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Movement Disorders Clinical Practice Jan 2024Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course.
BACKGROUND
Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course.
OBJECTIVES
To estimate the probability of preserving ambulatory ability and survival in NBIA.
METHODS
In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods.
RESULTS
One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03).
CONCLUSIONS
KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.
Topics: Humans; Female; Pantothenate Kinase-Associated Neurodegeneration; Iron Metabolism Disorders; Hemochromatosis; Brain; Neurodegenerative Diseases; Muscle Spasticity; Walking; Iron; Parkinsonian Disorders
PubMed: 38291840
DOI: 10.1002/mdc3.13933 -
Neurochemical Research Jun 2024Parkinson's disease (PD) is characterized by oxidative stress and neuroinflammation as key pathological features. Emerging evidence suggests that nuclear factor...
Parkinson's disease (PD) is characterized by oxidative stress and neuroinflammation as key pathological features. Emerging evidence suggests that nuclear factor erythroid 2 related factor 2-antioxidant response element (Nrf2-ARE), phosphatidylinositol 3‑kinase-protein kinase B (PI3K-Akt), c-Jun N-terminal kinase-extracellular signal-regulated kinase 1/2 (JNK-ERK1/2), and toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kB) pathways play pivotal roles in PD pathogenesis. Orientin, a phenolic phytoconstituent, has demonstrated modulatory potential on these pathways in various experimental conditions other than PD. In this study, we aimed to evaluate the neuroprotective effects of Orientin against rotenone-induced neurodegeneration in SH-SY5Y cell lines and the Swiss albino mice model of PD. Orientin was administered at doses 10 and 20 µM in cell lines and 10 and 20 mg/kg in mice, and its effects on rotenone-induced neurodegeneration were investigated. Oxidative stress markers including mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as inflammatory markers including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were measured. The expression levels of genes related to Nrf2-ARE (Nrf2), PI3K/Akt (Akt), JNK-ERK1/2 (TNF-α), and TLR4/NF-kB (TNF-α) pathways were measured to understand the modulatory effect of Orientin on these pathways. Additionally, behavioral studies assessing locomotor activity, muscle coordination, and muscle rigidity were conducted with mice. Our results indicate that Orientin dose-dependently attenuated rotenone-induced changes in oxidative stress markers, inflammatory markers, gene expression levels, and behavioral parameters. Therefore, our study concludes that Orientin exhibits significant neuroprotective benefits against rotenone-induced PD by modulating Nrf2-ARE, PI3K-Akt, JNK-ERK1/2, and TLR4/NF-kB pathways.
Topics: Animals; Neuroprotective Agents; Mice; Flavonoids; NF-E2-Related Factor 2; Toll-Like Receptor 4; Proto-Oncogene Proteins c-akt; Rotenone; Humans; NF-kappa B; Male; Glucosides; Oxidative Stress; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; MAP Kinase Signaling System; Parkinson Disease; Signal Transduction
PubMed: 38276990
DOI: 10.1007/s11064-024-04099-8 -
American Journal of Respiratory Cell... Apr 2024Alveolar septation increases gas-exchange surface area and requires coordinated cytoskeletal rearrangement in lung fibroblasts (LFs) to balance the demands of...
