Tulburări neurobiochimice, neurometabolice şi impactul lor asupra randamentului intelectual la copilul dislexic

 Neurobiochemical and neurometabolic disorders and their impact on intellectual performance in dyslexic infant

First published: 12 aprilie 2021

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Pedi.62.2.2021.4885


The brain should not be seen only as an independent organ. The development of the neural tube with maturation to the brain is also the subject of reactions and transformations, especially neurochemical and neurometabolic. It seems that delaying the development or stopping the evolution of certain brain areas also involves a defective neurochemistry that can change a child’s entire life, but especially affecting at different levels his intellectual and socio-professional in­te­gration skills. We want to issue a warning, from this point of view, on some special neuropediatric as well as psy­cho­pe­da­go­gical peculiarities in the dyslexic child of pre­school and school age. Aspects of neurobiology, neu­ro­­che­mis­try, neurogenetics and neurometabolism are presented which, unfortunately, can describe an un­fa­vo­rable cascade of events with an impact on certain processes and intellectual activities in the child. Also, this article is complemented by psychopedagogical aspects, without which these children could not be helped to evolve in a way and, implicitly, would be doomed to major psychological trauma.

infantile neuropsychiatry, molecular events, psychopedagogy, dyslexia


Creierul nu trebuie privit doar ca un organ de sine stătător. Dez­vol­tarea tubului neural cu maturarea până la creier re­pre­zin­tă, de asemenea, obiectul unor reacţii şi transformări, mai ales neurochimice şi neurometabolice. Se pare că întârzierea dez­vol­tării sau oprirea în evoluţie a anumitor arii cerebrale com­­por­tă, de asemenea, o neurochimie defectuoasă care poa­­te schimba viaţa întreagă a unui copil, dar mai ales afec­tând la diferite niveluri capacităţile intelectuale şi de in­te­gra­re socioprofesională ale acestuia. Dorim să tragem un mic sem­nal de alarmă, din acest punct de vedere, asupra unor par­ti­cu­la­ri­tăţi neuropediatrice speciale, precum şi psi­ho­pe­da­go­gice la copilul dislexic de vârstă preşcolară sau şcolară. Sunt prezentate aspecte de neurobiologie, neurochimie, neu­ro­ge­ne­ti­că şi neu­ro­me­ta­bo­lism, care, din nefericire, pot să descrie o cascadă de evenimente cu impact nefavorabil asupra unor procese şi ac­ti­vi­tăţi intelectuale la copil. De asemenea, acest articol este com­ple­tat de aspecte psihopedagogice, fără de care aceşti copii nu ar putea fi ajutaţi să evolueze într-un fel şi, implicit, ar fi sortiţi unor traume psihice majore.

Dyslexia – general and particular considerations

Dyslexia, also known as reading disorder, is characterized by trouble with reading even though the patient has a normal intelligence(1). Distinctive individuals are affected to different degrees(2). Those may comprise difficulties in spelling words, reading quickly, writing words, “sounding out” words in the head, pronouncing words when reading aloud and understanding what one reads(3). Often, these difficulties are first noticed at kindergarten and school. At the highest degree of its neuropathology, dyslexia was observed in children from orphanages, of preschool and school age. Despite a certain “intelligence” of synthesis, association and identification of written information, however, high degrees of dyslexia and alexia have been reported. This is why a careful psychological observation is absolutely necessary, and this is immediately noticeable by the specialized educator who works with these children. Adolescents and children with dyslexia have higher rates of attention deficit hyperactivity disorder (ADHD), developmental language impairments, and difficulties with basic mathematical operations and numbers(4).

