Q10 Ubiquinol in Autism Spectrum Disorder and in Phelan-McDermid Syndrome.

Randomized, Placebo-controlled, Cross-over, Double-blind Study of a Metabolic Support Therapy With Q10 Ubiquinol and a Multivitamin B and E Complex in Two Cohorts of Patients With Idiopathic and Syndromic Autism (Phelan-McDermid Syndrome)

This double-blind, cross-over, randomized, controlled trial (RCT) has the aim of evaluating the effectiveness of a metabolic support therapy in two cohorts of patients with idiopathic Autism Spectrum Disorder or Phelan-McDermid syndrome, commonly associated with syndromic autism. Each patient will receive Q10 ubiquinol + Vit. E and B for 4 months and only Vit. E and B for 4 months in a double-blind, cross-over design. Primary outcome measures of efficacy include Vineland Adaptive Behavior Scales, Childhood Autism Rating Scale, Clinical Global Impression-Improvement and Visual Analog Scales; secondary outcome measures include several questionnaires and tests of autism, cognitive function, problem behaviors, quality of life, communication and comorbid disorders, as well as measures of oxidative stress.

Autism Spectrum Disorder (ASD) is a clinically and genetically heterogeneous collection of different conditions, sharing socio-communicative deficits, repetitive behaviors, restricted interests, and dysfunctional sensory processing. Currently there are no pharmaceutical compounds effective on core ASD symptoms. Enhanced oxidative stress and mitochondrial dysfunction represent one of the most replicated abnormalities detected both systemically and in the Central Nervous System (CNS) of autistic individuals. Abnormalities in redox parameters are significantly correlated with the severity of autistic behaviors. Although oxidative stress usually represents the consequence and not the primary cause of ASD, reduced ATP production and oxidative damage can seemingly contribute an additional burden to the dysfunction directly produced by ASD-causing genetic or epigenetic defects. Importantly, redox abnormalities have been detected also in young autistic children and are not correlated with age. Therefore, enhanced oxidative stress and mitochondrial dysfunction represent an ASD-related "state-dependent" characteristic present in a consistent number of autistic individuals regardless of their age and of their specific underlying pathogenetic underpinnings. Sustaining mitochondrial function while controlling redox imbalance thus represents a viable "indirect" therapeutic approach, potentially able to ameliorate behavioral and neuropsychological deficits in many autistic individuals.

Coenzyme Q10 (CoQ10, ubiquinone or ubiquinol) is a lipid soluble compound present in the majority of living cells. By increasing energy production and antioxidant capacity, CoQ10 is predicted to limit the damage generated by the neuroinflammation and excitotoxicity well documented in ASD brains, ultimately leading to excessive neuritic pruning and/or cell apoptosis. Administration of Q10 ubiquinol to autistic children, as frequently prescribed to children with mitochondrial disorders, yielded promising results with an extremely low incidence and minor impact of side effects in two open trials and in three RCTs involving numerous other active compounds. In the present RCT, each patient will receive Q10 ubiquinol (50-100 mg b.i.d.) + Vit. E (60 mg/die) and polyvitamin B for 4 months and only Vit. E and B for another 4 months (total duration 8 months) in a double-blind, cross-over design. The focused co-administration of Q10 ubiquinol with only two known antioxidants, vitamin E and a multivitamin B complex, is designed to synergistically boost the increase in energy production and cell protection viewed as deriving primarily from Q10 ubiquinol administration. This study was also designed to overcome two limitations present in previous RCTs evaluating the effects of Q10 Ubiquinone (precursor of Q10 ubiquinol) in ASD children and adults: (a) The administration of a very limited number of active compounds, as compared to cocktails containing many active substances, allows to focus here on the efficacy of Q10 ubiquinol; (b) the administration of Q10 ubiquinol, rather than its precursor Q10 ubiquinone, avoids the potential risk of reduced response due to pharmacokinetic interference with the biotransformation of the precursor into the active compound.

