Hippocampal proteome comparison of infant and adult Fmr1 deficiency mice reveals adult-related changes associated with postsynaptic density.

Deficiency in fragile X mental retardation 1 (Fmr1) leads to loss of its encoded protein FMRP and causes fragile X syndrome (FXS) by dysregulating its target gene expression in an age-related fashion. Using comparative proteomic analysis, this study identified 105 differentially expressed proteins (DEPs) in the hippocampus of postnatal day 7 (P7) Fmr1-/y mice and 306 DEPs of P90 Fmr1-/y mice. We found that most DEPs in P90 hippocampus were not changed in P7 hippocampus upon FMRP absence, and some P90 DEPs exhibited diverse proteophenotypes with abnormal expression of protein isoform or allele variants. Bioinformatic analyses showed that the P7 DEPs were mainly enriched in fatty acid metabolism and oxidoreductase activity and nutrient responses; whereas the P90 PEPs (especially down-regulated DEPs) were primarily enriched in postsynaptic density (PSD), neuronal projection development and synaptic plasticity. Interestingly, 25 of 30 down-regulated PSD proteins present in the most enriched protein to protein interaction network, and 6 of them (ANK3, ATP2B2, DST, GRIN1, SHANK2 and SYNGAP1) are both FMRP targets and autism candidates. Therefore, this study suggests age-dependent alterations in hippocampal proteomes upon loss of FMRP that may be associated with the pathogenesis of FXS and its related disorders. SIGNIFICANCE: It is well known that loss of FMRP resulted from Fmr1 deficiency leads to fragile X syndrome (FXS), a common neurodevelopmental disorder accompanied by intellectual disability and autism spectrum disorder (ASD). FMRP exhibits distinctly spatiotemporal patterns in the hippocampus between early development and adulthood, which lead to distinct dysregulations of gene expression upon loss of FMRP at the two age stages potentially linked to age-related phenotypes. Therefore, comparison of hippocampal proteomes between infancy and adulthood is valuable to provide insights into the early causations and adult-dependent consequences for FXS and ASD. Using a comparative proteomic analysis, this study identified 105 and 306 differentially expressed proteins (DEPs) in the hippocampi of postnatal day 7 (P7) and P90 Fmr1-/y mice, respectively. Few overlapping DEPs were identified between P7 and P90 stages, and the P7 DEPs were mainly enriched in the regulation of fatty acid metabolism and oxidoreduction, whereas the P90 DEPs were preferentially enriched in the regulation of synaptic formation and plasticity. Particularly, the up-regulated P90 proteins are primarily involved in immune responses and neurodegeneration, and the down-regulated P90 proteins are associated with postsynaptic density, neuron projection and synaptic plasticity. Our findings suggest that distinctly changed proteins in FMRP-absence hippocampus between infancy and adulthood may contribute to age-dependent pathogenesis of FXS and ASD.

Post-operative gamma knife radiosurgery for WHO grade I intracranial meningiomas: A single-center, retrospective study.

Objective: To explore the results of the Gamma Knife radiosurgery (GKRS) for World Health Organization (WHO) grade I intracranial meningiomas after surgical resection. Methods: A total of 130 patients who were pathologically diagnosed as having WHO grade I meningiomas and who underwent post-operative GKRS were retrospectively reviewed in a single center. Results: Of the 130 patients, 51 patients (39.2%) presented with radiological tumor progression with a median follow-up time of 79.7 months (ranging from 24.0 to 291.3 months). The median time to radiological tumor progression was 73.4 months (ranging from 21.4 to 285.3 months), whereas 1-, 3-, 5-, and 10-year radiological progression-free survival (PFS) was 100, 90, 78, and 47%, respectively. Moreover, 36 patients (27.7%) presented with clinical tumor progression. Clinical PFS at 1, 3, 5, and 10 years was 96, 91, 84, and 67%, respectively. After GKRS, 25 patients (19.2%) developed adverse effects, including radiation-induced edema (n = 22). In a multivariate analysis, a tumor volume of ≥10 ml and falx/parasagittal/convexity/intraventricular location were significantly associated with radiological PFS [hazard ratio (HR) = 1.841, 95% confidence interval (CI) = 1.018-3.331, p = 0.044; HR = 1.761, 95% CI = 1.008-3.077, p = 0.047]. In a multivariate analysis, a tumor volume of ≥10 ml was associated with radiation-induced edema (HR = 2.418, 95% CI = 1.014-5.771, p = 0.047). Of patients who presented with radiological tumor progression, nine were diagnosed with malignant transformation. The median time to malignant transformation was 111.7 months (ranging from 35.0 to 177.2 months). Clinical PFS after repeat GKRS was 49 and 20% at 3 and 5 years, respectively. Secondary WHO grade II meningiomas were significantly associated with a shorter PFS (p = 0.026). Conclusions: Post-operative GKRS is a safe and effective treatment for WHO grade I intracranial meningiomas. Large tumor volume and falx/parasagittal/convexity/intraventricular location were associated with radiological tumor progression. Malignant transformation was one of the main cause of tumor progression in WHO grade I meningiomas after GKRS.

