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The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS.
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OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.
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While the traditional lung function tests are used to assess lung capacity and pulmonary function, they cannot evaluate respiratory driving function and the integrity of the conduction pathway from the central nervous system to the respiratory motor neuron in the spinal cord and to the diaphragm. The inspiratory trigger is sent from the central nervous system through the phrenic nerve and drives the diaphragm to generate inspiratory movement. Therefore, phrenic nerve stimulation and diaphragmatic electromyography are two fundamental methods to assess respiratory function. There are several useful tools to assess respiratory motor system including electrical or magnetic phrenic nerve stimulation, diaphragmatic needle electromyography, and diaphragmatic ultrasound. By these means, physicians can assess current respiratory status in different neurological diseases that affect respiratory muscles, follow-up of the severity of respiratory impairment, help to predict the chance of successfully weaning from ventilatory support, and confirm clinical diagnoses such as diaphragmatic myoclonus. Although some of these tests require special training, applying these neurophysiological assessments in clinical practice is highly recommended.
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Diafragma , Nervio Frénico , Electromiografía , Humanos , Respiración , Músculos RespiratoriosRESUMEN
Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder with a dramatic clinical presentation. It was recently discovered that MADD may present at an advanced age. The clinical and laboratory data of an index patient and patients previously diagnosed at our institution were collected. A systematic review of previous studies retrieved from the PubMed, MEDLINE, and Embase databases published by February 1, 2020 was performed to collect patients with very-late-onset MADD (VLO-MADD, onset age > 60 years) globally and patients with late-onset MADD (LO-MADD, onset age < 60 years) in Taiwan. The clinical characteristics of the VLO-MADD patients were compared to those of LO-MADD patients. We report a patient with VLO-MADD who developed the first symptom at the age of 61 years. The patient presented with a Reye-like syndrome after taking aspirin for coronary artery disease. Repeated bouts of weakness were noted. Two variants of c.250â¯G > A (;) 419C > T were observed in the ETFDH gene. Another four patients with VLO-MADD were identified globally. Eighteen patients with LO-MADD were collected from our department and previously reported patients in Taiwan. There was no difference in the clinical symptoms (except for the onset age) or laboratory data between these two groups. Homozygous variants were not observed in any patients in the VLO-MADD group but were detected in 12 patients (66.6%) in the LO-MADD group (pâ¯=â¯0.014). Patients with MADD may first show symptoms in their 6th decade or beyond. The disease course may lead to erroneous diagnoses in this age group.