Can Hemorrhagic Stroke Genetics Help Forensic Diagnosis in Pediatric Age (<5 Years Old)?

When stroke occurs in pediatric age, it might be mistakenly interpreted as non-accidental head injury (NAHI). In these situations, a multidisciplinary approach is fundamental, including a thorough personal and familial history, along with accurate physical examination and additional investigations. Especially when the clinical picture is uncertain, it is important to remember that certain genetic conditions can cause bleeding inside the brain, which may resemble NAHI. Pediatric strokes occurring around the time of birth can also be an initial sign of undiagnosed genetic disorders. Hence, it is crucial to conduct a thorough evaluation, including genetic testing, when there is a suspicion of NAHI but the symptoms are unclear. In these cases, a characteristic set of symptoms is often observed. This study aims to summarize some of the genetic causes of hemorrhagic stroke in the pediatric population, thus mimicking non-accidental head injury, considering elements that can be useful in characterizing pathologies. A systematic review of genetic disorders that may cause ICH in children was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We selected 10 articles regarding the main genetic diseases in stroke; we additionally selected 11 papers concerning patients with pediatric stroke and genetic diseases, or studies outlining the characteristics of stroke in these patients. The disorders we identified were Moyamoya disease (MMD), COL4A1, COL4A2 pathogenic variant, Ehlers-Danlos syndrome (E-D), neurofibromatosis type 1 (Nf1), sickle cell disease (SCD), cerebral cavernous malformations (CCM), hereditary hemorrhagic telangiectasia (HHT) and Marfan syndrome. In conclusion, this paper provides a comprehensive overview of the genetic disorders that could be tested in children when there is a suspicion of NAHI but an unclear picture.

Cdk5 mediates rotational force-induced brain injury.

Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

Discriminating head trauma outcomes using machine learning and genomics.

A percentage of the population suffers prolonged and persistent post-concussion symptoms (PCS) following average head injuries or develops severe neurological dysfunction following minor head trauma. Genetic variants that may contribute to individual response to head trauma have been investigated in some studies, but to date none have explored the use of machine learning (ML) methods with genomic data to specifically explore outcomes of head trauma. Whole exome sequencing (WES) was completed for three groups of individuals (N = 60): (a) 16 individuals with severe neurological responses to minor head trauma, (b) 26 individuals with persistent PCS and (c) 18 individuals with normal recovery from concussion or mTBI. Gradient boosted tree algorithms were applied to the data using XGBoost. By using variants with CADD scores above 15 in the training set (randomly sampled 70%), we identified signatures that accurately distinguish to accurately distinguish the test groups with an average area under the curve (AUC) of 0.8 (SE = 0.019). Metrics including positive and negative prediction values, as well as kappa were all within acceptable range to support the prediction accuracy. This study illustrates how ML methods in combination with WES data have the potential to predict severe or prolonged responses to head trauma from healthy recovery. KEY MESSAGES: Linear association analysis has been inconclusive in concussion genetics. Non-linear methods as boosted trees can offer better insights in small samples. Strong discrimination trends can be achieved from exome data of cases and controls.

The emerging neurological spectrum of AARS2-associated disorders.

BACKGROUND: The AARS2 gene encodes a mitochondrial alanyl-transfer RNA synthetase. Defects in this gene have been linked with autosomal recessive inheritance of a variety of different clinical phenotypes. CASE: A 13 year-old boy developed behavioral and psychiatric problems following a mild head injury. At age 21 he developed tremor, parkinsonism, and eye nystagmus. MRI revealed white matter changes consistent with a leukoencephalopathy. Genetic studies revealed two pathogenic mutations in the AARS2 gene (c.647dupG and c.595C > T). LITERATURE REVIEW: Only 47 cases of AARS2-associated disorders have been reported, with equal numbers of males and females, and age at onset ranging from infancy to 44 years. The most common clinical problems include movement disorders (71%), cognitive impairment (67%), corticospinal signs (64%), behavioral or psychiatric features (46%), and eye signs (34%). Imaging evidence suggestive of leukoencephalopathy is common, but not invariant. Premature ovarian failure is frequent in females, but not universal. CONCLUSIONS: Defects in the AARS2 gene are a rare cause for a variety of movement disorders, often associated with brain imaging evidence suggestive of leukoencephalopathy.

