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BMC Medical Genomics Jun 2024TTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and...
BACKGROUND
TTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and cardiac disorders. Homozygous or compound heterozygous mutations tend to cause a wide spectrum of phenotypes with congenital or childhood onset. The onset and severity of the features were considered to be correlated with the types and location of the TTN variants.
METHODS
Whole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed.
RESULTS
TTN c.38,876-2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans, was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases.
CONCLUSIONS
Here we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.
Topics: Humans; Female; Connectin; Pedigree; Male; Exome Sequencing; Arthrogryposis; Contracture; Mutation; Pregnancy; Fetus; Adult
PubMed: 38937733
DOI: 10.1186/s12920-024-01946-z -
PCN Reports : Psychiatry and Clinical... Jun 2024Delayed neuropsychiatric sequelae (DNS) is a syndrome that appears days to weeks after acute carbon monoxide (CO) poisoning. DNS shows various neuropsychiatric symptoms,...
BACKGROUND
Delayed neuropsychiatric sequelae (DNS) is a syndrome that appears days to weeks after acute carbon monoxide (CO) poisoning. DNS shows various neuropsychiatric symptoms, such as mental deterioration and parkinsonism.
CASE PRESENTATION
Our case was a 37-year-old male with schizophrenia. He attempted suicide by CO poisoning and was brought to our emergency department (Day 0). He was ventilated with normobaric oxygen therapy for 3 days and moved to the psychiatric ward with clear consciousness. We restarted antipsychotics, and he gradually presented akinesia and rigidity. Additionally, around Day 32, he showed disorganized behaviors, mental deterioration, incontinence, and gait disturbance. Brain magnetic resonance imaging (MRI) showed slightly abnormal findings on Day 35. Although we suspected DNS on the clinical course and the MRI findings, catatonia and side-effects of antipsychotics were also considered. Finally, electroencephalography (EEG) on Day 38 with apparent abnormalities, including diffuse slow waves, resulted in our diagnosis of DNS, and he underwent hyperbaric oxygen therapy. His condition was dramatically improved, and his diffuse slow waves on EEG disappeared on Day 83. We also followed his clinical presentations and brain MRI until 33 months. Throughout the whole follow-up, his cognition, movement, and psychiatric symptoms remained stable. However, his brain MRI showed progressive atrophy in bilateral frontal lobes and increasing white matter lesions throughout the whole course.
CONCLUSION
EEG, as well as brain MRI, may be crucial in the differential diagnosis of DNS in patients with complex conditions involving medications and severe mental illnesses.
PubMed: 38910909
DOI: 10.1002/pcn5.218 -
Ophthalmology Science 2024Knowing the surgical safety of anterior chamber liquid biopsies will support the increased use of proteomics and other molecular analyses to better understand disease...
PURPOSE
Knowing the surgical safety of anterior chamber liquid biopsies will support the increased use of proteomics and other molecular analyses to better understand disease mechanisms and therapeutic responses in patients and clinical trials. Manual review of operative notes from different surgeons and procedures in electronic health records (EHRs) is cumbersome, but free-text software tools could facilitate efficient searches.
DESIGN
Retrospective case series.
PARTICIPANTS
A total of 1418 aqueous humor liquid biopsies from patients undergoing intraocular surgery.
METHODS
Free-text EHR searches were performed using the Stanford Research Repository cohort discovery tool to identify complications associated with anterior chamber paracentesis and subsequent endophthalmitis. Complications of the surgery unrelated to the biopsy were not reviewed.
MAIN OUTCOME MEASURES
Biopsy-associated intraoperative complications and endophthalmitis.
RESULTS
A total of 1418 aqueous humor liquid biopsies were performed by 17 experienced surgeons. EHR free-text searches were 100% error-free for surgical complications, >99% for endophthalmitis (<1% false positive), and >93.6% for anesthesia type, requiring manual review for only a limited number of cases. More than 85% of cases were performed under local anesthesia without ocular muscle akinesia. Although the most common indication was cataract (50.1%), other diagnoses included glaucoma, diabetic retinopathy, uveitis, age-related macular degeneration, endophthalmitis, retinitis pigmentosa, and uveal melanoma. A 50- to 100-μL sample was collected in all cases using either a 30-gauge needle or a blunt cannula via a paracentesis. The median follow-up was >7 months. There was only one minor complication (0.07%) identified: a case of a small tear in Descemet membrane without long-term sequelae. No other complications occurred, including other corneal injuries, lens or iris trauma, hyphema, or suprachoroidal hemorrhage. There was no case of postoperative endophthalmitis.
