Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

Cerebellar high‐grade gliomas are rare, and likely to affect younger patients compared with those of cerebral origin. Recent genetic analyses have revealed that isocitrate dehydrogenase (IDH) 1/2 mutations are rare in infratentorial gliomas. In this paper, we report two elderly cases of IDH‐mutated cerebellar high‐grade glioma with unusual histological features and uncommon patient ages. One case was an 83‐year‐old man, whose tumor was predominantly composed of densely packed round‐to‐polygonal epithelioid cells. The other was a 75‐year‐old woman's high‐grade astrocytoma characterized by cord‐like structures and the perivascular papillary arrangements with varying amounts of myxoid matrix. The former harbored IDH1 R132H mutation, whereas the latter had IDH2 R172K mutation. According to our literature review, eight cases of IDH‐mutated infratentorial gliomas including the present cases have been reported, and four had mutations other than IDH1 R132H. Moreover, we herein report the first elderly case of IDH2‐mutation. Although the number is limited, IDH‐mutant infratentorial diffuse gliomas may have clinical, histological and genetic features different from supratentorial cases.     

Insular primary glioblastomas with IDH mutations: Clinical and biological specificities

Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower‐grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH‐wildtype (IDH‐wt) pGBMs. IDH‐mutant (IDH‐mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH‐mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH‐wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long‐surviving case, but genetic alterations in the astrocyte‐sGBM pathway were generally prevalent in IDH‐mut pGBMs. Our results present a unique phenotype of IDH‐mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs.     

Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord

The 2016 edition of the World Health Organization Classification of Tumors of the Central Nervous System introduced “diffuse midline glioma H3 K27M mutant” as a new diagnostic entity. These tumors predominately affect pediatric patients and arise from midline structures such as the brainstem, thalamus and spinal cord. Here, we report a rare patient with spinal ganglioglioma carrying an H3 K27M mutation. A 10‐year‐old boy presented with an intramedullary tumor in the cervical spinal cord. The lesion was partially removed and histologically diagnosed as ganglioglioma. After the remnant tumor grew within 3 months after surgery, the patient underwent radiotherapy. Genetic analyses revealed an H3F3A K27M mutation but no other genetic alterations such as IDH and BRAF mutations. This case may point to pathological heterogeneity in gliomas with H3 K27M mutations.     

West syndrome caused by ST3Gal‐III deficiency

West syndrome consists of infantile spasms, hypsarrhythmia, and developmental arrest. Most patients remain mentally retarded and many develop Lennox‐Gastaut syndrome. Using homozygosity mapping followed by exome sequencing we identified an ST3GAL3 mutation in three infants with West syndrome. ST3GAL3 encodes a sialyltransferase involved in the biosynthesis of sialyl‐Lewis epitopes on cell surface–expressed glycoproteins. The mutation affected an essential sialyl‐motif and abolished enzymatic activity. Abnormalities in proteins involved in forebrain γ‐aminobutyric acid (GABA)ergic synaptic growth and function were recently proposed to account for infantile spasms. Dysfunctional ST3GAL3 may thus result in perturbation of the posttranslational sialylation of proteins in these pathways.     

Intact working memory in non‐manifesting LRRK2 carriers – an fMRI study

Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non‐manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non‐manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non‐manifesting first‐degree relatives of Parkinson's disease patients (38 carriers). A block‐design fMRI N‐back task, with 0‐back, 2‐back and 3‐back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole‐brain or region‐of‐interest between‐groups differences were found on any of the task conditions. These results indicate that non‐manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N‐back task, remaining relatively intact. These finding shed light on the pre‐motor cognitive changes in this unique ‘at risk’ population and should enable more focused cognitive assessments of these cohorts.     

High‐Sensitivity C‐Reactive Protein is a Strong Risk Factor for Death after Acute Ischemic Stroke among Chinese

Background and purpose: Elevated plasma C‐reactive protein (CRP) has been suggested as a risk factor for ischemic stroke (IS) and coronary ischemic disease. Evidence has shown that high‐sensitivity CRP (hs‐CRP) is related to a worsening prognosis after IS, but hs‐CRP was rare in a large‐sample study in a Chinese population. We investigated the associations between hs‐CRP and outcome of Chinese patients after acute IS. Methods: Seven hundred and forty‐one consecutive acute IS patients (74.9% male, mean age 60.9 years), with baseline characteristics and hs‐CRP measured within 24 h after hospitalization, were admitted in this study. We also prospectively followed up for clinical outcome and death 3 months after disease onset. hs‐CRP was divided into two categories: hs‐CRP >3 mg/L and hs‐CRP ≤3 mg/L. Survival analysis using multivariable Cox regression was performed to analyze the association between hs‐CRP and stroke outcomes after adjusting for potential confounding factors. Results: Compared with low hs‐CRP, patients with high hs‐CRP (>3 mg/L) had a significantly higher rate of all‐cause death (0.71% vs. 10.00%; P < 0.001) at 3 months after stroke onset. High hs‐CRP was an independent risk factor for all‐cause death (HR, 6.48; 95% CI, 1.41 to 29.8; P= 0.016), as well as history of atrial fibrillation (HR, 5.24; 95% CI, 1.83 to 15.0; P= 0.002), no statin therapy during hospitalization (HR, 4.56; 95% CI, 2.18 to 9.55; P < 0.001), high homocysteine (>15.1 mmol/L) (HR, 2.66; 95% CI, 1.26 to 5.60; P= 0.01); fasting glucose (>6.1 mmol/L) (HR, 9.14; 95% CI, 3.34 to 25.0; P < 0.001), NIHSS at admission (HR, 2.35; 95% CI, 1.35 to 4.09; P= 0.003) and history of coronary heart disease (CHD) (HR, 2.34; 95% CI, 1.06 to 5.17; P= 0.035). Kaplan–Meier survival curves showed a higher risk of death for patients with hs‐CRP >3 mg/L (P= 0.016). Conclusion: Elevated plasma hs‐CRP independently predicted risk of all‐cause death within 3 months after acute IS in Chinese patients.     

