Abstract
BackgroundChildhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences.MethodsWe pursued a multidisciplinary study of CDD (n = 17) and three comparison groups: low-functioning ASD (n = 12), high-functioning ASD (n = 50), and typically developing (n = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces.ResultsWe observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as TRRAP, ZNF236, and KIAA2018, play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces.ConclusionsGiven that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level.
Highlights
Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology
We studied four cohorts: (1) subjects with CDD (n = 17, Table 1), (2) low-functioning [full-scale Intelligence quotient (IQ) (FSIQ) ≤ 75] subjects with Autism spectrum disorder (ASD) (LFASD, n = 12) and early-onset delays (
The specific protein-changing variants identified in CDD subjects were rare and not previously associated with disease, we reviewed the literature and found some overlap between CDD candidate genes and genes potentially associated with other neurological disorders (Table 2)
Summary
Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Heller termed the condition dementia infantilis, which was included in the ICD-10 [5] and DSM-IV [6] as childhood disintegrative disorder (CDD). CDD was defined by normal development for at least the first 2 years of life followed by regression before age 10 years in at least two of the following areas: (1) expressive or receptive language, (2) social skills or adaptive behavior, (3) bowel or bladder control, (4) play, and (5) motor skills. CDD was subsumed by the diagnosis ASD in the DSM-5 [1], since there was little scientific basis for including CDD as a separate disorder [9]
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