Mild phenotypes of phosphoglycerate dehydrogenase deficiency by a novel mutation of PHGDH gene: Case report and literature review.

Phosphoglycerate dehydrogenase (PHGDH) deficiency is a rare autosomal recessive genetic disease of serine biosynthesis. Its typical features are congenital microcephaly, epileptic seizures, and psychomotor developmental delay. Here, we reported the first Chinese familial cases with genetically confirmed PHGDH deficiency and reviewed several previous reports. Two siblings in this family presented with microcephaly, psychomotor retardation, and epilepsy in early juvenile. Brain magnetic resonance imaging (MRI) showed only a slight change of enlarged ventricle. Biochemical investigations revealed low serum serine and glycine concentrations. The whole-exome sequencing (WES) results identified a missense variant in the PHGDH gene (NM_006623.4: exon11: c.1211T>A, p. Val404Asp). Although two patients in this Chinese family carried the same pathogenic mutation in the PHGDH, their symptoms and responses to treatment were not exactly the same. We found a novel variant in the PHGDH gene and expanded the genotypic and phenotypic spectrum of serine biosynthesis disorders.

Primary versus postoperative gamma knife radiosurgery for intracranial benign meningiomas: a matched cohort retrospective study.

OBJECTIVE: The aims of this study were to investigate the long-term outcomes of primary versus postoperative Gamma Knife radiosurgery (GKRS) for benign meningiomas. METHODS: Three hundred and forty meningioma patients underwent GKRS were retrospectively reviewed. Patients in the postoperative GKRS group were matched to those in the primary GKRS group, in a 1:1 ratio. RESULTS: The study consisted of 122 patients, including primary (n = 61) and postoperative (n = 61) GKRS group. Thirty-four patients (27.9%) occurred radiological progression after a median follow-up of 72.5 (range, 24.2-254.5) months. The median time to radiological progression was 85.1 (range, 20.7-205.1) months. The radiological progression-free survival (PFS) was 100%, 93%, 87%, and 49%, at 1, 3, 5, and 10 years respectively. Thirty-one patients (25.4%) occurred clinical progression. The clinical PFS was 92%, 89%, 84%, and 60%, at 1, 3, 5, and 10 years. In combined group, only max diameter ≥ 50 mm was associated with radiological (p = 0.020) and clinical PFS (hazard ratio [HR] = 2.896, 95% confidence interval [CI] = 1.280-6.553, p = 0.011). Twenty-five patients (20.5%) developed GKRS related adverse effects, including radiation-induced edema (n = 21). Non-skull base tumors (HR = 3.611, 95% CI = 1.489-8.760, p = 0.005) and preexisting peritumoral edema (HR = 3.571, 95% CI = 1.167-10.929, p = 0.026) were significantly related to radiation-induced edema in combined group. There was no significant difference in radiological PFS (p = 0.403), clinical PFS (p = 0.336), and GKRS related adverse effects (p = 0.138) between primary and postoperative GKRS groups. CONCLUSIONS: Primary GKRS could provide similar radiological and clinical outcomes, as well as similar complication rate compared with postoperative GKRS. For selective benign meningioma patients (asymptomatic or mildly symptomatic tumors; unfavorable locations for surgical resection; comorbidities or an advanced age), GKRS could be an alternative primary treatment.

Characteristic of Tumor Regrowth After Gamma Knife Radiosurgery and Outcomes of Repeat Gamma Knife Radiosurgery in Nonfunctioning Pituitary Adenomas.