Neuroanatomical and neurobiological aspects of dyslexia

At present, dyslexia is considered to be due to a defect in the ability to integrate information across different functional systems and is specifically associated with abnormal functioning of the hub region that connects information between different systems and specific areas of the left hemisphere(5). The confrontation in decisively defining the neurobiology of dyslexia is built in from the argument that phonological deficit has multiple components (phonological awareness, impaired lexical retrieval and poor verbal short-term memory), each of which involves different neural areas and specific networks(6). Previous studies docu­men­ted differences between dyslexic and control brains, in the left perisylvian cortical and elemental white matter, thalamus, corpus callosum and cerebellum(7). One of the many theories was that the development of dyslexia is anticipated by a failure of neuronal migration(8) from the ventricular zone up towards the cortical plate. High-rate myelination of the left perisylvian cortex is often associated with dyslexia(9). This region comprises Broca’s area (associated with speech production) and Wernicke’s area (responsible, among other functions, with speech comprehension). Those at risk for dyslexia are defined to have poorly gray matter and cortical thickness, notably of the areas surrounding the perisylvian cortex at junctions of the parietal, temporal and occipital lobes(10). There is also a hypoactivation of the left inferior frontal, temporoparietal and occipitotemporal regions of the left hemisphere, the same brain areas that are involved in recognizing symbols and letters, translating sounds into phonological meaning, and associating letters with sounds(10). The brain changes are somehow immediately detectable in dyslexic children, even when compared to children at similar reading levels and non-dyslexic. This suggests that people with this disorder have very particular structural characteristics and are not randomly characterized by a delayed development of the brain. In children from young dyslexic families, diverse changes are identified early in the development, such as abnormal anatomy of the sulcal patterns and neural connectivity, implying as well decreased white matter of the arcuate fasciculus. Some regions of the brain can also reveal high-rate maturation earlier than normal in those with dyslexia, including the posterior corpus callosum and the temporoparietal region of the left hemisphere (which is part of the reading network) and right hemisphere (which makes up the attentional networks)(11). Also, from a neuroanatomical point of view, it is interesting the succession of phonological and reading processes, determined or influenced by the contribution of certain brain areas and their maturation. One of the primary roles, from this point of view, has the white matter. Through the techniques of nuclear magnetic resonance and electroencephalography, the activity of the brain and the integrity of certain brain structures were highlighted. The neuroanatomical areas that appear to be involved by having a functional and structural advancement following phonological and reading interventions are the left thalamus, left middle occipital gyri, bilateral inferior frontal gyri, right insula, and right posterior cingulate gyrus(12,13).

Neurochemical, neurometabolic
and neurogenetic considerations

First of all, our whole body is a multiple amount of initiation, development, transmission and completion of chemical reactions. Regardless of the symptom, regardless of which pathology this symptom is affected, it is based on chemical reactions between the body’s fluids and the body’s cellular apparatus. That is why the role of biologist, chemist and biochemist specialized in neuropathology is of paramount importance. Modern institutes of pediatric neurology and pediatric neuropsychiatry are equipped with at least 10 research laboratories, exclusively composed of neurobiologists and neurochemists, each one specialized in the neuropathology of different neurological and psychiatric dysfunctions in children. It is very important to understand the cellular and molecular biology of the neuron. The symptom is a “cardinal helper”, but to get to the symp­tom we must study many more processes that take place, otherwise the understanding will be superficial and not at all in the help of the dyslexic child or with another neuropsychiatric condition.

From the point of view of synaptic transmission, the theory that stands to explain the intimate neuromolecular processes related to dyslexia brings into evidence a heightened level of glutamatergic pathway (Glu or Glx) signaling in dyslexic individuals(14), since glutamate concentrations and activity were found to be positively correlated with cortical excitability(15).

As for neurotransmitters and their contribution/effect in terms of dyslexia, gamma-aminobutyric acid (GABA) forces the modulation of gamma band(16) and gamma band neurophysiological correlates of GABA concentrations have been observed in the visual(17,18), temporal(19) and motor(20) cortex of healthy individuals. The impact of neurotransmitters in slow neurometabo­lites regulations is much less understood, but glutamate and choline (Cho) were implicated as the effective neurotransmitters. Specifically, during auditory signal processing in humans, an association between glutamate concentration in hippocampus and frontal areas was reported(21). Meanwhile, studying perturbations in neurometabolite levels may notify about underlying brain cytoarchitectonic discrepancy between regular and dyslexic readers. Total N-acetylaspartate (tNAA) concentration reflects neuronal density, functional via­bility(22), but also maintains and reinforces myelination(23). Choline is considered a marker of cell membranes in the voxel, which could reveal glial cell density(24), the amount of myelin(25) or corresponding membrane turnover from interruption or synthesis(26). Dysfunctions in cortical connectivity have been considered in individuals with dyslexia, by multiple theories of dyslexia, not reduced to the hyperexcitability and impaired auditory tested models. Nevertheless, the findings of the neurometabolites in dyslexia can afford valuable insights to a broader understanding of neurobiochemical processes underlying dyslexia. Antecedently, only few studies exploring concentrations of neurometabolites in dyslexia have been done. A fundamental work was carried out by Rae(27), who found lower choline/N-acetylaspartate (NAA) ratio in the left temporoparietal lobe and right cerebellum in 14 dyslexics compared to 15 typically reading males.

