Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot-Marie-Tooth disease and identification of H256R as a frequent mutation.

BACKGROUND AND AIMS: Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot-Marie-Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort. METHODS: Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected. RESULTS: We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis. CONCLUSIONS: In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.

Arc-Mediated Synaptic Plasticity Regulates Cognitive Function in a Migraine Mouse Model.

Previous clinical and basic studies have shown that migraine is associated with cognitive impairment, anxiety, and depression. It severely affects the quality of life. In this study, C57BL/6 mice were randomly divided into four groups: IS group, IS+M group, and IS+S group with repeated application of dural inflammatory soup (IS) stimulation to establish a migraine model, followed by PBS, memantine, and sumatriptan interventions, respectively; the blank control group underwent the same treatment procedure but with PBS instead of IS and intervention drugs. The cognitive function of the mice was used as the main outcome indicator. After application of the IS, mice showed reduced pain threshold for mechanical stimulation, decreased learning memory capacity, attention deficit, a reduced number of dendritic spines in hippocampal neurons, and altered synaptic ultrastructure. The cognitive function indexes of mice in the IS+M group recovered with changes in Arc protein expression to a level not statistically different from that of the Control group, while the IS and IS+S groups remained at lower levels. The present results suggest that Arc-mediated synaptic plasticity may be an essential mechanism of cognitive dysfunction in migraine.

Downregulation of GABAARα1 Aggravates Comorbidity of Epilepsy and Migraine via the TLR4 Signaling Pathway.

Epilepsy and migraine are among the most prevalent neurological disorders. By being comorbid, the presence of one disorder increases the likelihood of the other. Although several similar clinical features of epilepsy and migraine have been observed as early as the 19th century, only in recent years have researchers engaged in finding a common pathogenic mechanism between them. In this study, the epilepsy-migraine comorbidity rat model was generated, and the pathophysiological basis of epilepsy-migraine comorbidity was examined. Male rats were divided into four groups: control, migraine, epilepsy, epilepsy-migraine comorbidity. After establishing the models, the amount of scratching and the pain threshold of the rats were observed. Western blot and immunofluorescence staining were used to detect the protein expression levels of TLR4 and GABAARα1 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Subsequently, co-immunoprecipitation of GABAARα1 and TLR4 was performed. Then, the rats were divided into three groups: comorbidity, comorbidity + TAK-242, and comorbidity + muscimol. After drug intervention, the seizure latency, seizure level, amount of scratching, and pain threshold were observed. Western blot was used to detect the protein expression levels of TLR4 and GABAARα1 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Our results demonstrate that the seizure attacks in comorbidity and epilepsy groups performed severely, and the comorbidity and migraine groups displayed a remarkable increase in the amount of head-scratching and a noticeable decrease in the facial mechanical withdrawal threshold. Further analysis revealed considerably increased Toll-like receptor 4 (TLR4), associated with reduced γ-aminobutyric acid type A receptor α1 (GABAARα1) and microglia enhanced in the epilepsy-migraine comorbidity rat. Additionally, co-immunoprecipitation proved GABAARα1 binding TLR4. Following muscimol to activate GABAARα1, seizure attacks and migraine-like behavior were rescued. GABAARα1 level increment was accompanied by the decline of TLR4, while TAK-242, the inhibitor of TLR4, only decreased TLR4 without affecting GABAARα1 expression. It also ameliorated the migraine-like behavior with no impact on seizure activity. We propose that GABAARα1 binding and negatively regulating TLR4 contribute to epilepsy-migraine comorbidity; TLR4 is a critical intermediate link in epilepsy-migraine comorbidity; immune-induced neuroinflammation in microglia may be involved in migraine and epilepsy-migraine comorbidity.

Elevated blood and cerebrospinal fluid glucose levels affect the severity and short-term prognosis of Guillain-Barré syndrome.

