20391
MMN and Glutamatergic E-I Imbalance in Children and Adults with ASD and Phelan-Mcdermid Syndrome
The discovery of effective treatments in ASD has been a challenge because of the phenotypic, aetiological and genetic heterogeneity of the disorder, and the poorly understood underlying pathophysiology(ies). Recently, identification of monogenic forms of ASD offers novel opportunities for the understanding of pathophysiological mechanisms. ASD is caused by a haplo-insufficiency of SHANK3 (Phelan-McDermid Syndrome (PMS) in approximately 1% of cases. Individuals with PMS present with different degrees of Intellectual Disability (ID), motor problems and 50-80% have autistic symptoms. SHANK3 is a scaffold protein of the postsynaptic density of glutamatergic synapses. This suggests that SHANK3 deficiency may impact glutamatergic function (Excitatory-Inhibitory imbalance), and cortical network function Here we explore abnormalities in mismatch negativity, which relies on NDMDAR signalling, and has shown to underpin sensory processing abnormalities, as a potential biological risk marker.
Objectives:
(1) To comprehensively characterise children and adults with PMS in terms of ASD symptoms, neuropsychiatric comorbidities and IQ.
(2) To compare differences in MMN as assessed using an auditory oddball task in children and adults with PMS, ASD and typical development.
Methods:
Because of severe to profound intellectual disabilities associated with PMS, methods have been adapted to account for the low comprehension skills and often lack of speech of the participants. In particular, participants’ autistic symptoms are assessed using gold standard assessments (i.e. ADOS), parental interviews (i.e. ADI-R), and parental completion of questionnaires (i.e. Repetitive Behaviour Scale, Short Sensory profile, etc.). Intellectual ability is measured using the Mullen Scales of Early Learning (for younger and more intellectually impaired participants), or the British Picture Vocabulary Scales and Raven’s Colour Progressive Matrices (for more able participants). Mismatch Negativity (MMN) is assessed using an auditory oddball task). MMN is a well‑established method in evoked‑potential research in which an unpredictable change in a repetitive sound sequence elicits the mismatch negativity (MMN) response. It is said to be associated with pre-attentive cognitive operations in audition.
Results:
The study is currently on-going. EEG and clinical data from 5 PMS participants, 11 typically developing children and 16 children with ASD have already been collected. By May 2015, data from at least 10 PMS vs 20 idiopathic ASD individuals will be presented and discussed.
Conclusions:
Comprehensive multi-level characterisation of children harbouring SHANK3 deficits may help to identify common vs. distinct (biochemical, brain imaging) biomarkers related to synaptic defects and their link to behavioural and clinical abnormalities in ASD.