Page 46 - Read Online

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

of life (QoL), communication, and comorbidities.

Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and
adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was
especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS
"restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including
hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods.

Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation,
adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately
70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now
warranted.

Keywords: 22q13 deletion syndrome, autism, autism spectrum disorder, coenzyme Q10, Phelan-McDermid
syndrome, SHANK3, vitamin B, vitamin E.

INTRODUCTION
Phelan-McDermid syndrome (PMS, OMIM#606232) is a rare genetic neurodevelopmental disorder mainly
characterized by global developmental delay, severe deficits in expressive language, and intellectual
[1-4]
disability (ID) . The prevalence of PMS has been estimated in the range of 2.5-10 cases per million
[5]
births . However, the prevalence of PMS is likely to be underestimated and over 3,000 individuals self-
identified as PMS patients worldwide are registered in the “Phelan-McDermid Syndrome International
[5]
Registry” of the PMS Foundation (https://www.pmsf.org/international/) . Autism Spectrum Disorder is
present in as many as 30%-80% of PMS patients, while at least 0.5%-2.0% of autistic individuals carry a
[6-8]
genetic abnormality related to PMS in chr. 22q13 . A wide range of other neurological and behavioral
signs/symptoms may also be present, such as muscle hypotonia and deficits in motor coordination, seizures,
structural brain abnormalities, gastrointestinal symptoms, renal malformations, and minor dysmorphic
features [1-4,7,8] . Recently, other psychiatric disorders were found to be associated with PMS, including
catatonia, mood, and psychotic disorders . Lasting regressions in communication, self-care, and motor
[9]
function beginning within 3 years of the onset of psychiatric illness were found to exert a very negative
impact on clinical prognosis .
[10]

The pathophysiology of PMS is due to a spectrum of genetic anomalies in the terminal region of the long
arm of chromosome 22, ranging from disruptive single-nucleotide variants to ring chromosomes and large
deletions affecting multiple genes . SHANK3 (OMIM *606230), located in the distal portion of the long
[2]
arm of chromosome 22, is the strongest candidate gene to determine PMS [3,11] ; however, genotype-
phenotype correlations in PMS are complex, as even interstitial deletions sparing SHANK3 have been
described in some PMS patients . The size of PMS-causing deletions can be extremely variable, ranging
[12]
from 0.22 to 9.22 Mb , and a multitude of genes distributed along this terminal region may contribute to
[8]
[13]
phenotypic heterogeneity and clinical severity . Furthermore, rare autosomal recessive forms of
mitochondrial disorders have been found to emerge from the coincidence of a large PMS-causing deletion
on one chr. 22q13 allele and of a missense mutation or small deletion not detectable by array-CGH located
on the other allele . The larger chr.22 segment deleted in PMS hosts several genes involved in
[14]
mitochondrial function (SCO2, CHKB, TYMP, TRMU, NDUFA6, SAMM50, SULT4A1) [13,15] . Abnormalities
in electron transport chain (ETC) complex activity have been detected in 30/51 (59%) individuals with
PMS , supporting the hypothesis that mitochondrial dysfunction could contribute to the pathological
[15]
process and phenotypic expression of PMS in many patients.