In his presidential address to the Society of Pediatric Research in 1971, William Nyhan proposed the term ‘behavioral phenotype’ to designate self-injurious behavior that is a characteristic feature of Lesch–Nyhan syndrome. In the ensuing years, behavior phenotypes have been described in many genetic disorders with both Mendelian and non-Mendelian inheritance. Patterns of inheritance vary, for example, Lesch–Nyhan syndrome, is a Mendelian X-linked recessive disorder that involves a single gene, hypoxanthine-guanine phosphoribosyltransferase1 (HPRT1), that encodes an enzyme involved in purine metabolism . HPRT1 deficiency shows a spectrum of presentations dependent on the extent of enzyme loss, a dose–response effect. Classical Lesch–Nyhan syndrome with the full syndrome occurs with less than 1% enzyme. Those with over 2% enzyme do not self-injure but present with dystonia and those with levels of, for example, 8% enzyme deficiency neither self-injure nor present with dystonia. When the full spectrum of enzyme deficiency is considered, the neurocognitive phenotype is most characteristic across the full spectrum of enzyme deficiency .
Both genetic and epigenetic mechanisms are associated with behavioral phenotypes in neurodevelopmental disorders. Epigenetics refers to heritable changes in gene expression in the absence of alterations in the DNA sequence [3–5]. Epigenetic modifications play a major role in tissue and cell-type-specific differences in gene expression ).
In Fragile X syndrome (FXS), the genetic mutation (repeat expansion) is inherited in a Mendelian manner (X-linked dominant inheritance). Here too, there is a spectrum of presentations depending on the number of trinucleotide repeats that are inherited leading to differences in behavioral phenotype [7,8]. Although Fragile X syndrome is not an epigenetic disorder abnormal methylation of the Fragile X Mental Retardation 1 (FMR-1) Cytosine base followed immediately by a Guanine base (CpG)-island, thought to be acquired early in embryogenesis, is responsible for the absence of FMR-1 transcription. The altered methylation at the promoter working in cis to disrupt FMR1 gene expression resembles classic imprinting disorders like Prader–Willi syndrome (PWS) but the mechanism is not one of imprinting. Still Fragile X Mental Retardation Protein may have some epigenetic/chromatin-associated roles.
PWS is a classic imprinting disorder and is epigenetic [6,9]. Imprinting refers to the differential expression of alleles for a particular gene depending on the parental origin of the allele. The genetic mechanism in PWS is uniparental dysomy (two copies of the chromosome 15 from the mother and no copy from the father). The pathogenesis is because of disrupted imprinting/epigenetic marks in cis at a single locus (typical for imprinting/epigenetic disorders). The primary mechanism is methylation that occurs at a single locus and turns off the parent's gene by the attachment of a methyl group.
This is different from Mendelian disorders of the epigenetic machinery (MDEMs) that result from genetic mutations in components of the epigenetic machinery, which are thought to have broad transepigenetic effects at many genes. Overall PWS is a non-Mendelian epigenetic disorder.
In Rett syndrome, the genetic cause was identified as a loss of function mutation in the X-linked gene methyl-CpG binding protein 2 (MECP2) . Rett syndrome is a MDEM. MECP2 is involved in chromatin shaping and regulation of gene expression that is involved in neuronal development and synaptic function. The DNA methylation machinery and the histone machinery affect the expression of many genes in trans. Within the epigenetic machinery, genetic mutations may occur in writers, erasers, or readers of epigenetic marks as well as in chromatin remodelers. MECP2 is a reader of epigenetic marks .
This issue of Current Opinion begins with Sotos syndrome, a MDEM that has a characteristic neurobehavioral phenotype (Harris and Farner, 2019, pp. 55–59). This study is followed by three microdeletion syndromes (Williams syndrome, 22q11.2, Smith Magenis’ syndrome or 17 minus syndrome) that result in behavioral phenotypes. For Williams syndrome, the authors examine psychological and social function in this syndrome. (Royston et al., 2019, pp. 60–66), in 22q11.2 microdeletion; they consider psychosis (O’Rouke and Murphy, 2019), in Smith Magenis (17p- syndrome) behavior and sleep disturbance are discussed (Shayota and Elsea, 2019, pp. 73–78). The next two studies focus on the sex chromosome abnormalities examining the neurocognitive and behavioral phenotypes of 47,XXY and 47,XXX syndromes (van Rijn, 2019, pp. 79–84) and social skills and relationships in Turner's syndrome [XO (absence of one X chromosome)] (Wollstonecraft and Skuse, 2019, pp. 85–91). The final study addresses diagnostic criteria and treatment outcomes in fetal alcohol spectrum disorders (FASD) (Mukherjee, 2019, pp. 92–96).
Harris and Fahrer (pp. 55–59) review Sotos syndrome, a MDEM. MDEMs are neurodevelopment disorders involving genes that encode the epigenetic protein machinery that read, write, and erase posttranslational signals on DNA and histones and remodel chromatin . Sotos syndrome is a MDEM genetic disorder with epigenetic consequences. Its neurobehavioral phenotype illustrates the essential role epigenetic mechanisms play in neurologic development. The authors review recent advances in the molecular pathogenesis of Sotos syndrome, discuss epigenetic mechanisms involved in the neurobehavioral phenotype, and illustrate the implications of how understanding the molecular pathogenesis of Sotos syndrome may lead to the development of diagnostic tests and therapeutic interventions. For example, in Sotos syndrome, its DNA methylation epigenetic signature as measured in peripheral blood can be functionally comparable to clinically relevant target tissues such as the brain .