Regarding the neurogenetics of dyslexia, the transmission pattern is based on the heritability analysis accomplished through the standardized accepted methods (transmission of the condition in family group studies, regression studies that compare dyslexia prevalence in groups of twins, whether identical or not etc.) which demonstrate that the disorder is not normally transmitted as a Mendelian character and is a heterogeneous condition from a genetic point of view(28).

In the following, we will briefly present the genetic candidates of dyslexia and dyslexia-corresponding loci. The heritability that characterizes dyslexia (which is different than in other intellectual impairment) has undoubtedly stimulated the efforts to search, to identify and structurally characterize candidate genes whose mutation could be a crucial component of the disorder. In order to proceed, positional cloning technique is normally used, that grants the abnormal phenotype to be associated to a specific chromosomal fragment, which later sequences itself, so as to determine the nature of the gene (or genes) enclosed in it. The essential methodological tool in positional cloning is linkage or association analysis, which determinates dyslexia co-heritability with a sufficiently increased number of polymorphic genetic markers (generally SNP, single nucleotide poly­morphisms), whose position in each chromosome is known(29). Linkage and association experimental studies have described several loci that are potentially related to dyslexia (DYX1 to DYX9, according to the Human Gene Nomenclature Committee [ uk/nomenclature/], even supposing the corresponding analysis has only been replicated in four of them: DYX1, DYX2, DYX5 and DYX6)(30), besides as many additional loci that could characterize a susceptibility to the disorder. From three of these loci (DYX1, DYX2 and DYX5), it was possible to clone and identify a total of four genes, considered dyslexia candidate genes. The DYX1 locus corresponds to mutation of the DYX1C1 gene in this area, the DYX2 second locus for the disorder corresponds to DCDC2 gene, causing a serious modification in the normal neuronal migration process, which affects the pyramidal neurons of the hippocampus. The third locus, DYX3 for dyslexia, is located in chromosome 2, possibly in the 2p16-p15 area(31). DYX4, the fourth locus of the disease, is found in the 6q11.2-q12 area. It is mainly related to spelling ability and phonological encoding(32). DYX5, the fifth locus related to dyslexia, corresponds to the chromosomal area 3p12-q13. The ROBO1 gene, considered as the fourth main dyslexia candidate gene, is located in this area. In case of DYX6, this locus corresponds to the chromosomal area 18p11.2125. DYX7, the seventh dyslexia locus, is found in the 11p15.5 area and suggests some subordinates, such as: 1) the SCT gene, which encodes secretin-neuropeptide of the VIP/glucagon family, whose presence is required for normal brain maturation and  development(33,34); 2) the STIM1 gene, that apparently plays a role in the regulation of nervous system development and in response to external stimuli and encodes a protein that seems to participate in many cellular regularly processes and signal transduction pathways(35); 3) the MTR1 (TRPM5) gene(36); and 4) the HRAS gene, which encodes a GTP-ase involved in a signal transduction mechanism susceptible in long-term potentiation regulation, synaptic plasticity and neural growth and differentiation(37). DYX8, the eighth dyslexia locus, corresponds to the chromosomal area 1p34-p36.143,144, revealing the peculiarity that it has a gene homologous to KIAA0319, named KIAA0319L. The locus has also been related to ADHD(38). DYX9, the last dyslexia locus, is found in Xq27.3(39). It may be desirable to take into account that this area has been related to the so-called fragile X (chromosome) syndrome(40), one of the most frequent forms of hereditary mental retardation, which includes many speech disturbances(41,42).