Role of the HIF­1α/SDF­1/CXCR4 signaling axis in accelerated fracture healing after craniocerebral injury.

The hypoxic state of the brain tissue surrounding craniocerebral injury induces an increase in the secretion of HIF­1α during the healing process. HIF­1α can promote mesenchymal stem cell (MSC) migration to ischemic and hypoxic sites by regulating the expression levels of molecules such as stromal cell­derived factor­1 (SDF­1) in the microenvironment. Stem cells express the SDF­1 receptor C­X­C chemokine receptor type 4 (CXCR4) and serve a key role in tissue repair, as well as a number of physiological and pathological processes. The present study aimed to determine the role of HIF­1α/SDF­1/CXCR4 signaling in the process of accelerated fracture healing during craniocerebral injury. Cultured MSCs underwent HIF­1α knockdown to elucidate its effect on the proliferative ability of MSCs, and the effect of SDF­1 in MSCs was investigated. It was also determined whether HIF­1α could promote osteogenesis via SDF­1/CXCR4 signaling and recruit MSCs. The results indicated that HIF­1α knockdown suppressed MSC proliferation in vitro, and SDF­1 promoted cell migration via binding to CXCR4. Furthermore, HIF­1α knockdown inhibited MSC migration via SDF­1/CXCR4 signaling. Considering the wide distribution and diversity of roles of SDF­1 and CXCR4, the present results may form a basis for the development of novel strategies for the treatment of craniocerebral injury.

VEGFR2 signaling drives meningeal vascular regeneration upon head injury.

Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRß and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.

Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach.

Brain injuries are associated with oxidative stress and a need to restore neuronal homeostasis. Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma. The aim of this study was to explore the potential role of variants in other ion channel genes in the development of such responses. We conducted whole exome sequencing (WES) on16 individuals who developed a range of neurological and concussion-related symptoms following minor or trivial head injuries. All individuals were initially tested and shown to be negative for mutations in known FHM genes. Variants identified from the WES results were filtered to identify rare variants (minor allele frequency [MAF] <0.01) in genes related to neural processes as well as genes highly expressed in the brain using a combination of in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, and Mutation Assessor). Rare (MAF <0.001) or novel heterozygous variants in 7 ion channel genes were identified in 37.5% (6/16) of the cases (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4), rare variants in neurotransmitter genes were found in 2 cases (GABRG1 and GRIK1), and rare variants in 3 ubiquitin-related genes identified in 4 cases (SQSTM1, TRIM2, and HECTD1). In this study, the largest proportion of potentially pathogenic variants in individuals with severe responses to minor head trauma were identified in genes previously implicated in migraine and seizure-related autosomal recessive neurological disorders. Together with results implicating variants in the hemiplegic migraine genes, CACNA1A and ATP1A2, in severe head trauma response, our results support a role for heterozygous deleterious mutations in genes implicated in neurological dysfunction and potentially increasing the risk of poor response to trivial head trauma.

Head trauma is the major risk factor for cerebral sinus-vein thrombosis.

BACKGROUND: Cerebral sinus vein thrombosis (CSVT) is a rare disease with significant neurological sequelae and high mortality rate. Incidence of CSVT diagnosis in the western world has increased despite the reduced occurrence of infections. AIM: To identify risk factors that may explain the predisposition to site specific thrombosis. METHODS: Ninety consecutive patients diagnosed with acute CSVT in tertiary hospital. As a control group we used the data extracted from the National Trauma Registry and Healthcare Services. RESULTS: Trauma history up to one month prior to diagnosis of CVST was found in 13 (14%) patients. Six patients had skull fractures, the others had blunt trauma. The overall SMR was 941 (p<0.0001); the separate results for men and women were 1206 and 543, respectively. Infections confined to the head and neck in 7% of the cases and brain tumor were observed in 8%. At the time of CVST, 23 of 50 (46%) women had a hormonal risk factor. The SMR for OC use was 1.63 (p=0.0298). Prothrombotic polymorphisms were detected in 16 of 63 (25.4%) patients who were tested for factor V Leiden and prothrombin G20210A mutation (OR=3.47, p=0.002) in comparison to 49% in DVT patients (OR=9.95, p<0.0001). CONCLUSIONS: Assessment for CVST in patients with recent trauma and headache even after intact head CT is required. The other risk factors, such as hormone related and prothrombotic polymorphisms, were not specific just for CVST and the latter play a lesser role in CVST than in DVT.

