Abstract
Recently, Mendelian disorders of the DNA methylation machinery have been described
which demonstrate the complex roles of epigenetics in neurodevelopment and disease.
For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset
progressive neurologic disorders, whereas defects of the de novo methyltransferases
DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore,
patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders
of histone machinery and imprinting disorders, highlighting the interconnectedness
of the many epigenetic layers. Disorders of the DNA methylation machinery include
both the aforementioned “writers” and also the “readers” of the methyl mark, such
as MeCP2, the cause of Rett syndrome. Any dosage disruption, either haploinsufficiency
or overexpression of DNA methylation machinery leads to widespread gene expression
changes in trans, disrupting expression of a subset of target genes that contribute to individual
disease phenotypes. In contrast, classical imprinting disorders such as Angelman syndrome
have been thought generally to cause epigenetic dysregulation in cis. However, the recent description of multilocus methylation disorders challenges this
generalization. Here, in addition to summarizing recent developments in identifying
the pathogenesis of these diseases, we highlight clinical considerations and some
unexpected therapeutic opportunities, such as topoisomerase inhibitors for classical
imprinting disorders.
Keywords
intellectual disability - imprinting - Rett syndrome - Angelman syndrome