CONCLUSIONS
Anterior chamber liquid biopsy during intraocular surgery is a safe procedure and may be considered for large-scale collection of aqueous humor samples for molecular analyses. Free-text EHR searches are an efficient approach to reviewing intraoperative procedures.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38881613
DOI: 10.1016/j.xops.2024.100517 -
Cureus May 2024Stereotactic radiosurgery (SRS) is a well-established treatment modality for the management of uveal melanoma, achieving high tumor control and eye retention rates....
Stereotactic radiosurgery (SRS) is a well-established treatment modality for the management of uveal melanoma, achieving high tumor control and eye retention rates. There are several SRS treatment platforms available, including the recently developed self-shielding gyroscopic radiosurgery (GRS) system. We report the first use of GRS in the treatment of uveal melanoma. We report the treatment of a 63-year-old female patient with a left-sided uveal melanoma. Akinesia of the ocular globe in the orbit was achieved by retrobulbar anesthesia. The treatment plan used six isocenters (three with the 10 mm and three with the 7.5 mm apertures) and 140 beams to cover 99.2% of the planning target volume (PTV) with 21 Gy at the 54% isodose line. Treatment was delivered in a single session with the GRS device. The total workflow time from retrobulbar anesthesia to completion of treatment was 122 minutes. The procedure was flawless, clinically well tolerated by the patient, and reliably performed in an outpatient setting, thus comparable to our published experience with robotic SRS. The evaluation of new radiosurgery treatment platforms is critical to maintaining quality standards and refining future treatments.
PubMed: 38854187
DOI: 10.7759/cureus.59859 -
BioRxiv : the Preprint Server For... May 2024The cardinal symptoms of Parkinson's disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal...
The cardinal symptoms of Parkinson's disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal dopamine neurons in PD produces motor symptoms by shifting the balance of striatal output from the direct (go) to indirect (no-go) pathway in large part through changes in the excitatory connections and intrinsic excitabilities of the striatal projection neurons (SPNs). Here, we report using two different experimental models that a transient increase in striatal dopamine and enhanced D1 receptor activation, during 6-OHDA dopamine depletion, prevent the loss of mature spines and dendritic arbors on direct pathway projection neurons (dSPNs) and normal motor behavior for up to 5 months. The primary motor cortex and midline thalamic nuclei provide the major excitatory connections to SPNs. Using ChR2-assisted circuit mapping to measure inputs from motor cortex M1 to dorsolateral dSPNs, we observed a dramatic reduction in both experimental model mice and controls following dopamine depletion. Changes in the intrinsic excitabilities of SPNs were also similar to controls following dopamine depletion. Future work will examine thalamic connections to dSPNs. The findings reported here reveal previously unappreciated plasticity mechanisms within the basal ganglia that can be leveraged to treat the motor symptoms of PD.
PubMed: 38854096
DOI: 10.1101/2024.05.28.596192 -
Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
Clinical Parkinsonism & Related... 2024Nocturnal and sleep-related motor disorders in people with Parkinson's disease (PD) have a wide spectrum of manifestations and present a complex clinical picture....