Royston et al. (pp. 60–66) review psychological and social function in Williams syndrome, a rare genetic disorder, estimated to occur in between 1 in 7500 and 1 in 20 000 live births . It is caused by a hemizygous sporadic microdeletion of 26–28 genes on chromosome 7q11.23. Although enhanced sociability and expressive language skills are sometimes considered strengths in young children with Williams syndrome, they may have a negative impact on outcomes in later life. As the child grows older these social and language domains are increasingly asynchronous with other areas of development. The authors find greater focus is needed in longitudinal research on risk factors to establish interventions that minimize such social and emotional difficulties. Moreover, it is important to examine how specific strengths might be used to moderate their difficulties in other developmental areas. What is needed is a detailed examination of the relationship between multiple domains instead of targeting specific impairments alone for intervention. Utilizing accepted therapies effective in other conditions, for example, in autism spectrum disorder, might be implemented to improve social communication and emotional problems in Williams syndrome.
The 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion in humans with deletion of 30–40 genes. Those affected have high rates of cooccurring mental disorder, attention-deficit hyperactivity disorder (ADHD) in childhood, and psychosis in late adolescence and early adult life . O’Rouke and Murphy (pp. 67–72) find that recent research highlights negative symptoms, functional impairment, dysphoric mood, inattention symptoms, and childhood diagnosis of ADHD; all are important clinical predictors of the risk for psychosis in 22q11.2DS. Moreover, they find that new neuroimaging findings suggest that the cortex is significantly thinner in people with 22q11.2DS with psychosis compared to those without psychosis. This finding replicates similar findings in nondeleted schizophrenia. Like similar age of onset of psychotic symptoms, this finding provides additional support for 22q11.2DS as a biological model of schizophrenia. Finally, they note that microdeletions are significantly more likely to involve protein-coding genes. Several rare copy number variants associated with nondeleted schizophrenia in the general population are associated with the presence of psychosis in people with 22q11.2DS.
Smith Magenis syndrome (SMS) is a microdeletion syndrome characterized by abnormality in the short (p) arm of chromosome 17. SMS is typically the result of haploinsufficiency of retinoic acid induced 1. It is the result of a ∼3.7 Mb interstitial deletion of chromosome 17p11.2. The authors report that behavioral and sleep disturbances in SMS present in early life and worsen as the child grows older. Behavioral problems are pervasive and include self-injurious behavior, disruptive aggression, stereotypies, and food-seeking behaviors. Self-injury has a very high prevalence comparable to Lesch–Nyhan syndrome occurring in 90% of those affected . Frequent nighttime waking and daytime sleepiness are characteristic sleep disturbances. The authors propose that the sleep disorder is at least in part the result of abnormal melatonin secretion and associated dysregulation of the circadian clock . Although administration of melatonin and β-adrenergic antagonists demonstrate efficacy in case reports, the authors propose that a well-formulated study is still needed to establish this treatment as standard care. Management must be individualized to the clinical behavioral phenotype described by the authors.
Sex chromosome trisomies (SCT) occur in about 1 in 650–1000 live births. These children have an extra X or Y chromosome. A subgroup of individuals with SCT is at increased risk for neurobehavioral problems and psychopathology [16,17]. Thorough examination of SCT's is needed to establish neurodevelopmental pathways that underlie risk for neurobehavioral problems and psychopathology. The authors report on neurocognitive factors that may drive this increased risk for disorders. These include impairments in language development, dysregulated executive functioning, social cognitive deficits, and difficulty in emotion regulation. Insight into these cognitive mechanisms is needed to improve diagnostic screening. Close monitoring of children with SCT is needed to positively influence developmental outcome. Early psychosocial support and tailored and targeted interventions are important to outcome. SCT can be identified prenatally. This allows identification of early markers of ‘at-risk’ developmental pathways in childhood. Finally, variability in the phenotype in SCT may help in identifying risk and protective factors that shape developmental outcome of affected children. Both genetic factors and environmental factors must be considered.
Turner syndrome (45X or XO syndrome) occurs in about 1 in 2500 newborn girls worldwide. Most girls and women with Turner syndrome have normal intelligence. Wolstencroft and Skuse (pp. 85–91) report that Turner syndrome is associated with a range of social-cognitive processing problems which coexist with executive function deficits . These cognitive abnormalities, together with differences in physical appearance predispose to problems in social engagement and interaction. Typically, such social interaction deficits are apparent in adolescence and persist throughout the lifespan. Frequently, they result in social isolation. In comparison to typically developing young women, romantic relationships are limited and typically begin in later life. The authors find that despite the recognition of social deficits there are few studies of qualitative, subjective social interaction experiences. It remains unclear to what extent affected women (especially in adolescence) are aware of their social differences and the extent to which they feel them to be problematic.
Mukherjee (pp. 92–96) reviews the diagnosis and management of FASD. He indicates that a great deal of progress has been made in the last 45 years in both the areas of diagnosis and management of FASD. The spectrum includes fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder. With newly recognized increasing prevalence, there needs to be greater attention paid to this disorder. It is a relatively common neurodevelopmental disorder. In the United States, a cross-sectional study of 13 146 first-grade children in four regions of the country, conservatively, found a prevalence of 1–5% with a doubling of these rates using a weighted approach . The diagnostic process has improved over recent years through use of emerging technologies: measurement of ethanol biomarkers (free fatty ethyl esters) in meconium, digital tools that allow better quantification of facial features, neuropsychological testing, and neuroimaging (Diffusion Tensor Imaging and FMRI). Despite these advances, neurodevelopmental profiles of FASD require further delineation. Conduct disorder is a major concern and may be linked to midline brain structure (e.g., corpus callosum) abnormality . This abnormality in brain structure is consistent with the somatic marker model . Management approaches specific to FASD are needed and are the subject of ongoing research.
We thank Jill Fahner for clarification of epigenetic mechanisms in neurogenetic syndromes described in this editorial.
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Conflicts of interest
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