2016 Gatlinburg Conference Poster
PS-54
Title: Profiles of Regression in Individuals with Rare Genetic Syndromes Associated with Autism Spectrum Disorder
Authors: Audrey Thurm, Cristan Farmer, Latha Soorya, Joan Han, Forbes Porter
Introduction: Autism spectrum disorder is associated with many genetic abnormalities, including abnormalities in genes
involved in brain development and metabolic function (Frye, 2015; Ghaziuddin & Al-Owain, 2013). A subset of children with
autism spectrum disorder (ASD) experience significant regression of skills in the first few years of life. The etiology of regression
is unknown, but both environmental and biological mechanisms are suspected. Given that regression may be associated with
certain genetic vulnerabilities in ASD (e.g., Molloy, Keddache, & Martin, 2005) and in specific related genetic conditions (Neul et
al., 2014), we sought to elucidate the profile of regression in individuals with specific rare genetic disorders associated with ASD
(i.e., Phelan-McDermid Syndrome, PMS; WAGR syndrome; and Smith-Lemli Opitz Syndrome, SLOS).
Methods: Individuals participating in syndrome-specific studies at NIH were enrolled in a general screening protocol of
neurocognitive and behavioral phenotyping. An ASD diagnostic evaluation, including the Autism Diagnostic Interview-Revised
(ADI-R), was completed by research reliable clinicians. The ADI-R contains a section on loss of language and other skills, which
was used for this report. A total of 85 participants aged 2-24 years are represented, including 40 with PMS, 24 with WAGR
syndrome, and 21 with SLOS.
Results: The following proportion of each group met DSM-5 criteria for ASD: PMS, 78%; WAGR, 8%; SLOS, 24%. Regression in
some form occurred most commonly in the PMS group (28%), followed by 13% percent in WAGR and 14% percent in SLOS. A loss
of at least five words was reported for n=2 WAGR (neither with ASD), n=2 SLOS (both with ASD), and n=5 PMS (all with ASD).
Within WAGR, language loss included prior daily spontaneous use of the words (n=1) and prior occasional word use (n=1). Both
SLOS patients who lost language had used daily spontaneous speech before loss and one regained language. Four of five PMS
patients with language loss had previously used daily spontaneous speech. One child with PMS regained speech 5 months later;
losses persisted for the remainder. None of the language losses in any group were associated with physical illness.
Regression in skills other than language (domains of hand movements, motor, self-help, play, or social) was reported for n=3
WAGR (none with ASD), n=2 SLOS (one with ASD), and n=11 PMS (eight with ASD). Two WAGR patients had skill losses in either
motor or self-help; the third had reported losses in all domains but play. Loss in one WAGR subject was associated with
chemotherapy. One SLOS patient had definite loss of motor skills and one SLOS patient experienced loss in self-help, play, and
social domains. Each of the PMS subjects with other skill loss had reported losses in at least two domains. Loss in these domains
was associated with illness in five patients. Both language and skill regression was reported for five in the PMS group (all with
ASD), one in the WAGR group (no ASD), and one in the SLOS group (no ASD).
Discussion: The current study confirms the existence of regression in a proportion of individuals with specific neurogenetic
disorders. Further, use of a systematic instrument that documents timing and type(s) of regression indicates a wide age range
and wide range of behavioral areas in which loss is occurring across the genetic disorders. Future use of more fine-grained
detailed analyses of pre-loss skill attainment and post-loss functioning will be essential to tease out the relevance of regression in
these genetic conditions to phenotype and developmental outcome. Descriptions of regression can then begin to be tied to
either prenatal or postnatal underlying molecular biology, as has begun with other specific genetic disorders (Pescosolido et al.,
2014).
References/Citations:
• Frye, R. E. (2015). Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum
disorder. Epilepsy Behav, 47, 147-157.
• Ghaziuddin, M., & Al-Owain, M. (2013). Autism spectrum disorders and inborn errors of metabolism: an update. Pediatr
Neurol, 49(4), 232-236.
• Molloy, C. A., Keddache, M., & Martin, L. J. (2005). Evidence for linkage on 21q and 7q in a subset of autism
characterized by developmental regression. Molecular Psychiatry, 10(8), 741-746.
2016 Gatlinburg Conference Poster
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PS-54
Neul, J. L., Lane, J. B., Lee, H. S., Geerts, S., Barrish, J. O., Annese, F., . . . Percy, A. K. (2014). Developmental delay in Rett
syndrome: data from the natural history study. Journal of Neurodevelopmental Disorders, 6(1), 20.
Pescosolido, M. F., Stein, D. M., Schmidt, M., El Achkar, C. M., Sabbagh, M., Rogg, J. M., Morrow, E. M. (2014). Genetic
and phenotypic diversity of NHE6 mutations in Christianson syndrome. Annals of Neurology, 76(4), 581-593.