OBJECTIVE: This study aimed to report the characteristic of tumor regrowth after gamma knife radiosurgery (GKRS) and outcomes of repeat GKRS in nonfunctioning pituitary adenomas (NFPAs). DESIGN AND METHODS: This retrospective study consisted of 369 NFPA patients treated with GKRS. The median age was 45.2 (range, 7.2-84.0) years. The median tumor volume was 3.5 (range, 0.1-44.3) cm3. RESULTS: Twenty-four patients (6.5%) were confirmed as regrowth after GKRS. The regrowth-free survivals were 100%, 98%, 97%, 86% and 77% at 1, 3, 5, 10 and 15 year, respectively. In multivariate analysis, parasellar invasion and margin dose (<12 Gy) were associated with tumor regrowth (hazard ratio [HR] = 3.125, 95% confidence interval [CI] = 1.318-7.410, p = 0.010 and HR = 3.359, 95% CI = 1.347-8.379, p = 0.009, respectively). The median time of regrowth was 86.1 (range, 23.2-236.0) months. Previous surgery was associated with tumor regrowth out of field (p = 0.033). Twelve patients underwent repeat GKRS, including regrowth in (n = 8) and out of field (n = 4). Tumor shrunk in seven patients (58.3%), remained stable in one (8.3%) and regrowth in four (33.3%) with a median repeat GKRS margin dose of 12 (range, 10.0-14.0) Gy. The actuarial tumor control rates were 100%, 90%, 90%, 68%, and 68% at 1, 3, 5, 10, and 15 years after repeat GKRS, respectively. CONCLUSIONS: Parasellar invasion and tumor margin dose (<12 Gy) were independent risk factors for tumor regrowth after GKRS. Repeat GKRS might be effective on tumor control for selected patients. For regrowth in field due to relatively insufficient radiation dose, repeat GKRS might offer satisfactory tumor control. For regrowth out of field, preventing regrowth out of field was the key management. Sufficient target coverage and close follow-up might be helpful.

Pituitary hemorrhage in pituitary adenomas treated with gamma knife radiosurgery: incidence, risk factors and prognosis.

Objective: The aims of this study were to investigate the incidence, risk factors and prognosis of pituitary hemorrhage in pituitary adenomas treated with gamma knife radiosurgery (GKRS). Methods and materials: Between December 1993 and December 2016, 751 consecutive pituitary adenoma patients treated with GKRS were retrospectively reviewed in a single center. There were 271 male (36.1%) and 480 female (63.9%) patients with a median age of 38.5 (range, 7.2-84.0) years. The number of nonfunctioning pituitary adenomas (NFPAs) and functioning pituitary adenomas were 369 (49.1%) and 382 (50.9%) respectively. The median follow-up time was 61.1 (range, 12.1-304.4) months. Results: In this study, 88 patients (11.7%) were diagnosed with pituitary hemorrhage before GKRS, 55 patients (7.3%) developed new or worsened pituitary hemorrhage after GKRS (excluding 3 patients with new or worsened pituitary hemorrhage due to tumor regrowth). The median time to new or worsened pituitary hemorrhage after GKRS was 18.9 (range 3.1-70.7) months. Overall, 128 patients (17.0%) were diagnosed with pituitary hemorrhage in the entire series. After adjustment with logistic regression, nonfunctioning pituitary adenomas (NFPAs) (odds ratio [OR]=2.121, 95% confidence interval [CI]=1.195-3.763, p=0.010) and suprasellar extension (OR=2.470, 95% CI=1.361-4.482, p=0.003) were associated with pituitary hemorrhage before GKRS. NFPA (OR=3.271, 95% CI=1.278-8.373, p=0.013) was associated with new or worsened pituitary hemorrhage after GKRS. Five patients received surgical resection for new or worsened pituitary hemorrhage were considered as GKRS treatment failure. Two patients with new hypopituitarism were considered to be owed to new or worsened pituitary hemorrhage after GKRS. Conclusions: New or worsened pituitary hemorrhage after GKRS was not an uncommon phenomenon. NFPA was an independent risk factor of new or worsened pituitary hemorrhage after GKRS. New or worsened pituitary hemorrhage after GKRS could lead to GKRS treatment failure. GKRS might be a precipitating factor of pituitary hemorrhage.