Alveolar septation increases gas-exchange surface area and requires coordinated cytoskeletal rearrangement in lung fibroblasts (LFs) to balance the demands of contraction and cell migration. We hypothesized that DBN (drebrin), a modulator of the actin cytoskeleton in neuronal dendrites, regulates the remodeling of the LF cytoskeleton. Using mice bearing a transgelin-Cre-targeted deletion of Dbn in pulmonary fibroblasts and pericytes, we examined alterations in alveolar septal outgrowth, LF spreading and migration, and actomyosin function. The alveolar surface area and number of alveoli were reduced, whereas alveolar ducts were enlarged, in mice bearing the deletion (DBNΔ) compared with their littermates bearing only one -Flox allele (control). Cultured DBNΔ LFs were deficient in their responses to substrate rigidity and migrated more slowly. Drebrin was abundant in the actin cortex and lamella, and the actin fiber orientation was less uniform in lamella of DBNΔ LFs, which limited the development of traction forces and altered focal adhesion dynamics. Actin fiber orientation is regulated by contractile NM2 (nonmuscle myosin-2) motors, which help arrange actin stress fibers into thick ventral actin stress fibers. Using fluorescence anisotropy, we observed regional intracellular differences in myosin regulatory light chain phosphorylation in control LFs that were altered by deletion. Using perturbations to induce and then release stalling of NM2 on actin in LFs from both genotypes, we made predictions explaining how DBN interacts with actin and NM2. These studies provide new insight for diseases such as emphysema and pulmonary fibrosis, in which fibroblasts inappropriately respond to mechanical cues in their environment.
Topics: Mice; Animals; Actins; Neuropeptides; Lung; Actin Cytoskeleton; Myosin Light Chains
PubMed: 38271699
DOI: 10.1165/rcmb.2023-0229OC -
Toxins Dec 2023The current data regarding poisoning associated with ingestion of fungus-infected cicada nymphs are limited. We performed a retrospective cohort study of patients who...
The current data regarding poisoning associated with ingestion of fungus-infected cicada nymphs are limited. We performed a retrospective cohort study of patients who ingested fungus-infected cicada nymphs and were referred to the Ramathibodi Poison Center for consultation from June 2010 to June 2022. Thirty-nine patients were included for analysis. Most were men (53.8%). Mean age was 40.2 ± 15.0 years. All nymphs were ingested as a health/food supplement. Thirty-one patients (79.5%) reported gastrointestinal symptoms. Median time from ingestion to symptom onset was 5 h. Twenty-nine patients (74.4%) reported neurological symptoms, including tremor, myoclonus, muscle rigidity, nystagmus/ocular clonus, drowsiness, dysarthria, seizure, and confusion. Some complained of dizziness, urinary retention, and jaw stiffness. Most patients (94.9%) were admitted to the hospital. Median hospital stay was 3 days. Ibotenic acid was detected in the blood and urine samples of one patient. All received supportive care. Four patients developed infectious complications. No deaths occurred. Consuming fungus-infected cicada nymphs may cause poisoning in humans. Gastrointestinal and neurological symptoms were common. Ibotenic acid might be the underlying cause. The main treatment is supportive care and appropriate management of complications. Education of the general public is advocated to prevent the incidence of this type of poisoning.
Topics: Male; Humans; Adult; Middle Aged; Female; Thailand; Ibotenic Acid; Retrospective Studies; Fungi; Eating
PubMed: 38251239
DOI: 10.3390/toxins16010022 -
Frontiers in Psychiatry 2023We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial...
We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.
PubMed: 38250256
DOI: 10.3389/fpsyt.2023.1301272 -
Cureus Dec 2023In the realm of well-being, the essence of maintaining optimal oral health is gaining more recognition. This quantifying quotient is being compromised in cerebral palsy... (Review)
Review
In the realm of well-being, the essence of maintaining optimal oral health is gaining more recognition. This quantifying quotient is being compromised in cerebral palsy (CP) patients due to multitude variations. Spastic CP predominantly impacts bodily motions, muscle synchronization, command, muscle tone, reflexes, stance, equilibrium, and can additionally influence both delicate and large-scale motor abilities. For individuals with spastic CP, the rigidity extends its influence over both their upper and lower limbs. When this stiffness takes hold in the upper limb, it poses significant challenges in executing everyday activities, causing issues with precise grasping and coordination of muscle movements. Consequently, using a toothbrush effectively becomes a formidable task resulting in widespread caries and periodontal diseases in spastic CP patients. The central focus of this review is to explore the oral health challenges of spastic cerebral palsy patients and mapping out a path towards the most efficient time-tested and innovative dental management approaches for preserving oral health in these patients.
