Search Results (92)

A 51-year-old female presented to the emergency department with vertigo, visual disturbances, involuntary rapid repetitive eye movements, incoordination, and imbalance. Physical examination revealed opsoclonus, myoclonus, and bilateral limb and gait ataxia. Initial workup was negative for intracranial abnormalities, and no abnormalities were noted on blood work or cerebrospinal fluid analysis. Tumor markers were within normal limits. As part of her diagnostic workup, a positron emission tomography (PET) scan was performed, which showed a highly FDG-avid solitary 7 mm left axillary lymph node. Ultrasound-guided percutaneous biopsy revealed metastatic poorly differentiated carcinoma. Histopathological examination could not conclusively distinguish between adenocarcinoma and squamous cell carcinoma. She was diagnosed with seronegative opsoclonus-myoclonus ataxia syndrome of paraneoplastic origin from an occult primary malignancy and started on pulsatile corticosteroids and intravenous immunoglobulin (IVIG), with only moderate symptomatic improvement. Given the anatomic location and immunohistochemical staining pattern of the lymph node, the malignancy was considered as being of primary breast origin. A left axillary lymph node dissection was performed, with 1/12 nodes testing positive for poorly differentiated carcinoma. The patient experienced significant improvement in her neurological symptoms 2–3 days following resection of the solitary malignant lymph node, largely regaining her functional independence. She went on to receive adjuvant radiotherapy to the breast and axilla, as well as adjuvant hormonal therapy. Full article

Cervical myoclonus (CM) has been associated with intervertebral disc extrusion (IVDE), with a higher prevalence in French Bulldogs. The presence of CM in other breeds and with other aetiologies has not been reported. The purpose of this study was to describe the signalment, neurological examination, neuroanatomical localisation and grade, imaging findings, diagnosis, treatment, follow-up and resolution of CM in dogs. An observational multicentred retrospective analysis identified 173 dogs with CM; of those, 113 met the inclusion criteria. French Bulldogs (n = 52/113, 46%), Beagles (n = 8/113, 7.1%), Chihuahuas and Shih-Tzus (n = 6/113 for each, 5.31%) were the most affected breeds. Apparent cervical pain was the most common finding on neurologic examination (n = 70/113, 62%). Magnetic resonance imaging (MRI) was consistent with nerve root impingement in 17% (n = 19/113) of the dogs. The most frequently diagnosed conditions were degenerative (n = 100/113, 88.5%), inflammatory (n = 8/113, 7.1%), neoplastic (n = 3/113, 2.7%), vascular (n = 1/113, 0.9%) and congenital (n = 1/113, 0.9%) in origin. Dogs with a neoplastic aetiology tended to be older than those with other causes. Follow-up was recorded in 77 dogs, and 75 of these (n = 75/77, 97.4%) had resolution of the CM. The results supported that cervical myoclonus can be caused by various underlying conditions and can affect different dog breeds. Full article

Lafora progressive myoclonus epilepsy (LD, OMIM#254780, ORPHA:501) is an ultra-rare and severe autosomal recessive neurological disorder that typically manifests in early adolescence. It is characterized by the accumulation of insoluble forms of aberrant glycogen in the brain and peripheral tissues. Given the urgent need for reliable tools to monitor disease progression, we aimed to identify reliable biomarkers in minimally invasive fluids, which could also provide valuable insights into the natural history of the disease. Plasma-EDTA samples from eleven LD patients and healthy controls were analyzed to identify potential biomarkers of LD using a high-throughput assay. The findings were subsequently validated using specific enzyme-linked immunosorbent assays (ELISAs). Eleven cytokines and growth factors were identified to be significantly reduced in LD patient samples compared to healthy controls. Among these, four mediators [platelet-derived growth factor subunit B (PDGF-BB), epidermal growth factor (EGF), brain derived growth factor (BDNF), and macrophage migration inhibitory factor (MIF)] exhibited the greatest fold change between the groups and were further validated. Given the minimally invasive nature of plasma sampling and the straightforward quantification via ELISA assays, these biomarkers hold strong promise for rapid translation to the clinic, potentially enhancing early diagnosis and longitudinal disease monitoring in LD patients. Full article