Initial Gamma Knife Radiosurgery for Large or Documented Growth Asymptomatic Meningiomas: Long-Term Results From a 27-Year Experience.

OBJECTIVE: The aims of this study were to investigate the long-term outcomes of initial Gamma Knife radiosurgery (GKRS) for large (≥20 mm) or documented growth asymptomatic meningiomas. DESIGN AND METHODS: This was a single-center retrospective study. Fifty-nine patients with large (≥20 mm) or documented growth asymptomatic meningiomas undergoing initial GKRS were enrolled. The median age was 56 (range, 27-83) years. The median time of follow-up was 66.8 (range, 24.6-245.6) months, and the median tumor margin dose was 13.0 Gy (range, 11.6-22.0 Gy). RESULTS: Tumors shrunk in 35 patients (59.3%) and remained stable in 23 (39.0%). One patient (1.7%) experienced radiological progression at 54 months after GKRS. The PFS was 100%, 97%, and 97% at 3, 5, and 10 years, respectively. Nine patients (15.3%) occurred new neurological symptoms or signs at a median time of 8.1 (range, 3.0-81.6) months. The symptom PFS was 90% and 78% at 5 and 10 years, respectively. Fifteen patients (25.4%) occurred peritumoral edema (PTE) at a median time of 7.2 (range, 2.0-81.6) months. One patient underwent surgical resection for severe PTE. In univariate and multivariate analysis, Only tumor size (≥25 mm) and maximum dose (≥34 Gy) were significantly associated with PTE [hazard ratio (HR)= 3.461, 95% confidence interval (CI)=1.157-10.356, p=0.026 and HR=3.067, 95% CI=1.068-8.809, P=0.037, respectively]. CONCLUSIONS: In this study, initial GKRS can provide a high tumor control rate as well as an acceptable rate of complications in large or documented growth asymptomatic meningiomas. GKRS may be an alternative initial treatment for asymptomatic meningiomas.

FMRP-absence-induced up-regulation of hypothalamic MAP1B expression decreases AgRP level linking with reduces in food intake and body weight.

Fragile X mental retardation protein (FMRP), strongly associated with fragile X syndrome, plays important roles by regulating gene expression via interacting with other RNA binding proteins in the brain. However, the role of FMRP in hypothalamus, a central part responsible for metabolic control, is poorly known. Our study shows that FMRP is primarily located in the hypothalamic arcuate nucleus (ARC). Using proteomic analysis, we identified 56 up-regulated and 22 down-regulated proteins in the hypothalamus of Map1b KO mice, with microtubule-associated protein 1 B (MAP1B) being the most outstanding increased protein (more than 10 folds). Immunofluorescent assays showed that MAP1B significantly increased in the Map1b-KO ARC, in which the number of agouti-related peptide (AgRP)-staining neurons significantly reduced, but not altered for pro-opiomelanocortin (POMC) neurons. We further showed an age-dependent reduces in food intake and body weight of the KO mice, along with the decreases of MAP1B and AgRP at the same time points. In hypothalamic GT1-7 cells, the AgRP expression decreased upon knockdown of FMRP or overexpression of MAP1B, and increased in response to overexpression of FMRP or knockdown of MAP1B. Co-knockdown or co-overexpression of FMRP and MAP1B led to a reverse expression of AgRP compared to overexpression of knockdown of FMRP alone, demonstrating that MAP1B is essential for the regulatory effect of FMRP on AgRP expression. Taken together, these data suggest that FMRP-deficiency-induced increase of hypothalamic MAP1B and decrease of AgRP might be associated with reduces in food intake and body weight.

Long-term results of Gamma Knife Radiosurgery for Postsurgical residual or recurrent nonfunctioning Pituitary Adenomas.

