Table 1.

Summary of molecular defects and potential epigenetic therapeutic targets in selected neurodevelopmental (NDD) and autism spectrum disorders (ASD)

Disorders	Molecular defect	Potential epigenetic targets	Ref.
NDD
Down syndrome	Trisomy for chromosome 21—results in overexpression of genes leading to abnormal brain development	Goal—Suppress expression from one chromosome 21	[157]
		• Whole chromosome silencing in trisomic neurons
		• Insertion of an inducible X-inactive specific transcript (XIST) into DYRK1A locus in induced pluripotent stem cells from a Down syndrome patient
		• XIST-mediated silencing reversed the deficits in neuronal proliferation and neural rosette formation
		• Potential novel approach to therapy in Down syndrome
Kabuki syndrome	Mutations in the myeloid/lymphoid or mixed-lineage leukemia 2 (MLL2) gene, a methyltransferase that methylates histone H3 at Lys-4	Goal—Promote methylation of H3K4	[144–146]
		• Histone methylating agents or MLL2 mimics
		• Histone deacetylase (HDAC) inhibitors have been shown to up-regulate H3K4 methylation
Fragile X syndrome	Expansion of a CGG trinucleotide repeat (>200 triplet) results in hypermethylation of the 5’-untranslated region and the upstream CpG island within the promoter of FMR1 gene resulting in transcriptional repression of the FMR1 gene	Goal—Transcriptional reactivation of FMR1	[65, 66, 158]
		• DNA demethylation agent 5-azadeoxycytidine
		• Histone hyperacetylation agents such as 4-phenylbutyrate, sodium butyrate, and trichostatin A
		• Non-epigenetic approaches based on synaptic biology
ASD
Rett syndrome	MeCP2 mutation resulting in loss of MeCP2 function	Goal—Normalize MeCP2 levels	[148, 150]
		• Viral delivery of MeCP2 complementary DNA under native promoter to restore physiological levels of MeCP2 protein
		• Insufficient evidence that epigenetic modifiers (HDAC inhibitors or histone acetyltransferase inhibitors) augment MeCP2-mediated function
Angelman syndrome	Mutation or deletion of the maternal UBE3A gene	Goal—Restore UBE3A expression in neurons	[38, 40]
		• Unsilence the imprinted paternal UBE3A allele—topotecan
		• Inhibition of paternal UBE3A antisense RNA transcript expression
Prader–Willi syndrome	Mutation in the paternal chromosome 15q11.2–13; loss of expression of paternally-derived genes	• Identifying the epigenetic architecture in this region will help in identifying novel therapeutic targets	[42]

UBE3A = ubiquitin protein ligase E3A