PubMed: 38196433
DOI: 10.7759/cureus.50246 -
Pain Practice : the Official Journal of... Jun 2024Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by rigidity and painful spasm primarily affecting the truncal and paraspinal musculature...
BACKGROUND
Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by rigidity and painful spasm primarily affecting the truncal and paraspinal musculature due to autoimmune-mediated neuronal hyperexcitability. Spinal cord stimulation (SCS) is an approved therapy for managing painful neuropathic conditions, including diabetic peripheral neuropathy and refractory angina pectoris. We describe the novel use of SCS for the treatment of spasm and rigidity in a 49-year-old man with seropositive stiff person syndrome (SPS). The patient was treated with intravenous immunoglobulin (IVIG) and oral medications over a 13-month period with minimal improvement, prompting consideration of SCS. To our knowledge, this is the first report of the successful use of SCS in SPS with the demonstration of multifaceted clinical improvement.
METHODS
Following a successful temporary SCS trial, permanent implantation was performed. Spasm/stiffness (Distribution of Stiffness Index; Heightened Sensitivity Scale; Penn Spasm Frequency Scale, PSFS), disability (Oswestry Disability Index, ODI; Pain Disability Index, PDI), depression (Patient Health Questionnaire-9, PHQ-9), sleep (Pittsburgh Sleep Quality Index, PSQI), fatigue (Fatigue Severity Scale, FSS), pain (Numerical Pain Rating Scale, NPRS), quality of life (EuroQoL 5 Dimension 5 Level, EQ-5D-5L), and medication usage were assessed at baseline, 6-month, and 10-month postimplantation.
RESULTS
ODI, PHQ-9, FSS, NPRS, PSQI, and EQ-5D-5L scores showed a notable change from baseline and surpassed the defined minimal clinically important difference (MCID) at 6-month and 10-month follow-up. Oral medication dosages were reduced.
CONCLUSIONS
The novel use of SCS therapy in seropositive SPS resulted in functional improvement and attenuation of symptoms. We present possible mechanisms by which SCS may produce clinical response in patients with SPS and aim to demonstrate proof-of-concept for a future comprehensive pilot study evaluating SCS-mediated response in SPS.
Topics: Humans; Stiff-Person Syndrome; Male; Middle Aged; Spinal Cord Stimulation; Muscle Rigidity; Spasm; Treatment Outcome
PubMed: 38185725
DOI: 10.1111/papr.13340 -
Journal of Veterinary Internal Medicine 2024Muscular dystrophies (MDs) are a large, heterogeneous group of degenerative muscle diseases. X-linked dystrophin-deficient MD in cats is the first genetically...
BACKGROUND
Muscular dystrophies (MDs) are a large, heterogeneous group of degenerative muscle diseases. X-linked dystrophin-deficient MD in cats is the first genetically characterized cat model for a human disease and a few novel forms have been identified.
HYPOTHESIS/OBJECTIVES
Muscular dystrophy was suspected in a young male domestic shorthair cat. Clinical, molecular, and genetic techniques could provide a definitive diagnosis.
ANIMALS
A 1-year-old male domestic shorthair cat presented for progressive difficulty walking, macroglossia and dysphagia beginning at 6 months of age. The tongue was thickened, protruded with constant ptyalism, and thickening and rigidity of the neck and shoulders were observed.
METHODS
A complete neurological examination, baseline laboratory evaluation and biopsies of the trapezius muscle were performed with owner consent. Indirect immunofluorescence staining of muscle cryosections was performed using several monoclonal and polyclonal antibodies against dystrophy-associated proteins. DNA was isolated for genomic analyses by whole genome sequencing and comparison to DNA variants in the 99 Lives Cat Genome Sequencing dataset.
