Autistic Traits and Further Clinical Manifestations in Phelan-Mcdermid Syndrome (22q13 deletion syndrome)

Background: Phelan-McDermid syndrome (22q13.3 deletion syndrome or PMS), is a genetic disorder characterized by global developmental delay, severe speech impairments, intellectual disability, hypotonia and autism spectrum disorder to a variable degree. The loss of a functional copy of the SHANK3 gene, responsible for the codification of a scaffolding protein in the postsynaptic density, causes the clinical phenotype of PMS. Recent studies suggest that deletions or mutations compromising SHANK3 can cause a monogenic form of both ASD and intellectual disability, accounting for around 1% of the overall ASD cases [Guilmatre et al 2012; Durand et al 2007; Moessner et al 2007] and 0.3-1% of the ID [Cooper et al 2011; Gong et al 2012]. Literature also reports a higher prevalence of medical and psychiatric comorbidities and developmental regression in patients with 22q13.3 deletions [Scoorya et al 2013; Denayer et al 2012].

Objectives: To describe the clinical phenotype of a sample of participants with PMS, using standardized tools for the assessment of repetitive or otherwise altered behaviors, global adaptive functioning and ASD. Furthermore, we seek correlations between the clinical phenotype and the information provided by previous genetic reports regarding length of deletion and other abnormalities, such as ring chromosomes, deletions or duplications in multiple regions or mosaicisms, among others.

Methods: Forty-four participants were recruited in coordination with the PMS Association in Spain or through direct contact with their clinicians at the HGUGM in Madrid. Mean age is 10.41 and the sample shows an equal gender distribution.

Clinical assessment was conducted through a variety of questionnaires and scales measuring altered behavior (CBCL, ABC-C, RBS-R), adaptive behavior (Vineland-3) and social responsiveness (SRS). We assessed ASD –related development and symptoms by means of gold-standard diagnostic instruments, ADI-R and ADOS-2.

Results: Preliminary results of 30 participants are available, showing great variability in their clinical symptoms. Despite all patients showing mild to severe intellectual disability and deficiencies in language acquisition, the severity of the difficulties in social communication and restrictive, stereotyped or altered behavior appears to be variable, with some individuals presenting behavioral abnormalities (self-injuries, sleep disturbances, attention deficit or hyperactivity, among others). A majority of participants showed impaired development with autistic traits during early childhood; however, only some of them meet criteria for ASD at present evaluation, according to DSM-5 . Developmental regression or stark developmental standstill affecting language, motor or daily living skills is possibly present in 6 to 10 cases, with an age of onset ranging from two years to adolescence.

Evaluations are still taking place; these results may therefore suffer modifications.

Conclusions: Clinical manifestations of the Phelan-McDermid syndrome are heterogeneous, showing a wide range of symptom severity. We observe differences between present moment and early years in relation to autistic-like behaviors. Neuropsychiatric disturbances and aberrant behaviors are also reported. Developmental regression may begin at a later age (early adolescence) and occur in combination with a period of psychiatric distress. Further investigation is required to ascertain possible associations between clinical features and genotype-phenotype correlations.