Head injury, α-synuclein genetic variability and Parkinson's disease.

BACKGROUND AND PURPOSE: Head injury has been linked to Parkinson's disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated. METHODS: From 2001 to 2012, 561 incident idiopathic PD cases and 721 population controls from central California were enrolled. Subjects reported on head injuries throughout their lifetime and were assessed for genetic variability in the SNCA 5' region (D4S3481; Rep1) and 3' untranslated region (rs356165). In unconditional logistic regression models adjusted for confounders, interactions between head injuries and genetic risk variants were investigated. RESULTS: Parkinson's disease risk in individuals with head injury who are carriers of at least one 263 bp allele in D4S3481 or rs356165 variants was 3-4.5-fold higher compared with non-carriers without head injuries. However, tests for interaction between head injury and SNCA D4S3481or rs356165 were not statistically significant. CONCLUSIONS: Our study finds some evidence that head injury and D4S3481 or rs356165 variants jointly increase the risk of PD but little evidence of interaction.

[Clinical and prognostic significance of genetic markers in craniocerebral injury (Part III)].

It is now becoming increasingly clear that the course and outcome of craniocerebral injury (CCI) are determined not only by its biomechanism, severity, patient's age, presence of premorbid factors, etc., but also by individual features of the genome of each patient, which puts traumatic brain injury among multifactorial diseases. The genome determines the presence or absence of«genetic predilection to the development of various complications and sequelae of CCI, which generally determines the progression of traumatic brain injury disease. The first part of the review by Potapov et al. (201 0) [2] was devoted to the role of apolipoprotein E (apoE) gene polymorphism in CCI, the second one [3]- to the role of inflammation and immune response genes in the course and outcome of CCI. The present (third) part will provide a review of modern data on the effect of genes underlying intracellular processes of oxidative stress, apoptosis, regeneration, and synthesis of neurotransmitters and their receptors.

The release of S-100B and NSE in severe traumatic head injury is associated with APOE ε4.

OBJECT: In this article we tested the hypothesis that the level of two biochemical markers of brain injury may be associated with the apolipoprotein E (APOE) ε4 allele. METHODS: In this prospective consecutive study patients with sTBI were included (n = 48). Inclusion criteria were Glasgow Coma Scale (GCS) score ≤ 8 at the time of intubation and sedation, patient age between 15 and 70 years, an initial cerebral perfusion pressure > 10 mmHg, and arrival to our level-one trauma university hospital within 24 h after trauma. Blood samples for neuron-specific enolase (NSE) and S-100B were collected as soon as possibly after arrival, and then twice daily (12-h intervals) for 5 consecutive days. Venous blood was used for APOE genotype determination. Clinical outcome at 3 months after injury was assessed with the Extended Glasgow Outcome Scale (GOSE). RESULTS: Significantly higher levels of the maximal S-100B (S-100B(max)) and area under the curve (S-100B(AUC)) were found in subjects with the APOE ε4 allele compared to those with non-ε4. A similar tendency was observed for NSE(max) and NSE(AUC), though not statistically significant. CONCLUSION: Our data indicate that there might be a gene-induced susceptibility to severe traumatic brain injury and that patients with the APOE ε4 allele may be more predisposed to brain cellular damage measured as S-100B and NSE. Thus, it seems to be of importance to consider the APOE genotype in interpreting the levels of the biomarkers.

Head injury, α-synuclein Rep1, and Parkinson's disease.

OBJECTIVE: To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson's disease (PD) risk. METHODS: Participants in the Farming and Movement Evaluation (FAME) and the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), 2 independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to Parkinson's disease (PD) diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury. RESULTS: Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9), and long Rep1 with increased risk (pooled OR, 1.4; 95% CI, 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR, 1.3; 95% CI, 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR, 5.4; 95% CI, 1.5-19; SEARCH OR, 2.3; 95% CI, 0.6-9.2; pooled OR, 3.5; 95% CI 1.4-9.2, p-interaction = 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03). INTERPRETATION: While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.

Prediction of time trends in recovery of cognitive function after mild head injury.