OBJECTIVE: This study aimed to explore the correlation of elevated glucose levels in the blood and cerebrospinal fluid with the progression and short-term prognosis of Guillain-Barré syndrome (GBS). METHODS: The medical records of 982 patients who were diagnosed with GBS in 31 representative tertiary hospitals, located in 14 provinces in southern China, were collected and retrospectively reviewed. Patients were grouped according to the levels of fasting plasma glucose (FPG) and cerebrospinal fluid (CSF) glucose, as well as the concentration of blood hemoglobinAlc (HbA1c). The Hughes grade scale was used to quantify functional outcomes. RESULTS: Compared to patients with normal FPG and CSF glucose levels, those in the high FPG and high CSF glucose groups were characterized by a higher proportion of severe patients (HFGS ≥ 3) at admission (58.8 vs. 73.1, P = 0.000; 57.6 vs. 71.2, P = 0.000), at nadir (67.4 vs. 83.0, P = 0.000; 66.2 vs. 80.4, P = 0.000), and at discharge (29.8 vs. 46.3, P = 0.000; 26.4 vs. 45.0, P = 0.000). Patients in the high HbA1c group also had more severe disability at admission (74.6 vs. 56.1, P = 0.005) and at nadir (80.3 vs. 64.3, P = 0.012) compared to the normal HbA1c group. Moreover, elevated levels of FPG and CSF glucose were significantly correlated with more severe disability at admission, at nadir, and at discharge. CONCLUSIONS: The present study showed that elevated glucose levels in the blood and cerebrospinal fluid were associated with the severity and short-term prognosis of GBS. TRIAL REGISTRATION: chicTR-RRc-17,014,152. ABBREVIATIONS: GBS, Guillain-Barré syndrome; FPG, fasting plasma glucose; CSF, cerebrospinal fluid; HFGS, Hughes Functional Grading Scale; HbA1c, hemoglobin A1c. DM, diabetes mellitus; NCS, nerve conduction study; AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor sensory axonal neuropathy; MV, mechanical ventilation.

Overall trend towards headache remission during the COVID-19 pandemic among Chinese patients with pre-existing headache highlights the role of family support.

BACKGROUND: The global status of the COVID-19 pandemic is not optimistic. This is a particularly vulnerable time for patients with pre-existing headache disorders. The present study aimed to investigate the impact of the COVID-19 pandemic on headache patients in China. METHODS: A survey was conducted through an online survey platform on June 6, 2020. Demographic characteristics, the PHQ-9, the ISI, a COVID-19 questionnaire and a headache profile survey were included in the online questionnaire. RESULTS: Eventually, a total of 15,000 participants from China completed the online questionnaire. Among them, 2806 participants had pre-existing headache disorders. Our analysis showed reductions in the duration of headaches (3.414 ± 6.859 vs 4.033 ± 7.325 h, P<0.001), number of headache days per month (1.788 ± 2.989 vs 2.092 ± 3.694, P<0.001), and headache intensity (4.110 ± 1.609 vs 4.290 ± 1.680, P<0.001) during the COVID-19 pandemic. Smoking (OR = 1.397, 95% CI 1.090 to 1.790, P = 0.008) and getting support from family members during social isolation (OR = 1.656, 95% CI 1.075 to 2.550, P = 0.022) were independent factors affecting the reduction in the duration of headaches. Education level (OR = 1.478, 95% CI 1.103 to 1.980, P = 0.009) and having a relative or acquaintance who contracted COVID-19 (OR = 0.643, 95% CI 0.458 to 0.902, P = 0.011) were the independent factors affecting the reduction in headache severity. Living in the Wuhan area, having symptoms or a diagnosis of COVID-19 and having relatives or acquaintances who had contracted COVID-19 were associated with the worsening of headaches. CONCLUSIONS: Participants experienced an overall trend towards the improvement of headaches during the COVID-19 pandemic. Family support might play an important role in the improvement of headaches.

Guillain-Barré syndrome triggered by surgery in a Chinese population: a multicenter retrospective study.

BACKGROUND: Surgery is a potential trigger of Guillain-Barré syndrome (GBS), a disorder which leads to an autoimmune-mediated attack of peripheral nerves. The present study was designed to explore clinical features of post-surgical GBS compared with those of general GBS in order to provide better clinical advice to patients undergoing surgery. METHODS: The medical records of GBS patients who were seen at 31 tertiary hospitals in southern China between January 1, 2013 and September 30, 2016 were retrospectively analyzed. Post-surgical GBS was defined as symptoms of GBS within 6 weeks after surgery. Clinical features of post-surgical GBS are described and are compared with general GBS. RESULTS: Among the 1001 GBS patient cases examined in this study, 45 (4.5%) patient cases exhibited symptoms of GBS within 6 weeks of undergoing surgery. Within this group, 36 (80.0%) patients developed initial symptoms of limb weakness. The average interval between surgery and symptom onset was 13.31 days. The most common type of surgery which triggered GBS was orthopedic surgery, followed by neurological surgery. Compared to general GBS, post-surgical GBS was characterized by a higher proportion of severe patients (Hughes functional grading scale (HFGS) score ≥ 3) upon admission and at nadir, higher HFGS scores at discharge, and longer hospital stays. Post-surgical GBS patients also had a significantly higher frequency of the acute motor axonal neuropathy subtype (37.9 vs. 14.2, respectively; P = 0.001). CONCLUSION: Surgery is probably a potential trigger factor for GBS, especially orthopedic surgery. Infections secondary to surgery may play a role. The possibility of preceding (post-operative) infections was not excluded in this study. Clinical presentation of post-surgical GBS is characterized by a more severe course and poorer prognosis, and should be closely monitored. TRIAL REGISTRATION: chicTR-RRc-17,014,152 .