Background and Objectives: Febrile seizures (FS) are neuronal disturbances frequently associated with abnormal electroencephalographic activity (EEG) as spike-wave discharges (SWDs). Fish oil (FO) has high amounts of omega-3 fatty acids (θ-3), and its effects on FS alterations are poorly understood. The aim of this work was to evaluate the effect of long-term FO supplementation on the EEG of the amygdala of adult male rats with early-life FS. Materials and Methods: Progenitor female Wistar rats, from puberty to gestation and delivery, were fed daily with a commercial diet supplemented with either fish oil (FO), palm oil (PO), or deionized water (CTRL). After parturition, male pups were exposed for 30 min to hyperthermia (HP) and then returned to their dams. After weaning, pups were fed a commercial diet and the respective treatments up to 155 days of age when electrodes were implanted in the amygdala. Results: During early life HP, the PO and CTRL groups reached maximal core temperature (CT) in comparison with the FO group. Furthermore, the FO group only has fewer myoclonus and long latency to adopt an uncontrolled posture. At an adult age, the FO group with early-life FS scored shorter periods of SWDs in amygdala EEG but without seizures and presented minor values of absolute power than the PO and CTRL groups. Conclusions: In adult rats, the long-term supplementation of FO minimizes the deleterious behavioral effects caused by early-life FS and decreases the occurrence and amplitude of SWDs in the EEG of the amygdala. Full article

Background: Childhood-onset progressive ataxias are rare neurodegenerative disorders characterized by cerebellar signs, sometimes associated with other neurological or extra-neurological features. The autosomal dominant forms, known as spinocerebellar ataxias (SCAs), linked to trinucleotide (i.e., CAG) repeat disorders, are ultra-rare in children. We describe three patients from two unrelated families affected by spinocerebellar ataxia type 2 (SCA2) and present a literature review of pediatric cases. Methods: The patients’ clinical and genetic data were collected retrospectively. Results: The first case was a 9.5-year-old boy, affected by ataxia with oculomotor apraxia and cerebellar atrophy, subcortical myoclonus, and peripheral axonal sensitive polyneuropathy caused by a pathologic expansion in ATXN2, inherited from his asymptomatic father. Two brothers with familial SCA2 presented neurodegeneration leading to early death in one case and progressive ataxia, parkinsonism, and epilepsy with preserved ambulation at age 18 years in the second. To date, 19 pediatric patients affected by SCA2 have been reported, 3 of whom had a phenotype consistent with progressive ataxia with shorter CAG repeats, while 16 had more severe early-onset encephalopathy, with longer alleles. Conclusions: Although they are ultra-rare, trinucleotide repeat disorders must be considered in differential diagnosis of hereditary progressive ataxias in children, especially considering that they require targeted genetic testing and can manifest even before a parental carrier becomes symptomatic. Thus, they must also be taken into account with negative family history and when Next-Generation Sequencing (NGS) results are inconclusive. Notably, the association between cerebellar ataxia and other movement disorders should raise suspicion of SCA2 among differential diagnoses. Full article

Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient’s death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus. Full article

Background and Objectives: Myoclonus is already associated with a wide variety of drugs and systemic conditions. As new components are discovered, more drugs are suspected of causing this disabling abnormal involuntary movement. This systematic review aims to assess the medications associated with drug-induced myoclonus (DIM). Materials and Methods: Two reviewers assessed the PubMed database using the search term “myoclonus”, without language restriction, for articles published between 1955 and 2024. The medications found were divided into classes and sub-classes, and the subclasses were graded according to their level of evidence. Results: From 12,097 results, 1115 were found to be DIM. The subclasses of medications with level A evidence were intravenous anesthetics (etomidate), cephalosporins (ceftazidime, cefepime), fluoroquinolones (ciprofloxacin), selective serotonin reuptake inhibitors (citalopram, escitalopram, paroxetine, sertraline), tricyclic antidepressant (amitriptyline), glutamate antagonist (amantadine), atypical antipsychotics (clozapine, quetiapine), antiseizure medications (carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, valproate), pure opioid agonist (fentanyl, morphine), bismuth salts, and mood stabilizers (lithium). The single medication with the highest number of reports was etomidate. Drug-induced asterixis is associated with a specific list of medications. The neurotransmitters likely involved in DIM are serotonin, dopamine, gamma-aminobutyric acid (GABA), and glutamate. Conclusions: DIM may be reversible with management that can include drug discontinuation, dose adjustment, and the prescription of a medication used to treat idiopathic myoclonus. Based on the main clinical constellation of symptoms and pathophysiological mechanisms found in this study, DIM can be categorized into three types: type 1 (serotonin syndrome), type 2 (non-serotonin syndrome), and type 3 (unknown). Full article

