Melatonin pathway dysregulation driving melatonin issues associated with autism?

The paper published by Anna Maruani and colleagues [1] provides the blogging fodder today and the observation that: "melatonin variations in ASD [autism spectrum disorder] could be mainly driven by melatonin pathway dysregulation."

Melatonin has been part-and-parcel of the autism research landscape for many, many years (see here). Most people with some knowledge of melatonin will probably know of its connection to the sleep-wake cycle and the reasoning behind the use of supplemental melatonin to [hopefully] improve sleep in some people and groups of people (see here). Indeed, for some of those diagnosed as being on the autism spectrum who present with often significant sleep-related problems (see here for example), the clinical use of melatonin has been nothing short of miraculous for some when it comes to improving several parameters of sleep [2]. But melatonin is also quite the molecular handyperson too (see here) outside of just the sleep-wake cycle...

As to the precise reason(s) why melatonin appears to be an issue for 'some autism', science so far has been pretty short on firm conclusions. The Maruani study set out to try and cast some further light on the hows-and-whys around melatonin, specifically looking at both measured levels of melatonin in plasma and also pineal gland volume (PGV), on the basis that the pineal gland produces melatonin. Researchers report estimated measurement of PGV "with magnetic resonance imaging (MRI) with a voxel-based volumetric measurement method" in "78 individuals with ASD, 90 unaffected relatives and 47 controls."

Their results were interesting: "We first found that both early morning melatonin level and PGV were lower in patients compared to controls." Those early morning melatonin levels - "collected between 8:30 and 10:30 a.m." - were measured using "a radioimmunoassay" method looking at plasma samples. As well as lower plasma melatonin being described in the autism group compared with the other groups, researchers also observed that: "Relatives displayed to a lesser extent a reduced level of melatonin compared to controls, but that did not reach significance z = 0.88, p = 0.38)." Potentially also interesting.

Further: "Analysis revealed that the volume of the pineal gland was lower in patients than in controls, and lower in relatives than in controls." Some additional statistical modelling led however to the conclusion that: "PGV acted as a modest contributor to the melatonin deficit observed in ASD." In other words, as per the title of this post "melatonin variations in ASD could be mainly driven by melatonin pathway dysregulation" over and above just the physical volume of the part of the brain charged with producing melatonin.

Mention of 'melatonin pathway dysregulation' in the Maruani results got me thinking about previous study results discussed on this blog (see here). The results from Pagan and colleagues [3] provided some pretty valuable insights into the biochemistry of melatonin and some of the 'in-betweener' compounds involved in it's formation. Specifically: "a disruption of the serotonin-NAS [N-acetylserotonin] -melatonin pathway in ASD." Add in other research (see here) talking about low levels of one of the metabolites of melatonin being noted in parents, and there's a case for looking further at the biochemistry of melatonin synthesis in relation to autism over and above just volumes of brain structures. Indeed, how about beginning with examinations of the starting material for melatonin - the amino acid tryptophan - and see where this might take us (see here and see here).

Oh, and it appears that the pineal gland is probably not the only place that melatonin is synthesised [4]. Perhaps further investigation in this area might also want to look at "the enterochromaffin (EC) cells throughout the gut" for example, and their potential role/effect with melatonin (and its precursors) and autism in mind...

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[1] Maruani A. et al. Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume. Front. Psychiatry. 2019. Feb 6.

[2] Maras A. et al. Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2018 Oct 11.

[3] Pagan C. et al. The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders. Transl Psychiatry. 2014 Nov 11;4:e479.

[4] Chen CQ. et al. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol. 2011;17(34):3888-98.

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