Nocturnal and sleep-related motor disorders in people with Parkinson's disease (PD) have a wide spectrum of manifestations and present a complex clinical picture. Problems can arise due to impaired movement ability (hypokinesias), e.g. nocturnal hypokinesia or early-morning akinesia, or to excessive movement (hyperkinesias), e.g. end-of-the-day dyskinesia, parasomnias, periodic limb movement during sleep and restless legs syndrome. These disorders can have a significant negative impact on the sleep, daytime functional ability, and overall quality of life of individuals with PD and their carers. The debilitating motor issues are often accompanied by a combination of non-motor symptoms, including pain and cramping, which add to the overall burden. Importantly, nocturnal motor disorders encompass a broader timeline than just the period of sleep, often starting in the evening, as well as occurring throughout the night and on awakening, and are not just limited to problems of insomnia or sleep fragmentation. Diagnosis can be challenging as, in many cases, the 'gold standard' assessment method is video polysomnography, which may not be available in all settings. Various validated questionnaires are available to support evaluation, and alternative approaches, using wearable sensors and digital technology, are now being developed to facilitate early diagnosis and monitoring. This review sets out the parameters of what can be considered normal nocturnal movement and describes the clinical manifestations, usual clinical or objective assessment methods, and evidence for optimal management strategies for the common nocturnal motor disorders that neurologists will encounter in people with PD in their clinical practice.
PubMed: 38845753
DOI: 10.1016/j.prdoa.2024.100258 -
Molecular Neurobiology Jun 2024MicroRNA (miRNA) are usually 18-25 nucleotides long non-coding RNA targeting post-transcriptional regulation of genes involved in various biological processes. The... (Review)
Review
MicroRNA (miRNA) are usually 18-25 nucleotides long non-coding RNA targeting post-transcriptional regulation of genes involved in various biological processes. The function of miRNA is essential for maintaining a homeostatic cellular condition, regulating autophagy, cellular motility, and inflammation. Dysregulation of miRNA is responsible for multiple disorders, including neurodegeneration, which has emerged as a severe problem in recent times and has verified itself as a life-threatening condition that can be understood by the continuous destruction of neurons affecting various cognitive and motor functions. Parkinson's disease (PD) is the second most common, permanently debilitating neurodegenerative disorder after Alzheimer's, mainly characterized by uncontrolled tremor, stiffness, bradykinesia or akinesia (slowness in movement), and post-traumatic stress disorder. PD is mainly caused by the demolition of the primary dopamine neurotransmitter secretory cells and dopaminergic or dopamine secretory neurons in the substantia nigra pars compacta of the midbrain, which are majorly responsible for motor functions. In this study, a systematic evaluation of research articles from year 2017 to 2022 was performed on multiple search engines, and lists of miRNA being dysregulated in PD in different body components were generated. This study highlighted miR-7, miR-124, miR-29 family, and miR-425, showing altered expression levels during PD's progression, further regulating the expression of multiple genes responsible for PD.
PubMed: 38823001
DOI: 10.1007/s12035-024-04261-x -
Rinsho Shinkeigaku = Clinical Neurology Jun 2024Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their... (Review)
Review
Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.
Topics: Humans; Animals; Movement Disorders; Mice; Basal Ganglia; Disease Models, Animal; Parkinson Disease
PubMed: 38811203
DOI: 10.5692/clinicalneurol.cn-001957 -
Cureus Apr 2024A 58-year-old male with a medical history of arterial hypertension, dyslipidemia, and psoriasis was admitted for a scheduled surgical removal of the thyroid gland....
A 58-year-old male with a medical history of arterial hypertension, dyslipidemia, and psoriasis was admitted for a scheduled surgical removal of the thyroid gland. During the surgery, the patient suffered severe blood loss caused by vascular complications. After the operation, his electrocardiogram showed diffuse ST segment elevation along with high-sensitivity cardiac troponin T elevation and severe left ventricular systolic dysfunction. An emergency coronary angiography showed unobstructed coronary arteries. However, the left ventriculography demonstrated akinesia of the apical segments and hyperkinesia of the basal segments during systole. The patient was diagnosed with Takotsubo syndrome and he was successfully stabilized over the course of the next few days. Takotsubo cardiomyopathy is characterized by transient left ventricular systolic dysfunction and although the clinical and electrocardiographical presentation is similar to an acute coronary syndrome, the coronary arteries are unobstructed. Stressful events, both physical or psychological, could trigger an excessive catecholaminergic response which can cause the syndrome. Repetitive echocardiograms in our patient demonstrated complete recovery of the systolic function after a few days.
PubMed: 38800257
DOI: 10.7759/cureus.59090