Background/Objectives: Cardiac arrest may cause significant hypoxic–ischemic injury leading to coma, seizures, myoclonic jerks, or status epilepticus. Mortality is high, but accurate prognostication is challenging. A multimodal approach is employed, in which electroencephalography (EEG) forms a key part with several recognised patterns of prognostic significance. Methods: In this retrospective study, clinical and qualitative features of the EEG of patients admitted to the Intensive Care Unit (ICU) at Kingston General Hospital following cardiac arrest from 2017 to 2020 were reviewed. The study included 81 adult patients (≥18 years). Outcome was assessed using the Cerebral Performance Category (CPC) as 1–2 (favourable) or 3–5 (unfavourable). EEG patterns were divided into groups within the highly malignant, malignant and benign patterns described in the literature. Results: There were a wide range of causes and 22% had a favourable outcome. Highly malignant, malignant and benign patterns were associated with survival in 0%, 70% and 100%, respectively, and favourable outcomes in 0%, 48% and 100%. All patients with seizures died, and 94% with myoclonus had unfavourable outcomes. In contrast, EEG reactivity and improvement on follow-up EEG were associated with a favourable outcome. Conclusions: Highly malignant EEG, seizures and myoclonus were associated with unfavourable outcomes, while patients with malignant EEG had better outcomes. Full article

Background: Runs of homozygosity (ROHs), continuous homozygous regions across the genome, are often linked to consanguinity, with their size and frequency reflecting shared parental ancestry. Homozygosity mapping (HM) leverages ROHs to identify genes associated with autosomal recessive diseases. Whole-exome sequencing (WES) improves HM by detecting ROHs and disease-causing variants. Methods: To streamline personalized multigene panel creation, using WES and ROHs, we developed a methodology integrating ROHMMCLI and HomozygosityMapper algorithms, and, optionally, Human Phenotype Ontology (HPO) terms, implemented in a Django Web application. Resorting to a dataset of 12,167 WES, we performed the first ROH profiling of the Portuguese population. Clustering models were applied to predict consanguinity from ROH features. Results: These resources were applied for the genetic characterization of two siblings with epilepsy, myoclonus and dystonia, pinpointing the CSTB gene as disease-causing. Using the 2021 Census population distribution, we created a representative sample (3941 WES) and measured genome-wide autozygosity (F_ROH). Portalegre, Viseu, Bragança, Madeira, and Vila Real districts presented the highest F_ROH scores. Multidimensional scaling showed that ROH count and sum were key predictors of consanguinity, achieving a test F1-score of 0.96 with additional features. Conclusions: This study contributes with new bioinformatics tools for ROH analysis in a clinical setting, providing unprecedented population-level ROH data for Portugal. Full article

Background: Hyperkinetic movement disorders involve excessive, involuntary movements such as ataxia, chorea, dystonia, myoclonus, tics, and tremor. Recent advances in artificial intelligence (AI) allow investigators to integrate multimodal instrumented movement measurements and imaging techniques and to analyze these data together at scale. In this systematic review, we aim to characterize AI’s performance in diagnosing and quantitatively phenotyping these disorders. Methods: We searched PubMed and Embase using a semi-automated article-screening pipeline. Results: Fifty-five studies met the inclusion criteria (n = 11,946 subjects). Thirty-five studies used machine learning, sixteen used deep learning, and four used both. Thirty-eight studies reported disease diagnosis, twenty-three reported quantitative phenotyping, and six reported both. Diagnostic accuracy was reported in 36 of 38 and correlation coefficients in 10 of 23 studies. Kinematics (e.g., accelerometers and inertial measurement units) were the most used dataset. Diagnostic accuracy was reported in 36 studies and ranged from 56 to 100% compared to clinical diagnoses to differentiate them from healthy controls. The correlation coefficient was reported in 10 studies and ranged from 0.54 to 0.99 compared to clinical ratings for quantitative phenotyping. Five studies had an overall judgment of “low risk of bias” and three had external validation. Conclusion: There is a need to adopt AI-based research guidelines to minimize reporting heterogeneity and bolster clinical interpretability. Full article

