DOI:10.1097/YCO.0000000000000483 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… Click to show full abstract
DOI:10.1097/YCO.0000000000000483 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 Xlinked recessive disorder that involves a single gene, hypoxanthine-guanine phosphoribosyltransferase1 (HPRT1), that encodes an enzyme involved in purine metabolism [1]. 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 [2]. 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 celltype-specific differences in gene expression [6]). 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,
               
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