Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence

Abstract

Neurodevelopmental disorders can be caused by many different genetic abnormalities that are individually rare but collectively common. Specific genetic causes, including certain copy number variants and single-gene mutations, are shared among disorders that are thought to be clinically distinct. This evidence of variability in the clinical manifestations of individual genetic variants and sharing of genetic causes among clinically distinct brain disorders is consistent with the concept of developmental brain dysfunction, a term we use to describe the abnormal brain function underlying a group of neurodevelopmental and neuropsychiatric disorders and to encompass a subset of various clinical diagnoses. Although many pathogenic genetic variants are currently thought to be variably penetrant, we hypothesise that when disorders encompassed by developmental brain dysfunction are considered as a group, the penetrance will approach 100%. The penetrance is also predicted to approach 100% when the phenotype being considered is a specific trait, such as intelligence or autistic-like social impairment, and the trait could be assessed using a continuous, quantitative measure to compare probands with non-carrier family members rather than a qualitative, dichotomous trait and comparing probands with the healthy population.

Development of Two Dimensional Measures of Restricted and Repetitive Behavior in Parents and Children

“…2,3 Contrary to traditional categorical nosological boundaries, recent findings indicate that the majority of these NDD/NPD are overlapping syndromes 4 that are best represented as a collection of dimensional traits that extend into the general population. 5,6 RRBs are also common throughout typical development. 7,8 Strong preferences for sameness in the environment, lining objects in straight lines, rigid routines, and an acute perceptual awareness of minute details are frequently observed in typically developing children between 2-7 years of age.…”

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

“…Even in the case of whole chromosome disorders, such as Down Syndrome, there is ample evidence of substantial phenotypic expression differences, modified again by genetic background [52,53], somatic mosaicism [54] and environmental influences [55,56], including synaptic and brain plasticity [17,[57][58][59][60]. The same is true for deletion syndromes, such as velocardiofacial syndrome and other deletions [61][62][63][64][65][66]. And, of course, there is constant interaction of the environment with a person, both prenatally and postnatally.…”

“…There are, however, still many challenges in showing how any one mutation can contribute toward a clear phenotype, particularly in the context of genetic background and possible environmental influences [205]. Bioinformatics confounders, such as poor data quality [206], sequence inaccuracy, and variation introduced by different methodological approaches [207] can further complicate biological and genetic inferences.…”

Vulnerabilidade no desenvolvimento da criança: influência das iniquidades sociais

“…Tais situações de vulnerabilidade determinam o comprometimento do crescimento e desenvolvimento dessas crianças. Devido a esse pressuposto, identificam-se evidências da influência de elementos biológicos, psicossociais e ambientais dos indivíduos e seus familiares sobre o seu desenvolvimento (2) . As precárias condições econômicas constituem situações de vulnerabilidade que, em certas circunstâncias, não estão isoladas, pois permeiam o relacionamento dos pais da criança, colaborando para aumentar os conflitos entre eles, com reflexos diretos no relacionamento com o filho -fenômeno que se denomina como miséria afetiva (3)(4) .…”

“…A ausência desse ambiente apoiador pode prejudicar a maturação dos circuitos cerebrais, sistemas metabólicos reguladores, havendo interrupção dos órgãos de desenvolvimento e aumento das probabilidades de ocorrerem, em longo prazo, problemas de aprendizagem, comportamento, como também o comprometimento da saúde física e mental da criança (5) . Para se identificar uma criança vulnerável, é necessário que se verifique a inter-relação da condição do meio social no qual ela habita, com sua condição orgânica (2) . A miséria, advinda da iniquidade social, é considerada uma situação que aumenta significativamente a vulnerabilidade da criança, podendo originar subnutrição, carência social e prejuízos nas atividades educacionais, bem como incide diretamente no bem-estar infantil, configurando-se como barreira para seu desenvolvimento (4) .…”