Introduction: The aim of this retrospective study was to analyze the long-term outcomes and factors associated with treatment failure of Gamma Knife radiosurgery (GKRS) for postsurgical residual or recurrent nonfunctioning pituitary adenomas (NFPAs). Design and Methods: A total of 148 cases of postsurgical residual or recurrent NFPA patients were enrolled in the study. There were 111 cases with residual tumor and 37 cases with recurrent tumor. The median age was 46.0 years (Range: 10.9-75.8 years). The median tumor volume at GKRS was 3.6 cm3 (Range: 0.3-74.5 cm3), and the median tumor margin dose was 14.0 Gy (Range: 9 - 20 Gy). Results: Tumor shrunk in 111 patients (75%), remained stable in 17 patients (11.5%), and progressed in 20 patients (13.5%) during a median of 64.5 months (Range: 14.5 - 236.0 months) of imaging follow-up. The progression-free survival rates were 99%, 91%, 88% and 74% at 1, 3, 5 and 10 years after GKRS, respectively. In a multivariate analysis, tumor margin dose (<13 Gy) was significantly associated with tumor progression (hazard ratio=3.526, 95% confidence interval=1.400-8.877, p=0.007). New hypopituitarism occurred in 22 out of 80 patients (27.5%), including hypogonadism (n=7), hypothyroidism (n=9), hypocortisolism (n=15) and growth hormone deficiency (n=1). In univariate and multivariate analysis, there were no factors significantly associated with new hypopituitarism. Six patients (4.1%) developed new or worsening visual dysfunction. Four patients (2.7%) developed new cranial neuropathy. Conclusion: In this study, GKRS can offer a high tumor control rate as well as a low rate of complications in postsurgical residual or recurrent NFPA patients.

Vestibular migraine with Wallenberg syndrome: a case report.

BACKGROUND: Vestibular migraine, a kind of acute vestibular syndrome, leads to both migraines and vertigo symptoms in a single patient. The occurrence of vestibular migraine has shown an obvious increase in female groups based on age. Though it is recognized that migraines may cause ischemic lesions in some brain regions, the relationship between vestibular migraine and cerebral infarction has seldom been reported, especially with no known research reports about vestibular migraine with Wallenberg syndrome. Based on this, the connection of the two diseases needs to be the focus of more research. CASE PRESENTATION: The patient, a 35-year-old lady, came to our department with severe vertigo and headaches for approximately two years. She suffered from migraines which attacked about twice yearly for nearly a decade. The diffusive weighted imaging showed a subacute infarction in the right lateral medullar. The clinical characteristics and MRI findings supported the diagnosis of vestibular migraine with Wallenberg syndrome. Along with the normal routine medication for vestibular migraine with Wallenberg syndrome, we also prescribed migraine therapy at the same time. In a 3-month follow-up, the patient had suffered only one vertigo attack and she reported that the migraines were less common and less intense than she was previously experiencing. CONCLUSIONS: Due to the fact that vestibular migraine is one of the risk factors of cerebral ischemia, we need to pay more attention to this phenomenon. The current case suggests that both routine medication on ischemic stroke as well as treatment for migraines should be used concurrently in vestibular migraine with Wallenberg syndrome.

A Species-Correlated Transitional Residue D132 on Human FMRP Plays a Role in Nuclear Localization via an RNA-Dependent Interaction With PABP1.

Fragile X mental retardation protein (FMRP), a key determinant of normal brain development and neuronal plasticity, plays critical roles in nucleocytoplasmic shuttling of mRNAs. However, the factors involved in FMRP nuclear localization remain to be determined. Using cross-species sequence comparison, we show that an aspartate in position 132 (D132), located within the conserved nuclear localization signal (NLS) of FMRP, appears in human and other mammals, while glutamate 132 (E132) appears in rodents and birds. Human FMRP-D132E alters the secondary structure of the protein and reduces its nuclear localization, while the reciprocal substitution in mouse FMRP-E132D promotes its nuclear localization. Human FMRP could interact with poly(A)-binding protein 1 (PABP1) which is impeded by the D132E mutation. Reversely, mouse FMRP could not interact with PABP1, but the E132D mutation leads to the FMRP-PABP1 interaction. We further show that overexpression of human FMRP-D132E mutant promotes the formation of cytoplasmic aggregates of PABP1 in human cells, but not of mouse FMRP-E132D in mouse cells. PABP1 knockdown reduces the nuclear localization of human FMRP, but not mouse FMRP. Furthermore, RNase A treatment decreases the PABP1 levels in the anti-V5-immunoprecipitates using the V5-hFMRP-transfected cells, suggesting an interaction between human FMRP and PABP1 in an RNA-dependent fashion. Thus, our data suggest that the FMRP protein with the human-used D132 accommodates a novel protein-RNA-protein interaction which may implicate a connection between FMRP residue transition and neural evolution.