Page 47 - Read Online

Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08 Page 3 of 21

Behavioral and psychological/physical treatments are considered the first line intervention, because there is
[16]
no pharmacological compound yet proven effective in ameliorating the core signs/symptoms of PMS .
Pharmacological treatment strategies adopted to improve psychiatric comorbidities and sleep disorders are
[17]
not different from those prescribed in the general population , but responses to traditional psychiatric
intervention are variable and sensitivity to the development of side effects is seemingly high .
[9]
Coenzyme Q10 (CoQ10, ubiquinone) is a lipid-soluble quinone present in the highest concentrations in
brain, heart, kidney, and liver tissue ; tissue levels reflect the extent of metabolic activity and energy of
[18]
[19]
each tissue and organ . CoQ10 can be found in three distinct redox states: oxidized (ubiquinone),
semiquinone (ubisemiquinone), and reduced (ubiquinol) . It is synthesized by human cells and can also be
[18]
[20]
partly obtained from dietary sources (on average 5 mg/day) . In the latter case, Q10 ubiquinone is reduced
to Q10 ubiquinol in the liver following gut absorption. Both ubiquinone and ubiquinol are currently
available as dietary supplements . CoQ10 plays an important role in supporting energy production in
[21]
living cells , and orally administered CoQ10, in the presence of partial tissue deficiency, can boost electron
[19]
transfer and ATP synthesis [22-24] . More specifically, CoQ10 is present in two intracellular pools, a protein-
[21]
bound pool (30%) and a free-cytosolic pool . The former plays a pivotal role in the electron chain
transport system responsible for the synthesis of ATP, whereby CoQ10 transfers electrons from complex I
and II to complex III by shuttling in its redox cycle . Through this mechanism, Q10 supplementation can
[21]
boost energy levels and reduce the risk of mitochondrial damage due to excessive oxidative stress [21-25] . The
cytosolic pool participates in other metabolic processes, most importantly playing an additional antioxidant
role by protecting lipids and other cell components, while also restoring reduced levels of other
antioxidants . Overall, increased energy production and antioxidant capacity are predicted to limit the
[21]
damage generated by the neuroinflammation and excitotoxicity well documented in ASD brains, ultimately
leading to excessive neuritic pruning and/or cell apoptosis [26,27] . Interestingly, serum coenzyme Q10 levels
were found to interact with genetic predisposition to a variety of neuronal diseases in a genome-wide
association study . Moreover, converging evidence strongly supports its neuroprotective effects [22,29,30] and
[28]
numerous disease processes can benefit from oral administration of CoQ10, including neurodegenerative
diseases [24,31-34] .

In an attempt to transfer this knowledge “from bench to bedside”, we designed a “metabolic support
therapy” (MST) encompassing Q10 ubiquinol or CoQ10 (50-100 mg b.i.d.) + vit. E (30-60 mg/die) + poly
vitamin B (B50 complex, 1/2 or 1 caps/die), under the hypothesis that its metabolic, antioxidant and
neurochemical effects could at least partly improve the clinical signs/symptoms of neurodevelopmental
disorders. Recently, we performed a retrospective chart review reporting small-to-moderate improvement
in cognitive and adaptive functioning, social interaction and motor coordination in 45/59 (76.3%) patients
with different neurodevelopmental disorders, with excellent tolerability . These results were especially
[35]
[35]
promising in five PMS patients, all displaying some measurable degree of clinical response .

Based on the evidence summarized above, we have now designed and performed an exploratory 32-week
randomized, double-blind, placebo-controlled, cross-over trial (RCT), with (A) the primary aim to evaluate
the efficacy and safety of MST in PMS patients and to begin dissecting the selective contribution of CoQ10
to efficacy and tolerability, as compared to vitamins alone; (B) the secondary aim to identify a panel of
psychodiagnostic tools endowed with sufficient sensitivity to reliably detect a small-to-moderate effect size
in a severely-compromised patient population. This information will then be used to design a confirmatory
RCT applying a targeted strategy.