Clinical and genetic parallels in congenital brain lesions without epilepsy

Background. The problem of preventing the development of gross congenital brain lesions and their successful treatment is more than relevant now. It is known that approximately in every third case of the development of congenital cerebral palsy (CP), it is impossible to identify the main pathogenetic factor. This determines the activity of the search for gene mechanisms for the formation of this phenotype. G. McMichael et al. were among the first to identify the most relevant directions of the influence of genes on the formation of the CP phenotype.Objective: to study the influence of gene determinants on the formation of the phenotype of CP, which is not accompanied by epilepsy.Materials and methods. Gene abnormalities in 18 patients with CP were divided into groups of determinable physiological processes. Genetic mutations were confirmed by next generation sequencing (NGS) and Sanger trio methods. For the study, samples of the patients' venous blood were taken.Results and discussion. The analysis showed that genes from different groups by determinants are to varying degrees associated with the formation of the CP phenotype. The “map of determinants” in the pathogenesis of CP is specific. The pathogenesis involves genetically determined disorders of cell division and neuroontogenesis (neuronal migration, sprouting, myelination, partly apoptosis), cell metabolism, including those whose disturbance leads to the formation of storage diseases, transmembrane transport, the exchange of neurotransmitters and the functioning of synapses, the formation of and the functioning of the cytoskeleton, as well as the regulation of immunity and oncogenesis. Malformations of the brain are more often associated with determinants of the regulation of the formation and functioning of the cytoskeleton, neuroontogenesis, as well as the processes of cell division (chromatin modification, transcription, replication). The pathogenesis of congenital cerebral palsy does not involve (according to our data) the determinants of canalopathy, energy supply of the cell, intracellular synthesis with the Golgi complex, and ribosomal synthesis.Conclusions. Genetically determined CP is a universal phenotype that implements the multidirectional effect of the genome. The influence of the genome does not apply to the energy supply of the cell, ribosomal synthesis and the functioning of the Golgi complex. In the absence of epilepsy in the phenotype, there is no influence of the genes of canalopathies.

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Risk factors for hip dislocation in dyskinetic cerebral palsy

Journal of Orthopaedic Surgery ◽

10.1177/23094990211001196 ◽

2021 ◽

Vol 29 (1) ◽

pp. 230949902110011

Author(s):

Kyoko Okuno ◽

Yukihiro Kitai ◽

Toru Shibata ◽

Hiroshi Arai

Keyword(s):

Risk Factors ◽

Cerebral Palsy ◽

Birth Weight ◽

Gestational Age ◽

Brain Mri ◽

Brain Lesion ◽

Brain Lesions ◽

Lesion Location ◽

Hip Displacement ◽

Gmfcs Level

Purpose: To investigate the risk factors for hip displacement in patients with dyskinetic cerebral palsy (DCP). Methods: We evaluated 81 patients with DCP, 45 males and 36 females, aged 10–22 years, risk factors for hip displacement were evaluated using multivariate logistic regression analysis with primary brain lesions, Gross Motor Function Classification System (GMFCS) level, gestational age, birth weight, Cobb’s angle, and complication of epilepsy as independent factors. Hip displacement was defined as migration percentage >30%. Primary brain lesions were classified into globus pallidus (GP), thalamus and putamen (TP), and others using brain magnetic resonance imaging (MRI). Perinatal and clinical features were compared between patients with GP lesions and those with TP lesions. Results: Hip displacement was observed in 53 patients (67%). Higher GMFCS levels (p = 0.013, odds ratio [OR] 2.6) and the presence of GP lesions (p = 0.04, OR 16.5) were independent risk factors for hip displacement. Patients with GP lesions showed significantly higher GMFCS levels, more frequent hip displacement, and lower gestational age and birth weight than those with TP lesions. Conclusion: Primary brain lesion location may be an important factor in predicting hip displacement among patients with DCP. Appropriate risk assessment using brain MRI may contribute to the early detection and intervention of hip displacement because brain lesion location can be assessed during infancy before GMFCS level is decided.

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SUBDURAL FLUID AS A CONSEQUENCE OF PNEUMOENCEPHALOGRAPHY

PEDIATRICS ◽

10.1542/peds.5.3.375 ◽

1950 ◽

Vol 5 (3) ◽

pp. 375-389

Author(s):

HONOR V. SMITH ◽

BRONSON CROTHERS

Keyword(s):

