acid, ocular symptoms and reduced mitochondrial respiratory chain enzyme activity in mild cases, which may survive into adulthood, to rapid death due to respiratory and circulatory failure in severe cases. COXPD32 needs to be considered in cases of unexplained acidosis, hyperlactatemia, feeding difficulties, development delay or regression, ocular symptoms, respiratory and circulatory failure, and symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia, and genetic testing can clarify the diagnosis.
Humans ; Male ; Acidosis, Lactic ; Brain ; Brain Stem ; Dystonia ; Dystonic Disorders ; Mitochondrial Diseases ; Infant

X-linked dystonia-parkinsonism (XDP) is an adult-onset debilitating neurodegenerative disorder presenting with motor and nonmotor symptoms. The treatment options for XDP are limited. We described a patient with XDP who underwent a unilateral transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) pallidothalamic tractotomy with a one-year follow-up. The patient reported an immediate improvement in his pain after the procedure. Compared to baseline, there was an improvement in his scores in the dystonia (31%), parkinsonism (35.1%), and activities of daily living (71%) subscales at 1-year follow up. The overall improvement at one year was 46%. There were no adverse events noted. Additional studies with larger sample size and follow-up would be needed to document its long-term safety and efficacy.
Dystonia 3, Torsion, X-Linked ; Dystonic Disorders ; Genetic Diseases, X-Linked

Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with choreoathetosis (ICCA). Reduced penetrance of PRRT2 has been observed in previous studies, whereas the exact penetrance has not been evaluated well. The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors. We screened 222 PKD index patients and their available relatives, identified 39 families with pathogenic or likely pathogenic (P/LP) PRRT2 variants via Sanger sequencing, and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature. Penetrance was estimated as the proportion of affected variant carriers. PRRT2 penetrance estimate was 77.6% (95% confidence interval (CI) 74.5%-80.7%) in relatives and 74.5% (95% CI 70.2%-78.8%) in obligate carriers. In addition, we first observed that penetrance was higher in truncated than in non-truncated variants (75.8% versus 50.0%, P = 0.01), higher in Asian than in Caucasian carriers (81.5% versus 68.5%, P = 0.004), and exhibited no difference in gender or parental transmission. Our results are meaningful for genetic counseling, implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders, with patients from Asia or carrying truncated variants at a higher risk.
Dystonia ; Epilepsy, Benign Neonatal/genetics* ; Humans ; Membrane Proteins/genetics* ; Mutation ; Nerve Tissue Proteins/genetics* ; Pedigree ; Penetrance ; Seizures/genetics*

No abstract available.
Dystonia*

GLUT1 deficiency is a rare neurometabolic disorder that can be effectively treated with ketogenic diet. However, this condition is underdiagnosed due to its nonspecific, overlapping, and evolving symptoms with age. We retrospectively reviewed the clinical course of nine patients diagnosed with GLUT1 deficiency, based on SLC2A1 mutations and/or glucose concentration in cerebrospinal fluid. The patients included eight boys and one girl who initially presented with seizures (44%, 4/9) or delayed development (44%, 4/9) before 2 years of age, except for one patient who presented with apnea as a neonate. Over the clinical course, all of the children developed seizures of the mixed type, including absence seizures and generalized tonic–clonic seizures. About half (56%, 5/9) showed movement disorders such as ataxia, dystonia, or dyskinesia. We observed an evolution of phenotype over time, although this was not uniform across all patients. Only one child had microcephaly. In five patients, ketogenic diet was effective in reducing seizures and movement symptoms, and the patients exhibited subjective improvement in cognitive function. Diagnosing GLUT1 deficiency can be challenging due to the phenotypic variability and evolution. A high index of clinical suspicion in pediatric and even older patients with epilepsy or movement disorders is key to the early diagnosis and treatment, which can improve the patient's quality of life.
Apnea ; Ataxia ; Cerebrospinal Fluid ; Child ; Clothing ; Cognition ; Dyskinesias ; Dystonia ; Early Diagnosis ; Epilepsy ; Epilepsy, Absence ; Female ; Glucose ; Humans ; Infant, Newborn ; Ketogenic Diet ; Microcephaly ; Movement Disorders ; Phenotype ; Quality of Life ; Retrospective Studies ; Seizures