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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 11 of 21

● Composite score 33 47.0 ± 2.7 (19-72)
Ongoing psychopharmacological treatment:
● Antiseizure medications 5 15.2%
● Atypical Antipsychotics 3 9.1%
● Lithium carbonate 1 3.0%
● Melatonin 3 9.1%
● Dietary supplements 1 3.0%

† ‡ §
IQ: Intelligence Quotient, CGI: Clinical Global Impression, VABS: Vineland Adaptive Behavior Scale.

Intellectual Disability (ID) or Global Developmental Delay (GDD), either alone (n = 19, 57.6%) or
associated with Autism Spectrum Disorder (ASD) (n = 13, 39.4%). All 33 patients also displayed
Developmental Motor Coordination Disorder, while 7 (21.2%) have a history of Bipolar Disorder. Severe
Language Developmental Disorder was present in 31 (93.9%) patients. Thirteen (42.9%) patients were taking
psychopharmacological treatment or nutraceuticals at baseline (T0), which were kept constant throughout
the study [Table 4].

Regarding primary outcome measures, several measures reached nominal significance in favor of the active
compound [CoQ10 + Vit. E + polyvitamin B] producing greater improvement than the active
comparator [Vit. E + polyvitamin B] [Table 5A for summary statistics and Figure 3, depicting single
patients]. Specifically, greater positive responses were recorded mainly in:

(a) Motor skill deficits, with VABS motor skill displaying a sizable improvement (MD +6.81, 95%CI: +1.89;
+11.72, P = 0.0147). This statistic includes only 10/33 patients whose age falls within the range for VABS
motor skill (0-6 years), but it is paralleled by non-significant improvements in VAS gross- and fine-motor
skills collected for all 33 patients, reaching a P = 0.058 in clinician-scored VAS for fine-motor skills. These
results are also consistent with clinical observation of widespread small-to-moderate improvement,
especially in fine-motor function. This positive effect was surprisingly most evident in three highly
compromised patients initially wheelchair-bound due to very large deletions spanning from SHANK3 to
TCF20 and beyond: all three became able to hold up and use fork and spoon during meals; for one, it
became feasible to sit up and undertake sessions of mild horse-assisted intervention.

(b) "Enjoyment in shared play", i.e., participation in play activities with others, employing exchanges of
glances and smiles (VAS, P = 0.0199). This variable exemplifies one of the benefits most consistently
reported by parents, namely increased responsiveness to environmental stimulation and greater social
motivation;

(c) Repetitive behaviors were significantly reduced according to parents (VAS, P = 0.0198), with a similar
trend also observed by clinicians (VAS, P = 0.0770). This observation describes a consistent subgroup of
patients and not a small subset because at T0, parents reported the presence of motor stereotypies in 27
(81.8%) patients, and during the intake visit, motor stereotypic behaviors were directly observed by the
clinician in 15 (45.5%) patients.

No effect modification by age was detected for enjoyment in shared play (P = 0.2896) and repetitive
behaviors (med P = 0.5297, par P = 0.5656), whereas the number of observations for VABS motor skills was
not sufficient to allow reliable testing of age effects.