ESPE Yearbook of Paediatric Endocrinology

Nat Med. 2020 Sep;26(9):1375–1379. doi: 10.1038/s41591-020-1007-0. PMID: 32778826.

In brief: A subtype of autism arising from a cluster of genes that regulate both cholesterol metabolism and brain development was identified by integrating multiple data modalities.

Comment: Autism spectrum disorder (ASD) is now estimated to affect 1:54 children in the USA, 80% of whom are boys. Genomic studies show extreme heterogeneity in the genetic aetiology of ASD.

– Firstly, these researchers identified genes that are expressed differentially in the developing brains of males and females in the prenatal period.– Secondly, they used whole exome sequencing and detected both – variants that were discordant between individuals with ASD and their healthy siblings, and variants that were shared between several siblings with ASD in the same family.– Next they searched for overlaps between the exon clusters identified in the brains and the autism mutations, and identified 33 neurodevelopmentally ASD-segregating variants.– Using two huge routine clinical datasets, they found that the blood lipid profiles of individuals with autism differ significantly from the physiological range.– Having ASD and an abnormal lipid profile were found to be associated with epilepsy, sleep disorders and attention deficit hyperactivity disorder. This suggests that dyslipidemia might contribute to altered neurodevelopment. Among individuals with ASD and abnormal lipid levels, risks were also higher for hypothyroidism, anaemia and vitamin D deficiency.– This novel ASD dyslipidemia-linked subtype is estimated to affect ~7% of invidivuals with ASD.

The notion that lipid metabolism is important in neurodevelopment is supported by the features of Rett syndrome and Smith-Lemli-Opitz syndrome. The former is characterized by autism and a mutation in a cholesterol metabolism gene. The latter is an inborn error of cholesterol synthesis, whereby the vast majority of those affected also have autistic behaviours. The authors conclude that the ASD subtype characterized by dyslipidemia shows that genes involved in lipid metabolism are crucial during mammalian brain development. It will be interesting to investigate if treatment with lipid-lowering drugs in children with autism and dyslipidemia might improve their autism and other neurological traits.