Epidemiological studies show that co-occurrence of neurodevelopmental disorders is the rule rather than the exception; essentially, all neurodevelopmental disorders coexist with other neurodevelopmental disorders much more commonly than would be expected by chance.
For example, up to 50% of individuals with ADHD present with movement difficulties consistent with developmental coordination disorder,10–40% have affective disorders, and 20–30% have tic disorders. Twin studies found that reading disorder, mathematics disorder, and ADHD are familial and heritable, and that the cause of co-occurrence of reading and mathematics disorders (28–64%), reading disorder and ADHD (10–40%), and mathematics disorder and ADHD (12–36%) is primarily explained by common genetic factors. There is substantial overlap at the diagnostic, neuropsychological, and aetiological levels among speech-sound disorders, language impairment, and reading disorders.
However, coexisting psychiatric disorders are common even among individuals with neurodevelopmental disorders who do not have intellectual disability….Epidemiological data suggest that rather than being considered as causally and pathophysiologically distinct, neurodevelopmental disorders should be thought of as different patterns of symptoms or impairments of a common underlying neurodevelopmental continuum.
Recent studies of large cohorts of individuals with a broad range of neurodevelopmental disorders provide strong evidence for several rare genetic causes for this group of disorders; they also show a positive association between the burden of genetic insult, quantified by the number and size of copy number variants, and the severity of the phenotypes. Furthermore, studies using exome sequencing for gene discovery suggest that hundreds of genes may be associated with neurodevelopmental disorders such as autism spectrum disorders, intellectual disability, and schizophrenia.
In addition, it has also been recognised that multiple genetic causes are shared among a number of apparently different neurodevelopmental disorders…we propose that developmental brain dysfunction results in clinical manifestations that include:
– the less severe disorders once encompassed by minimal brain dysfunction or minimal cerebral dysfunction (eg, learning disabilities, language disorders, developmental coordination disorder, and ADHD),
– the more severe classic neurodevelopmental disabilities (eg, intellectual disability, cerebral palsy, and autism spectrum disorders),
– and also at least a subset of neuropsychiatric disorders that were regarded as part of the neurological taint more than 150 years ago (eg, schizophrenia and possibly major affective disorders).
Developmental brain dysfunction, whether genetic or caused by an insult to the developing central nervous system—such as exposure to a teratogen, trauma, infection, severe nutritional deficiency, or hypoxia-ischaemia—is typically manifested as impairments in cognitive, neuromotor, or neuro behavioural functioning and, in some cases, observable anatomic or neurophysiological findings. An individual’s clinical diagnosis is determined by the specific pattern of impairments, but the common denominator is developmental brain dysfunction.
This is a broad conceptual categorisation, and not a final diagnosis, since categorical diagnoses and specific impairments must be identified to guide treatment….a substantial subset of various categorical neurodevelopmental and neuropsychiatric diagnoses share similar risk factors and commonly coexist, which is supported by the epidemiology of these disorders. This model also predicts that each particular cause can manifest as a spectrum of impairments of varying severity. The notable variation in the phenotypic expression of recurrent copy number variants and single gene mutations supports the notion of combining a number of neurodevelopmental and neuropsychiatric phenotypes together under the term developmental brain dysfunction. In cases with deletions evidence suggests the impact of the deleterious genetic variant is applied to the affected individual’s expected performance level based on genetic back ground, resulting in standardised cognitive (intelligence quotient) scores that are substantially lower than expected. Other copy number variants, single gene mutations, and non-genetic defects can vary among the three streams of development—cognitive, neurobehavioural, and motor—and among the components of an individual stream.
…if phenotypic traits are analysed independently, a genetic abnormality can be considered to be variably expressed for some functional domains and incompletely penetrant for others. However, when discrete deficits are viewed as manifestations of a common, underlying developmental impairment that we refer to as developmental brain dysfunction, we hypothesise that the penetrance of most copy number variant syndromes is likely to approach 100% across the lifespan.
…The current guidelines of the American Academy of Pediatrics recommend routine, standardised developmental screening in all children at their 9-month,18-month, and 30-month well-child preventive care visit. Other guidelines, from the American Academy of Neurology, Child Neurology Society, and American College of Medical Genetics, recommend chromosomal microarray analysis for children with unexplained global developmental delay. Therefore, the likelihood is that more children with developmental brain dysfunction of genetic origin will be identified early in life. Based on current research, it is tempting to propose that once a child is shown to have a specific genetic abnormality in clinical practice, parental core functional domains should be evaluated to more accurately predict the phenotypic consequences expected in the child and plan early intervention and treatment accordingly, for a truly personalised medicine approach.