Frequency of CNKSR2 mutation in the X‐linked epilepsy‐aphasia spectrum

Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling‐mediated neuronal proliferation, migration and differentiation. Mutations in the X‐linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy‐aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike‐waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X‐linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X‐linked EAS because of the specific genetic counseling implications.     

Allergy and risk of glioma: a meta‐analysis

We evaluated the association between allergic conditions and the risk of glioma in case–control and cohort studies published so far on this issue. A total of 12 studies (10 case–control and 2 cohort studies) were included in the analysis, involving 61 090 participants, of whom 6408 had glioma. When compared with non‐allergic conditions, the pooled odds ratio (OR) with any allergic conditions for glioma was 0.60 (95% CI: 0.52–0.69, P < 0.001), suggesting a significant negative association (protective effect) between allergy and glioma. Subgroup analysis showed that the ORs were 0.70 (95% CI: 0.62–0.79, P < 0.001), 0.69 (95% CI: 0.62–0.78, P < 0.001), and 0.78 (95% CI: 0.70–0.87, P < 0.001) for asthma, eczema, and hay fever, respectively. The significant association remained even after excluding the bias of proxy reporting (OR = 0.61; 95% CI: 0.50–0.75, P < 0.001). We conclude that allergic conditions may significantly reduce the risk of glioma.     

The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis

Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant‐induced mania: a systematic review and meta‐analysis.
Bipolar Disord 2010: 12: 702–706. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Antidepressant‐induced mania (AIM) has been associated with the serotonin‐transporter‐linked promoter region (5‐HTTLPR) polymorphism in some studies but not in others. We conducted a meta‐analysis of those studies and other studies of genetic predictors of AIM. Methods: MEDLINE‐based searches of genetic studies of AIM were conducted, and a meta‐analysis of six studies of 5‐HTTLPR was performed. Other polymorphisms were insufficiently studied to allow for meta‐analysis. Results: There was an association of the short (s) variant of 5‐HTTLPR and AIM [risk ratio (RR) = 1.35, 95% confidence interval (CI): 1.04–1.76, p = 0.02]. There was a higher frequency of s carriers (sl and ss genotypes) in those who developed AIM [RR = 1.38, 95% CI: 0.98–1.93), p = 0.06]. Conclusion: The 5‐HTTLPR polymorphism appears to have a moderate effect size association with AIM in patients with bipolar disorder.     

Association of tumor necrosis factor‐α and matrix metalloproteinase‐3 gene variants with stroke

Background and purpose: There is increasing evidence that the genetic variation in the genes coding for pro‐inflammatory markers and matrix metalloproteinase may play an important role in the pathogenesis of various human diseases including stroke. The aim of this study was to evaluate the association of genetic variants within the genes encoding tumor necrosis factor‐α (TNF‐α) and matrix metalloproteinase‐3 (MMP‐3), with stroke. Methods: Five hundred and twenty‐five ischemic stroke patients and 500 age‐ and sex‐matched controls were included in this study. We analyzed +488 G/A polymorphism in TNF‐α gene and −1612 5A/6A polymorphism in MMP‐3 gene. The genotypes were determined by Amplification Refractory Mutation System PCR. The strength of association between genotypes and stroke was measured by the odds ratio with 95% confidence interval (CI) and chi‐squared analysis. Results: Allelic and genotypic frequencies of TNF‐α G/A polymorphism differed significantly between patients and healthy controls (P < 0.001). A stepwise logistic regression analysis confirmed these findings (P < 0.001). Further, evaluating the association of this polymorphism with stroke subtypes, we found significant association with intracranial large artery atherosclerosis, extracranial large artery atherosclerosis, and stroke of undetermined etiology. As far as MMP‐3−1612 5A/6A polymorphism is concerned, there was no significant difference in genotypic distribution and allelic frequency between the patients and healthy controls (P = 0.5 and 0.9, respectively). We tested the gene–gene interaction between TNF‐α and MMP‐3 genes using the logistic regression model. However, there was no evidence for a gene–gene interaction between TNF‐α and MMP‐3. Conclusion: TNF‐α +488 G/A variant is an important risk factor for ischemic stroke in the South Indians from Andhra Pradesh, whereas MMP‐3−1612 5A/6A polymorphism is not associated with stroke in the same population.     