This trial addresses the efficacy of Q10 ubiquinol, paired with Vit. E and B, not only in "idiopathic" ASD, but also in "syndromic" ASD, using Phelan-McDermid syndrome (PMS) as a paradigm. PMS, also known as chromosome 22q13.3 deletion syndrome, represents one of the most studied syndromic forms of ASD. It is characterized by autism in as many as 70-80% of deletion carriers, in addition to early onset severe muscle hypotonia, developmental delay, facial dysmorphisms, absence of spoken language or severe language development disorder. Deletions or mutations of the SHANK3 gene, encoding a synaptic scaffold protein critical to glutamatergic synapse function, are primarily responsible for the syndrome, although larger 22q13.3 deletions encompass additional disease genes.

This study shall include up to 140 patients with idiopathic ASD and 60 patients with PMS. The study design of this RCT was balanced, so that half of the patients with ASD or PMS will receive Q10 ubiquinol during the first 4 months, and the remaining half will receive Q10 ubiquinol during the second 4 months. The purpose of this balancing is to observe not only whether Q10 ubiquinol produces and improvement in primary and secondary measures, but also if this improvement is sustained over time despite Q10 discontinuation or requires continued Q10 administration. In addition to clinical and psychometric parameters, oxidative stress will be measured at baseline and after 4 and 8 months, by drawing 8-10 ml of blood, isolating leukocytes by Ficoll gradient and assessing (a) protein carbonylation levels by oxyblot; (b) the activity of mitochondrial respiratory chain complexes normalized by citrate synthase activity; (c) the expression levels of mitochondrial respiratory chain complexes measured by Western-Blotting.

Inclusion Criteria:

1. Both parents or a legally authorized patient representative (LAR) must provide written informed consent. The parents and guardian must be able to understand and comply with the experimental protocol;
2. Subjects of both sexes, aged between 2 and 40 years old, may be included in the study;
3. The subject must meet DSM-5 criteria for a primary diagnosis of Autism Spectrum Disorder (idiopathic autism) or carry a documented deletion of human chromosome 22q13.33 or mutation in the SHANK3 gene (Phelan-McDermid Syndrome);
4. Subjects with idiopathic autism must pass the threshold score for Autism of the Autism Diagnostic Observation Schedule;
5. Baseline Children's Global Assessment Scale score must be between 45 and 59;
6. Patients treated with psychoactive drugs (neuroleptics, antiepileptics, etc.) are enrolled only if the treatment and dosage of these drugs has been constant for at least 3 months prior to enrollment in the trial and is kept constant throughout the 8-month duration of the trial;
7. Patients undergoing any kind of behavioral intervention must have must have started the intervention at least 3 months prior to enrollment and the intervention must remain unchanged throughout the 8-month duration of the trial;
8. The patient is able to swallow the capsule or his/her parents are available to open it and administer immediately its content in a small quantity of juice or soft-drink.

Exclusion Criteria:

Patients who meet any of the following criteria will not be recruited in the study:

1. Patients with autism secondary to known genetic syndromes other than Phelan-McDermid syndrome (for example, Rett syndrome, fragile-X syndrome, etc.);
2. Presence of brain malformations or major structural anomalies visible by magnetic resonance imaging;
3. Patients with autism secondary to epileptic encephalopathy or with idiopathic autism comorbid with seizures more frequent than one episode every 6 months despite ongoing antiepileptic drug therapy;
4. Patients with autism accompanied by marked facial dysmorphism and/or congenital malformations;
5. Patients treated with anticoagulants;
6. Patients with serious medical illnesses (chronic renal disease, severe liver disease, cardiovascular disorders, uncontrolled hypertension with systolic pressure values> 170 and diastolic pressure> 100 mm Hg, malignant tumors, HIV infection);
7. Patients with a history of acute cerebrovascular episodes;
8. Patients with a history of stomach bleeding or active peptic ulcer;
9. Patients with documented allergy, hypersensitivity or intolerance to one of the excipients of the experimental or comparative product.

Trial interruption criteria:

1. Patients whose medical conditions require starting treatment with anticoagulants.
2. Patients with severe medical conditions starting during the 8-month duration of the trial.
3. Patients who undergo a change in psychopharmacological or behavioral treatment during the 8-month duration of the trial.