Psychopedagogical particularities related to dyslexia

Despite some neurobiological and neurogenetic interdependence, dyslexia is still a clinical diagnosis, with no conclusive biochemical or neuroimaging markers, and there is no clinical laboratory test that can diagnose it. The diagnosis is established on history, observation and psychological evaluation. In the orphanages with normal program, in the auxiliary schools for girls, in the auxiliary schools for boys and in the art-vocational schools, the role of the specialized educator on different age stages (preschool, school, adolescent) is crucial and beneficial. The most delicate and difficult task is the one of specialized educators for preschool children with special educational needs. Also, the role of the pediatrician specialized in child neuropsychiatry is of great importance. Teaching approaches can be branched into four broad areas: individualized approaches, support approaches, assisted learning, and whole-school approaches. In ascertaining the most appropriate programmes and teaching strategies for dyslexic children, a number of factors must be considered, the most important being:

The context – the nature of learning and teaching, didactic material and the age and stage of the individual.

The assessment – in what way does the evaluation inform teaching, and the individual’s strong points and difficulties can be willingly identified from the results of the evaluation.

The curriculum – how can the teaching strategy/program be related to the curriculum: are any gains made by the programme voluntarly transferable to other features of the curriculum?

The learner – what are the individual factors which can help the learner make appropriate acquirements from the programme? Is the programme accepted by the individual’s learning style?(43).

It is important therefore to view/review teaching programmes in relation to the individual and not in relation to the syndrome – “dyslexia”(43). Some programmes may be carefully evaluated by educators, psychologist and pediatricians and have an established reputation as a successful multisensory/partially multitasking programme, but this does not by definition mean that the programme will be effective with all dyslexic children. Each child has to be teached/carried out/evaluated individually. Children with dyslexia can gain and acquire reading skills; never­theless, reading is often more effortful(44), and their all-inclusive reading achievement is under average if compared with non-dyslexic children(45). It is absolutely necessary to distinguish children’s reading and diagnose dyslexia early, because the early intervention with carefully selected reading correction/remediation can improve reading consequences(44,46). Moreover, as children and adolescents with dyslexia have increased risk for school failure, academic underachievement and internalizing problems (anxiety, depression), the appropriate interventions may prevent these secondary adverse events(46). Some preschool children attend difficulties in school performance, with somatic remonstrance which may result in school abandon, and low self-esteem and efficacy(45). Even after reading interventions and learning decoding skills, children may continue to be slower and more effortful readers. These provocations can also go along with difficulties in writing and note-taking (dysgraphia). Adolescents from high school may have some level of fluency, but the impact of the phonological deficit determines a slower reading and they do not reccuperate with their typically reading peers(46,47). An ordinary wrong conception is reversible diagnostic for dyslexia – this may occur in typically developing children, largely before 7 years age old(48). Another myth is that children can “outgrow” dyslexia; anyhow, at the same time, dyslexia does persevere into adulthood, and they may learn to be skilled in words that are important to their daily functional life (e.g., profession)(49). Still, another myth is that dyslexia occurs mainly in the Romanian language, however it can occur in other orthographies and other languages as well. Certainly, there are several aspects to be pointed out, but we believe that we have synthesized the most important aspects and psychopedagogical strategies for dyslexia.

Conclusions and remarks

The mechanisms of any intellectual delay in the child, regardless of the cause, are difficult both in terms of elucidation, but also in terms of neurobiological, neurochemical, neurogenetic and neurometabolic me­cha­nisms. From this point of view, dyslexia will remain a “continuum” of exploration, development and up to the point of the medical and psychopedagogical evidence. We tried briefly to emphasize a parallel between the medical and pedagogical characteristics of dyslexia and to highlight what differentiates them. The dyslexic child has the right to normality, to social and professional reintegration, as well as to professional training courses related to the place of employment he occupies. Degrees of intellectual disability should be seen as disabilities of a certain stage in brain maturation and not as a blameworthy handicap.  


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