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Page 14 of 21 Persico et al. Rare Dis Orphan Drugs J 2023;2:xx https://dx.doi.org/10.20517/rdodj.2023.08

improvement . Despite the exploratory nature of this RCT, the comparison between full MST vs. "vitamins
[35]
only" provides further evidence pointing towards the beneficial effects of CoQ10 as part of MST in PMS.
Clinical improvement in our PMS cohort appears to mostly occur in the domains of motor skills, cognition,
responsiveness to environmental stimuli (adaptive functioning), and stereotypic behaviors [Table 5]. Given
the severity and pathophysiology of this genetic syndrome and of neurodevelopmental disorders in general,
it is not surprising that most responders to MST appear "minimally improved", with only some patients
occasionally appearing "much improved". We did not detect significant effects on language and
communication skills, in contrast to our retrospective study . This discrepancy may reflect the more severe
[35]
language impairment present in PMS compared to other neurodevelopmental disorders, with its
documented structural underpinnings [11,56] . Importantly, the positive influence recorded here on parental
quality of life with MST compared to vitamins only, especially for mothers, provides converging support to
MST efficacy from a different point of observation. Finally, the extreme safety of this therapy is documented
by the rare, mild, and easily manageable side effects reported by parents, equally distributed between the
active compound and active comparator [Table 6].

Mitochondrial function plays a pivotal role in brain development and central nervous system (CNS)
function. Most brain energy supply is generated by mitochondrial oxidative phosphorylation, and each
different neuronal cell type presents local mitochondrial adaptation processes reflecting functional
[57]
heterogeneity . In addition to energy production, mitochondria are involved in neurogenesis and
apoptosis, neuronal migration and differentiation, and neuroplasticity by regulating redox homeostasis,
[58]
protein and lipid mediators, and intracellular calcium levels . Therefore, it is not surprising that
mitochondrial dysfunction and oxidative stress appear to be involved in the pathogenesis of many
neurodevelopmental disorders and that antioxidants produce clinical improvement in many patients [59-62] .
More specifically, Autism Spectrum Disorder (ASD) is frequently diagnosed in PMS patients and often
represents their first clinical diagnosis, formulated long before genetic testing . ASD represents a wide
[6-8]
collection of multiple genetic and/or epigenetic disorders (the "autisms"), sharing socio-communication
deficits, repetitive behaviors, insistence on sameness and abnormal sensory processing as their clinical
[63]
expression end-point . Enhanced oxidative stress and mitochondrial dysfunction represent one of the
most replicated abnormalities detected both systemically and in the Central Nervous System (CNS) of
[64]
autistic individuals . Targeted and untargeted studies of post-mortem brains, plasma, CSF, urines, and
peripheral blood mononuclear cells (PBMCs) consistently documented significant oxidative damage to
proteins, lipids and nucleotides, reductions in GSH/GSSG ratio, reduced activity levels of redox protection
enzymes, including superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx), glutathione-S-
transferase (GST), and glutamate-cysteine ligase, reduced activity of respiratory chain complex I and
complex IV due to mitochondrial oxidative damage [65-73] . Abnormalities in these redox parameters have been
found to be significantly correlated with the severity of autistic behaviors [74,75] and gastrointestinal
[78]
symptoms [76,77] , which are frequent among autistic children . Not surprisingly, the activity of complex I and
IV is significantly reduced in as many as 59% of PMS patients, whose clinical features often overlap with
those of mitochondrial diseases . In addition to non-specific impairment of energy metabolism, PMS-
[79]
causing chr. 22q11.3 deletions often span genes playing relevant roles in mitochondrial function .
[13]
Although oxidative stress response may represent an evolutionarily preserved strategy aimed at boosting
resilience and usually represents the consequence and not the primary cause of ASD-associated genetic
[80]
syndromes , reduced ATP production and excessive oxidative damage can potentially exacerbate the
[65]
dysfunction caused directly by ASD-causing genetic or epigenetic defects, thereby imposing an additional