Whole‐exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel,de novo GRIN2A mutation

We present a 4‐year‐old girl with profound global developmental delay and refractory epilepsy characterized by multiple seizure types (partial complex with secondary generalization, tonic, myoclonic, and atypical absence). Her seizure semiology did not fit within a specific epileptic syndrome. Despite a broad metabolic and genetic workup, a diagnosis was not forthcoming. Whole‐exome sequencing with a trio analysis (affected child compared to unaffected parents) was performed and identified a novel de novo missense mutation in GRIN2A, c.2449A>G, p.Met817Val, as the likely cause of the refractory epilepsy and global developmental delay. GRIN2A encodes a subunit of N‐methyl‐d ‐aspartate (NMDA) receptor that mediates excitatory transmission in the central nervous system. A significant reduction in the frequency and the duration of her seizures was observed after the addition of topiramate over a 10‐month period. Further prospective studies in additional patients with mutations in GRIN2A will be required to optimize seizure management for this rare disorder. This report expands the current phenotype associated with GRIN2A mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

A cryptic splicing mutation in the INF2 gene causing Charcot‐Marie‐Tooth disease with minimal glomerular dysfunction

Heterozygous mutations in the inverted formin‐2 (INF2) gene provoke focal segmental glomerulosclerosis (FSGS) and intermediate Charcot‐Marie‐Tooth (CMT) disease with FSGS. Here, we report four patients from a three‐generation family with a new cryptic splicing INF2 mutation causing autosomal dominant intermediate CMT with minimal glomerular dysfunction. Three males and one female with a mean age of 51 years (26‐87) presented with a slowly progressive sensorimotor polyneuropathy, pes cavus, and kyphoscoliosis. Mean age at CMT disease onset was 11.5 years (3‐17), and electrophysiological studies showed demyelinating and axonal features consistent with intermediate CMT. Plasma albumin and creatinine were normal in all four cases, and urine protein was normal in one case and mildly raised in three patients (mean: 0.32 g/L [0.18‐0.44], N < 0.14). Genetic analysis found a c.271C > G (p. Arg91Gly) variation in INF2 exon 2, and in vitro splicing assays showed the deletion of the last 120 nucleotides of INF2 exon 2 leading to a 40 amino acids in‐frame deletion (p. Arg91_p. Gln130del). This report expands the genetic spectrum of INF2‐associated disorders and demonstrates that INF2 mutations may provoke isolated CMT with no clinically relevant kidney involvement. Consequently, INF2 mutation analysis should not be restricted to individuals with coincident neuropathy and renal disease.     

Relationship between tumour location and preoperative seizure incidence in patients with gliomas: a systematic review and meta‐analysis

Aim. The aim of this meta‐analysis was to assess the relationship between tumour location and preoperative seizure incidence in patients with gliomas. Methods. Systematic computerised searches of PubMed and the Web of Knowledge were performed. The meta‐analysis of pooled odds ratio (OR) and 95% confidence interval (CI) for preoperative seizure risk, stratified by tumour location, were calculated. Results. Eleven studies with 2,047 patients were included for meta‐analysis. For gliomas with or without frontal lobe involvement, the preoperative seizure incidence ranged from 31.7% (19/60) to 85.7% (156/182) and 19.7% (12/61) to 85.7% (12/14), respectively; the pooled OR was 1.560 (95% CI: 1.266–1.923; Z: 4.17; p=0.000). For gliomas with or without temporal lobe involvement, seizure incidence was 22.6% (7/31) to 91.7% (11/12) and 26.7% (24/90) to 78.7% (174/221), respectively; the pooled OR was 1.070 (95% CI: 0.794–1.443; Z: 0.45; p=0.656). For gliomas with or without parietal lobe involvement, seizure incidence was 18.1% (3/16) to 100.0% (3/3) and 26.7% (28/105) to 80.4% (226/281), respectively; the pooled OR was 0.770 (95% CI: 0.570–1.040; Z: 1.71; p=0.088). For gliomas with or without occipital lobe involvement, seizure incidence was 0.0% (0/2) to 100.0% (2/2) and 26.8% (30/112) to 75.7% (56/74), respectively; the pooled OR was 0.336 (95% CI: 0.164–0.686; Z: 2.99; p=0.003). For gliomas with or without insula lobe involvement, seizure incidence was 34.8% (8/23) to 72.0% (77/107) and 34.3% (60/175) to 81.3% (247/304), respectively; the pooled OR was 1.058 (95% CI: 0.765–1.463; Z: 0.34; p=0.732). No significant publication bias was found. Conclusion. Our meta‐analysis indicates that frontal lobe gliomas are related to a higher preoperative seizure incidence, while occipital lobe gliomas are related to a lower incidence.