RESULTS AND CLINICAL IMPORTANCE
Aspartate aminotransferase (687 IU/L) and creatine kinase (24 830 IU/L) activities were increased and mild hypokalemia (3.7 mmol/L) was present. Biopsy samples from the trapezius muscle confirmed a degenerative and regenerative myopathy and protein alterations identified by immunohistochemistry resulted in a diagnosis of a in dystrophin-deficient form of X-linked MD. A stop gain variant (c.4849C>T; p.Gln1617Ter) dystrophin was identified by genome sequencing. Precision/genomic medicine efforts for the domestic cat and in veterinary medicine support disease variant and animal model discovery and provide opportunities for targeted treatments for companion animals.
Topics: Humans; Cats; Male; Animals; Dystrophin; Precision Medicine; Muscular Dystrophy, Duchenne; Whole Genome Sequencing; DNA; Cat Diseases
PubMed: 38180235
DOI: 10.1111/jvim.16971 -
Journal of Integrative Neuroscience Oct 2023Parkinson's disease (PD) is a common neurodegenerative disorder characterized by misfolding of α-synuclein. Clinical manifestations include slowly developing resting... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by misfolding of α-synuclein. Clinical manifestations include slowly developing resting tremor, muscle rigidity, bradykinesia and abnormal gait. The pathological mechanisms underlying PD are complex and yet to be fully elucidated. Clinical studies suggest that the onset of gastrointestinal symptoms may precede motor symptoms in PD patients. The microbiota-gut-brain axis plays a bidirectional communication role between the enteric nervous system and the central nervous system. This bidirectional communication between the brain and gut is influenced by the neural, immune and endocrine systems related to the gut microbiome. A growing body of evidence indicates a strong link between dysregulation of the gut microbiota and PD. In this review, we present recent progress in understanding the relationship between the microbiota-gut-brain axis and PD. We focus on the role of the gut microbiota, the unique changes observed in the microbiome of PD patients, and the impact of these changes on the progression of PD. Finally, we evaluate the role of current treatment strategies for PD, including probiotics, fecal microbial transplants, dietary modifications, and related drug therapies.
Topics: Humans; Parkinson Disease; Brain-Gut Axis; Gastrointestinal Microbiome; Probiotics; Brain
PubMed: 38176929
DOI: 10.31083/j.jin2206157 -
Nihon Yakurigaku Zasshi. Folia... 2024Parkinson's disease (PD), which has characteristic motor symptoms such as tremor, muscle rigidity, and akinesia, and as the disease progresses, Lewy bodies spread... (Randomized Controlled Trial)
Randomized Controlled Trial
Parkinson's disease (PD), which has characteristic motor symptoms such as tremor, muscle rigidity, and akinesia, and as the disease progresses, Lewy bodies spread throughout the brain, eventually causing Parkinson disease dementia (PDD). The clinical picture of PDD is similar to Dementia with Lewy bodies (DLB) and their pathological features are indistinguishable from each other. More than 80% of PD cases will eventually develop dementia and their prognosis are generally 3 to 4 years from the onset of dementia, regardless of disease duration or age of onset. We found that patients with severe olfactory impairment had lower cognitive function scores, more frequent onset of dementia, brain atrophy, and prominent cerebral metabolic abnormalities in a 3-year longitudinal study (Brain 135:161-169, 2012). This study demonstrated for the first time in the world that olfaction tests are useful in predicting dementia in PD, and similar results have been followed up worldwide. Based on these results, a randomized, double-blind, multicenter comparative study of donepezil in PD with severe olfactory dysfunction (DASH-PD study) was conducted and completed a 4-year follow-up period. The results were recently published showing the efficacy and safety of cholinesterase inhibitors for PD without dementia (eClinicalMedicine 51: 101571, 2022).
Topics: Humans; Parkinson Disease; Lewy Body Disease; Dementia; Longitudinal Studies; Donepezil
PubMed: 38171841
DOI: 10.1254/fpj.23064