Cerebral Palsy ◽

Subdural Hematoma ◽

Cerebral Atrophy ◽

Mental Deficiency ◽

Signs And Symptoms ◽

Brain Lesions ◽

Subdural Space ◽

Suitable Treatment ◽

Superior Longitudinal Sinus ◽

The Brain

When lumbar or cisternal pneumoencephalography is carried out on children with nonprogressive brain lesions causing mental deficiency, cerebral palsy or epilepsy, air is seen in the subdural space in at least a third of cases. This proportion is much larger in children 2 years of age or under. The roentgenographic appearances of subdural air are described and the importance of not attributing these appearances to cerebral atrophy or hypoplasia is emphasized. In approximately one third of cases in which air enters the subdural space, that is, in from 10% to 15% of all cases, recovery from pneumoencephalography is delayed by the development of signs and symptoms suggesting a rise in intracranial pressure. In such cases fluid can usually be found by needling the subdural space. Typically this fluid is characteristic of that found in subdural hematoma. There is no evidence that such a collection of fluid was present before pneumoencephalography. It is therefore suggested that as air enters the subdural space and the brain falls away from the dura, vessels may be torn as they cross this space to reach the superior longitudinal sinus, with the formation of what may be termed subdural hematoma artefacta. Although the incidence of this complication is moderately high, its effects are seldom serious, provided the situation is appreciated and suitable treatment given. The length of time the child spends in the hospital is, however, often greatly prolonged and occasionally operation proves necessary for removal of a subdural membrane. Since the subdural hematoma is an artefact occurring in the course of treatment, its removal does not influence the ultimate prognosis.

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Early Development of Locomotor Patterns and Motor Control in Very Young Children at High Risk of Cerebral Palsy, a Longitudinal Case Series

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.659415 ◽

2021 ◽

Vol 15 ◽

Author(s):

Annike Bekius ◽

Margit M. Bach ◽

Laura A. van de Pol ◽

Jaap Harlaar ◽

Andreas Daffertshofer ◽

...

Keyword(s):

Cerebral Palsy ◽

High Risk ◽

Young Children ◽

Early Development ◽

Muscle Activation ◽

Brain Lesions ◽

Very Young Children ◽

Gait Parameters ◽

Locomotor Patterns ◽

Over Time

The first years of life might be critical for encouraging independent walking in children with cerebral palsy (CP). We sought to identify mechanisms that may underlie the impaired development of walking in three young children with early brain lesions, at high risk of CP, via comprehensive instrumented longitudinal assessments of locomotor patterns and muscle activation during walking. We followed three children (P1–P3) with early brain lesions, at high risk of CP, during five consecutive gait analysis sessions covering a period of 1 to 2 years, starting before the onset of independent walking, and including the session during the first independent steps. In the course of the study, P1 did not develop CP, P2 was diagnosed with unilateral and P3 with bilateral CP. We monitored the early development of locomotor patterns over time via spatiotemporal gait parameters, intersegmental coordination (estimated via principal component analysis), electromyography activity, and muscle synergies (determined from 11 bilateral muscles via nonnegative matrix factorization). P1 and P2 started to walk independently at the corrected age of 14 and 22 months, respectively. In both of them, spatiotemporal gait parameters, intersegmental coordination, muscle activation patterns, and muscle synergy structure changed from supported to independent walking, although to a lesser extent when unilateral CP was diagnosed (P2), especially for the most affected leg. The child with bilateral CP (P3) did not develop independent walking, and all the parameters did not change over time. Our exploratory longitudinal study revealed differences in maturation of locomotor patterns between children with divergent developmental trajectories. We succeeded in identifying mechanisms that may underlie impaired walking development in very young children at high risk of CP. When verified in larger sample sizes, our approach may be considered a means to improve prognosis and to pinpoint possible targets for early intervention.

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Lipoprotein(a) Levels at Birth and in Early Childhood - The COMPARE Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab734 ◽

2021 ◽

Author(s):

Nina Strandkjær ◽

Malene Kongsgaard Hansen ◽

Sofie Taageby Nielsen ◽

Ruth Frikke-Schmidt ◽

Anne Tybjærg-Hansen ◽

...

Keyword(s):

Cord Blood ◽

Early Life ◽

Adult Population ◽

Venous Blood ◽

Blood Levels ◽

Predictive Values ◽

Lipoprotein A ◽

Genetically Determined ◽

Compare Study

Abstract Background and objective High lipoprotein(a) is a genetically determined causal risk factor for cardiovascular disease and 20% of the adult population has high levels (i.e. >42 mg/dL, >88 nmol/L). We investigated whether early life lipoprotein(a) levels measured in cord blood may serve as a proxy for neonatal venous blood levels, whether lipoprotein(a) birth levels (i.e. cord or venous) predict levels later in life, and whether early life and parental levels correlate. Methods The COMPARE study is a prospective cohort study of newborns (N=450) from Copenhagen, Denmark including blood sampling of parents. Plasma lipoprotein(a) was measured in cord blood (N=402), neonatal venous blood (N=356), and at 2 (N=320) and 15 months follow-up (N=148) of infants, and in parents (N=705). Results Mean lipoprotein(a) levels were 2.2(95%CI:1.9-2.5), 2.4(2.0-2.7), 4.1(3.4-4.9), and 14.6(11.4-17.9) mg/dL in cord, neonatal venous, and 2- and 15-months venous samples, respectively. Lipoprotein(a) levels in cord blood correlated strongly with neonatal venous blood levels (R2=0.95, p<0.001) and neonatal levels correlated moderately with 2- and 15-months levels (R2=0.68 and 0.67, both p<0.001). Birth levels ≥90th percentile predicted lipoprotein(a) >42 mg/dL at 15 months with positive predictive values of 89% and 85% for neonatal venous and cord blood. Neonatal and infant levels correlated weakly with parental levels, most pronounced at 15 months (R2=0.22, p<0.001). Conclusions Lipoprotein(a) levels are low in early life, cord blood may serve as a proxy for neonatal venous blood, and birth levels ≥90th percentile can identify newborns at risk of developing high levels.