Microglia-Astrocyte Cross Talk through IL-18/IL-18R Signaling Modulates Migraine-like Behavior in Experimental Models of Migraine.

Interleukin-18 (IL-18) is an important regulator of innate and immune responses, and is involved in the pain process, including neuropathic and cancer pain. The current study demonstrated that inflammatory soup (IS) dural infusions elicited the activation of microglia and astrocytes. In comparison, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. In comparison, blocking IL-18 signaling also suppressed the activation of astrocytes and nuclear factor-kappa B (NF-κB). IL-18 dural infusions induced nociceptive behavior and glia activation. IL-18 is a product of the activation of microglial toll-like receptor 4 (TLR4), and it acted on IL-18R expressed in astrocytes. Subsequently, it stimulated the activation of nuclear factor-kappa B (NF-κB), leading to the activation of astrocytes. In conclusion, IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn likely contribute to the development of hyperpathia or allodynia induced by migraines.

The dynamic expression of canonical Wnt/ß-catenin signalling pathway in the pathologic process of experimental autoimmune neuritis.

Background: Guillain-Barré syndrome (GBS), an autoimmune disease and an acute inflammation disorder, is currently the most frequent cause of acute flaccid paralysis worldwide. EAN, an animal model of GBS, is a CD4+ T cell-mediated autoimmune disease of the PNS. Wnt/ß-catenin signals are critically important to several fundamental aspects of peripheral nerve development and play a crucial role in Schwann cell proliferation. Here, we investigate the role of Wnt/ß-catenin signalling cascades in EAN rats.Methods: 28 male Lewis rats weighing 170 ± 10 g were randomly divided into control group (n = 7) and EAN groups (Early group; Peak group and Recovery group. n = 7 per group). EAN rats were immunized with P257-81 peptide; weighed daily, and the neurologic signs of EAN were evaluated every day. The sciatic nerve was taken on the days 10, 17, and 30 p.i. for H&E staining, transmission electron microscopy and immunohistochemical staining; blood samples were collected weekly from caudal vein to detect IFN-γ, IL-4, TGF-ß1; and the sciatic nerve was taken to examinate the dynamics expression of Wnt/ß-catenin pathway molecules.Results: In our study, we chose tail-root injection to better model GBS. Moreover, we observed that IFN-γ levels paralleled clinical EAN, and the levels of TGF-ß1 and IL-4 gradually increased and peaked in the recovery phase. In addition, we have shown that canonical Wnt signalling is upregulated and reached a peak in the late recovery phase.Conclusion: Our findings suggest that Wnt/ß-catenin signalling is associated with the promotion of remyelination in EAN rats.

Th17 cells and their cytokines serve as potential therapeutic target in experimental autoimmune neuritis.

BACKGROUND: Accumulating evidence has pointed that T helper 17 cells and their cytokines are pathogenic in Guillain-Barré syndrome (GBS). However, little is known concerning the IL-17 expression change trend during the whole course of disease, and whether drugs specially targeting Th17 cells or their cytokines have potential effects on experimental autoimmune neuritis (EAN) is uncertain. METHODS: We explored the IL-17 and receptor-related orphan receptor-gamma-t (RORγt) expression change trends in EAN rats to identify the stage of effect of Th17 pathway in EAN, and further, we investigated the effect of RORγt inhibitors by assessing clinical score, histological staining, and IL-17 and RORγt expression change trends in serum and tissues. RESULTS: The expression level of IL-17 and RORγt in serum and tissues increased with the progression of the disease in the EAN group and decreased after the disease reaching its peak. RORγt-IN-1 treatment strikingly reduced the neurological deficits by ameliorating inflammatory cell infiltration, deceased the serum IL-17 and RORγt levels, and further downregulated the expression of IL-17 and RORγt mRNA in spleen, lymphnodes, and sciatic nerve. CONCLUSIONS: Th17 cells and their cytokines are closely associated with the onset of GBS and the novel RORγt inhibitors may be prospective strategies in treating GBS.