Dystonia is a movement disorder with an estimated prevalence of 1.2% and is characterised by involuntary muscle contractions leading to abnormal postures and pain. Only symptomatic treatments are available with no disease-modifying or curative therapy, in large part due to the limited understanding of the underlying pathophysiology. However, the inherited monogenic forms of dystonia provide an opportunity for the development of disease models to examine these mechanisms. Myoclonus Dystonia, caused by SGCE mutations encoding the ε-sarcoglycan protein, represents one of now >50 monogenic forms. Previous research has implicated the involvement of the basal ganglia–cerebello-thalamo-cortical circuit in dystonia pathogenesis, but further work is needed to understand the specific molecular and cellular mechanisms. Pluripotent stem cell technology enables a patient-derived disease modelling platform harbouring disease-causing mutations. In this review, we discuss the current understanding of the aetiology of Myoclonus Dystonia, recent advances in producing distinct neuronal types from pluripotent stem cells, and their application in modelling Myoclonus Dystonia in vitro. Future research employing pluripotent stem cell-derived cellular models is crucial to elucidate how distinct neuronal types may contribute to dystonia and how disruption to neuronal function can give rise to dystonic disorders. Full article

Tubulinopathies are associated with malformations of cortical development but not Walker–Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker–Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker–Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker–Warburg-associated genes confirm this as not a new presentation of Walker–Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of. Full article

(1) Background: Niemann–Pick type C1 (NP-C1) is a lysosomal storage disorder that results in the defective trafficking of cholesterol and other cellular lipids in the endosomal–lysosomal pathway. This rare autosomal recessive disorder presents in three forms based on the age of onset. The adult form presents in patients greater than 15 years of age but is rarely seen after the age of 30. Common symptoms of the late adult-onset category of NP-C1 include progressive cognitive impairment and ataxia, with psychiatric and movement disorders presenting less frequently than in other forms of NP-C1. Dystonic movement disorders present most frequently, along with chorea, myoclonus, and parkinsonism. Herein, we present a rare case of NP-C1, diagnosed at age 35 with an initial symptom of supranuclear palsy. The goal of the presented case is to highlight the importance of the neurological examination and an inclusive differential diagnosis in patients with new-onset supranuclear palsy. (2) Methods: A single case report. (3) Results: A 46-year-old male with a past medical history of NP-C1 was admitted to the hospital for respiratory distress. He was noted to have a supranuclear gaze palsy with partially preserved voluntary saccades to the right. His mother revealed that he first had difficulty moving his eyes at the age of 34. After multiple consultations and genetic testing one year later, he was diagnosed with NP-C1. (4) Conclusions: Because NP-C1 affects many regions of the brain responsible for eye movements, neurological eye assessments can be a useful tool in diagnoses. Furthermore, eye movement abnormalities may be the initial presenting symptom of NP-C1, predisposing patients to misdiagnosis with progressive supranuclear palsy and other conditions that may mimic early-stage NP-C1. Definitive diagnosis is achieved through genetic testing. Filipin staining test was the gold standard in the past. The NP-C Suspicion Index was developed to assist in diagnoses, but its efficacy is unclear with late adult-onset NP-C1. Although no cure exists, early identification can facilitate an improved symptom management course for patients. Miglustat, a glucosylceramide synthase (GCS) inhibitor, is the approved therapy in Europe specific to NP-C1 for slowing and preventing the neurological manifestations of NP-C1. Delays between symptom onset and treatment initiation are likely to result in poorer outcomes and a progression of neurological symptoms. High doses may present tolerance concerns, especially in cases of delayed treatment and advanced neurological deficit. Full article

Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions. Full article

Opsoclonus-myoclonus ataxia syndrome (OMAS), also known as Kinsbourne syndrome, is a rare disorder that presents with myoclonus, ataxia, abnormal eye movements, irritability, and sleep disruptions, often in young children. We report a case of an infant barely 6 months old, with no significant past medical history, who presented to the emergency department with tremors, jerking motions of the head and arms, and rapid eye movements. After an extensive workup, she was found to have a neuroblastoma, which was subsequently surgically removed via thoracotomy. Despite an initial improvement in symptoms post-resection, the patient’s symptoms recurred. She was subsequently treated with dexamethasone, intravenous immunoglobulin (IVIG), and rituximab. After treatment, the patient was noted to have mild global developmental delays but was otherwise well. This case report highlights the rare occurrence of OMAS in an infant barely 6 months old at diagnosis. Using the PubMed database, a systematic review was conducted to highlight the clinical presentation, diagnosis, and management of OMAS. Full article