OBJECTIVE: To investigate relations between predictors and outcomes, and especially to identify predictors influencing the time trend in recovery after mild traumatic brain injury. METHODS: We included 59 patients with mild head injury in a prospective study. They underwent comprehensive assessment with neurological and neuroradiological examinations, serum S-100B analysis, and apolipoprotein E (APOE) genotyping. Neuropsychological testing was performed before and 6 months after discharge. Linear mixed models were used to assess associations between baseline predictors and neurocognitive performance and its change. RESULTS: A Glasgow Coma Scale score of less than 15, traumatic brain injury demonstrated with computed tomography, magnetic resonance imaging, and serum S-100B greater than 0.14 microg/L predicted impaired cognitive performance both at baseline and after 6 months; APOE genotype did not. There was significant improvement of performance after 6 months. APOE-epsilon4 genotype was the only independent factor significantly predicting less improvement. CONCLUSION: The presence of the APOE-epsilon4 allele predicts less recovery of cognitive function after mild head injury.

[Evaluation of the p53 Arg72Pro polymorphism as a prognostic factor in severe head injury and the inclusion of this indicator in a predictive model]. / Evaluación del polimorfismo Arg72Pro de p53 como factor pronóstico del traumatismo craneoencefálico grave y su participación en la construcción de un modelo predictivo.

BACKGROUND AND OBJECTIVE: Physiologic variables have traditionally been studied as prognostic factors in severe head injury. Until recently it was not thought that genetic factors might play a role. The main objective of this study was to construct a logistic regression model including physiologic variables and the p53 Arg72Pro polymorphism, which can promote neuron death through apoptosis. MATERIAL AND METHODS: We included 90 patients admitted to the postoperative recovery unit with severe head injury. Patients with previous neurologic deficits were excluded. Clinical variables were recorded. The p53 Arg72Pro polymorphism was analyzed using polymerase chain reaction of DNA in blood. Neurologic outcome was assessed on the Glasgow Outcome Scale. A predictive logistic regression model was then constructed based on relevant candidate variables (sex, age, poor Glasgow score, the Acute Physiology and Chronic Health Evaluation II score, pupil size, pupil reactivity, subarachnoid hemorrhage, number of days in the recovery unit, number of days on mechanical ventilation, and the early development of hypotension) in addition to the p53 Arg72Pro polymorphism. RESULTS: The Arg/Arg polymorphism was an independent predictor of poor outcome (odds ratio, 3.55; 95% confidence interval [CI], 1.11-1132; P = .032). The selected model (including the variables age, gene polymorphism, pupil reactivity, and Glasgow score) had adequate discriminatory power (sensitivity 823%, 95% CI 72.8%-91.8%; specificity 78.6%, 95% CI 63.4%-93.8%), classifying 81.1% of the patients correctly. The p53 Arg72Pro polymorphism, along with pupil reactivity, age and Glasgow score, is useful in a predictive model of good or poor outcome on discharge after head injury.

Risk of dementia associated with the ApoE epsilon4 allele and falls causing head injury without explicit traumatic brain injury.

OBJECTIVES: Severe head injury (HI) and the apolipoprotein E (ApoE) epsilon4 allele are risk factors for dementia. The corresponding effect of falls causing HI without explicit traumatic brain injury (TBI) in association with the ApoE epsilon4 is not known. MATERIALS AND METHODS: Altogether 134 persons aged 70 years or older constituted a retrospective population sample, who scored > or =26 in the MiniMental State Examination (MMSE) test at baseline and were clinically examined for dementia 9 years afterward. Fall-related HI causing superficial laceration or bruises or wounds that require suturing were prospectively recorded during the 9-year follow-up. We used Cox regression with age at the diagnosis of dementia as a dependent variable. RESULTS: Twenty-eight (21%) subjects had falls causing HI without explicit TBI, the ApoE epsilon4 allele was seen in 44 (33%), and clinical dementia was diagnosed in 25 (19%). Adjusted for the baseline MMSE score, sex and educational status, the hazard ratio for subsequent dementia in subjects having falls with HI without explicit TBI and the ApoE epsilon4 allele as compared with those who do not possess these characteristics was 2.70 (95% confidence interval, 1.02-7.16). CONCLUSIONS: According to the results of this small retrospective study, falls with HI without explicit TBI in connection with the ApoE epsilon4 allele is associated with subsequent dementia among older adults.