Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice.

Pathogenic variants in one allele of the KAT6A gene encoding the histone acetyltransferase KAT6A (MOZ, MYST3) cause Arboleda-Tham syndrome (ARTHS), characterised by developmental delay, cognitive impairment, and autism-like behaviours. As histone acetylation is reversible, and brain development continues after birth, treatments that address deficits in histone acetylation may ameliorate the condition. Here, we examined the effects of ARTHS mutations on histone acetylation in human cells and the effects of heterozygous loss of Kat6a in mice (Kat6a (+/-) ) on learning, memory, activity, and sociability. We found that KAT6A was required for normal levels of histone H3 lysine 23 acetylation (H3K23ac) in human cells and mouse brain. Kat6a (+/-) mice displayed hyperactivity and learning, memory, and sociability deficits compared with WT mice. Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in the rescue of H3K23ac levels in mouse brain and amelioration of the hyperactivity and learning impairments. Our results suggest that some individuals with ARTHS might benefit from ALCAR treatment. However, the suitability of ALCAR treatment would depend on the specific KAT6A variant and should be discussed with health professionals.