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Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08 Page 15 of 21

burden. Importantly, redox abnormalities have also been detected in young autistic children and are not
[69]
correlated with age . Therefore, enhanced oxidative stress and mitochondrial dysfunction represent a
"trait-dependent" characteristic present in a consistent number of PMS patients and autistic individuals,
regardless of their age and their specific underlying pathogenetic underpinnings. Since it is not yet possible
to directly correct the genetic alteration underlying PMS or its major downstream consequences, sustaining
mitochondrial function while controlling redox imbalance may represent a viable indirect therapeutic
approach, potentially able to ameliorate cognition and adaptive functioning, motor skills and stereotypic
behaviors in many patients, albeit with small-to-moderate effects and with large interindividual differences.

This is the first clinical trial to assess the efficacy and safety of CoQ10, vit. E and polyvit. B in PMS. In
reference to ASD, three RCTs have evaluated the effects of over 30 supplements including CoQ10, multiple
vitamins, minerals such as lithium, N-acetylcysteine, choline, acetyl-L-carnitine and inositol in 20, 55, and
67 autistic children and adults, respectively [81-83] . Several blood biomarkers were measured, including
nutritional (vitamins, minerals, and aminoacids) and metabolic parameters (oxidative stress, methylation,
sulfation, glutathione, and neurotransmitters). At baseline, the ASD sample showed significantly higher
levels of oxidative stress compared to typically developing controls. After 3 months of treatment, these
parameters were either improved or even normalized. Additionally, a behavioral improvement was
recorded for several symptoms, as well as in mean Parental Global Impressions-Revised scores, especially
[83]
[82]
for the hyperactivity, oppositional and receptive language subscales , and nonverbal intellectual ability .
These domains largely overlap with the areas of greatest improvement reported in our retrospective chart
[35]
review of neurodevelopmental patients . However, the administration of over thirty active compounds
hampers the possibility of detecting with reasonable certainty specific contributions by CoQ10 to the
observed improvement in biochemical and behavioral parameters. In contrast, more focused RCTs
demonstrated a sizable reduction in autistic symptoms following 30 wks of high-dose Vitamin C (110
[84]
mg/kg) or after high-dose Vitamin B6 (500-1,000 mg) . To our knowledge, only one RCT has selectively
[85]
supplemented 78 ASD children with placebo, 30 or 60 mg/day of CoQ10 (n = 26 per sample), recording
with the higher CoQ10 dose an improvement in several peripheral redox parameters, paired with a mild
reduction ASD severity, sleep disorders and gastrointestinal symptoms . This RCT differs from the present
[86]
study in experimental design (case-control vs. cross-over), duration (3 mo vs. 4 mo of active compound/
comparator), CoQ10 dosage (not based on body weight or age in ref. 86), and in the composition of active
compound and comparator (inactive placebo in ref. 86, vitamins E and B here). Nonetheless, its clinical
[35]
outcome appears convergent with our past and present observations.

From a methodological standpoint, multiple features of this RCT define its exploratory nature. On the one
hand, they may represent the limitations of the present study, but on the other hand, they will enable
investigators to precisely design targeted confirmatory trials in neurodevelopmental disorders. These points
can be summarized as follows:

(A) Initially, this study was undertaken assuming that vitamins would have been entirely inactive on the
severe clinical picture of PMS. However, this turned out not to be the case. On the one hand, the Time x
Treatment interactions observed on CGI-I and VAS “Restricted Interests” scores demonstrate that in many
patients, a four-month course of vitamin E and B seemingly paves the path to a greater response to CoQ10
[Figure 4]. On the other hand, a slight but detectable amelioration was recorded after the administration of
vitamin E and polyvitamin B to most patients [Figure 4A]. In some cases, the convergent observation by
parents, clinicians, and therapists blind to the treatment of a "much improved" therapeutic effect by
vitamins E and B is unlikely to represent a placebo effect in a severe syndrome such as PMS. For the above-
mentioned reasons, contrary to its initial expectation, this study has become an "active comparator-