Loss of Skills in Genetic Conditions Associated with ASD: Findings from the Developmental Synaptopathies Consortium.

Background: While literature on regression, or loss of skills, in ASD is mostly informed by studies of samples considered “idiopathic,” studies are starting to explore if and how specific genetic conditions present with distinct patterns of symptom onset or loss. While we know that regression is pathognomonic for some neurodevelopmental conditions such Rett Syndrome (Neul et al., 2014), large data sets and data from specific genetic conditions with risk factors that may elicit loss of skills (e.g., seizures) require exploration using existing definitions of patterns of onset. Such studies will inform if and how patterns of onset of delays and ASD symptoms in specific conditions compare with those seen in idiopathic ASD. Individuals with the conditions studied in the Developmental Synaptopathies Consortium display risk factors for loss of skills, including high rates of early onset epilepsy in Tuberous Sclerosis Complex and Phelan-McDermid Syndrome.

Objectives: The purpose of this study was to investigate milestone attainment and loss of skills in youth with Phelan-McDermid Syndrome (PMS), Tuberous Sclerosis Complex (TSC) and PTEN hamartoma tumor syndrome (PHTS).

Methods: Inclusion criteria for this analysis were that the child was able to walk independently, and that the child received an Autism Diagnostic Interview-Revised (ADI-R). Out of 98 participants with PMS, 82 were included (mean age 9±5 years, 54% male; 63% with a clinical ASD diagnosis). The TSC sample included 72 of 98 (mean age 8±5 years, 60% male; 54% with a clinical ASD diagnosis), and the PHTS included 28 of 40 (mean age 9±4 years, 79% male; 84% with a clinical ASD diagnosis). The ADI-R was used to determine rates and patterns of skill attainment and loss. In addition to questions pertaining to timing of first concerns, age of walking and age of first words, questions pertaining to language loss (Q11), general loss of other skills (Q20) and loss of social responsiveness (Q25) are reported.

Results: In all groups, the majority of parents reported that with hindsight, their child had exhibited behavioral or developmental problems in the first year of life (PMS, 66%; TSC, 74%; PHTS, 85%). Attainment of milestones and rates of skill loss are shown in Table 1 and indicate that loss was reported in 48% of the PMS group, 35% of the TSC group and 43% of the PHTS group. A fuller description of risk factors relating to these onset patterns, areas of loss, and current functioning in these cohorts will be provided.

Conclusions: A significant percentage of children in all three genetic condition groups were reported to have significant early delays in both language and motor domains, but also have parent report of lost skills, at rates that appear as high, if not higher than found in idiopathic ASD, using similar definitions as previous ASD studies. These findings raise further questions about the relationship of loss of skills to the existence of prior delays, and to the relationship of regression to specific genetic etiologies.