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Congenital cerebral palsy: genetic cause and nosological integrity

Russian Journal of Child Neurology ◽

10.17650/2073-8803-2020-15-3-4-65-77 ◽

2021 ◽

Vol 15 (3-4) ◽

pp. 65-77

Author(s):

P. I. Sokolov ◽

N. V. Chebanenko ◽

V. P. Zykov ◽

I. V. Kanivets ◽

A. G. Prityko ◽

...

Keyword(s):

Cerebral Palsy ◽

De Novo ◽

Muscle Tone ◽

Copy Number Variations ◽

Genetic Determinism ◽

Nucleotide Polymorphisms ◽

Reproductive Ability ◽

Genetically Determined ◽

Genomic Anomalies

The review provides an analysis of 73 full-text articles, the source of which was the Medline, OMIM, NCBI, Pubmed, Scopus, eLibrary.ru databases. The data of studies of the main pathogenetic mechanisms of the formation of the cerebral palsy (CP) phenotype, such as chromosomal aberrations, copy number variations, single nucleotide polymorphisms, associated with the development of the CP phenotype, are reviewed and analyzed. Epigenetic effects on the genome, as well as the effects of the genome on the mechanisms of epigenomic regulation, are examined in detail. The data on the genetic determinism of concomitant pathology and reactivity to therapeutic tactics are presented. Based on the study of data from numerous studies, the authors draw the following conclusions:1) the pathogenesis of the phenotype of CP includes a large number of genes that determine violations of cellular metabolism, neuroontogenesis, brain resistance to hypoxia, etc;2) genes whose abnormalities form a syndromic pathology are involved in the pathogenesis of CP;3) the multidirectionality and breadth of the effects of the gene pool with the outcome in a syndrome-specific distinctive picture of the CP allows us to propose the concept of a neurotropic genome;4) the mechanisms of gene involvement can vary from aberrations to epigenetic imbalances;5) different groups of genes can differentially influence the formation of individual syndromes in the phenotype of CP;6) there are data indicating a genetic determinism of the tendency to contracture, pharmacoreactivity to drugs that reduce muscle tone, reactivity to habilitation effects;7) genomic-epigenomic interactions normally ensure the body’s adaptation to environmental conditions, and with pathology, they increase the likelihood of regulatory breakdowns that lead to the formation of a CP phenotype;8) the exclusion from the diagnosis of CP of genetically determined cases of phenotype development is incorrect.The authors present two anthropogenic reasons for the increase in the frequency of occurrence of de novo identified gene abnormalities:1) anthropogenic impact on the environment, increasing the number of anomalies of the genome de novo; 2) iatrogenic effects of technologies for preserving life, vitality and reproductive ability of carriers of genomic anomalies. This effect leads to the fixation of anomalies in the genome of the population.A paradox is formulated, according to which, in the presence of technologies capable of preserving the life of carriers of genomic anomalies, in vivo technologies for genome correction are only just beginning to be put into practice. Based on this, it is concluded that it is necessary to intensify the development of methods for prenatal diagnosis and gene therapy of CP.

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A Critical Evaluation of Current Concepts in Cerebral Palsy

Physiology ◽

10.1152/physiol.00054.2018 ◽

2019 ◽

Vol 34 (3) ◽

pp. 216-229 ◽

Cited By ~ 9

Author(s):

Joline E. Brandenburg ◽

Matthew J. Fogarty ◽

Gary C. Sieck

Keyword(s):

Risk Factors ◽

Spinal Cord ◽

Cerebral Palsy ◽

Animal Models ◽

Critical Evaluation ◽

Brain Lesions ◽

Spastic Cerebral Palsy ◽

Diagnostic Symptoms ◽

Brain And Spinal Cord ◽

The Brain

Spastic cerebral palsy (CP), despite the name, is not consistently identifiable by specific brain lesions. CP animal models focus on risk factors for development of CP, yet few reproduce the diagnostic symptoms. Animal models of CP must advance beyond risk factors to etiologies, including both the brain and spinal cord.

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