Senthil K. Sundaram

Background: We had previously shown that arcuate fasciculus is poorly developed in patients with intellectual and developmental disabilities (IDD) using diffusion tensor imaging (DTI). In the present study, we used exome sequencing to identify the candidate variants in IDD patients with and without DTI abnormalities. Methods: Eighteen children with IDD (age: 67 ± 36 mo, 9 females) were included in the present study. The DTI was used to determine the integrity of arcuate fasciculus. The next-generation sequencing was performed on the Solid 4 platform. A novel, analytical strategy was developed to identify a set of candidate genes of interest. We then searched for novel, nonsynonymous variants in the patients within this subset of genes and in known IDD genes. Results: Seven novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to ultraconserved genes that are known to cause abnormal brain morphology in mutant mice. Similarly, three novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to known IDD genes. Two patients with underdeveloped arcuate fasciculus had novel, nonsynonymous variants in genes (MID1 and EN2) regulating axon guidance pathway. Conclusion: Exome sequencing identified several new genetic causes of IDD.

This study was performed to evaluate the cerebral protein synthesis rate of language brain regions in children with developmental delay with and without pervasive developmental disorder. The authors performed L-[1-¹¹C]-leucine positron emission tomography (PET) on 8 developmental delay children with pervasive developmental disorder (mean age, 76.25 months) and 8 developmental delay children without pervasive developmental disorder (mean age, 77.63 months). They found a higher protein synthesis rate in developmental delay children with pervasive developmental disorder in the left posterior middle temporal region ( P = .014). There was a significant correlation of the Gilliam Autism Rating Scale autism index score with the protein synthesis rate of the left posterior middle temporal region ( r = .496, P = .05). In addition, significant asymmetric protein synthesis (right > left) was observed in developmental delay children without pervasive developmental disorder in the middle frontal and posterior middle temporal regions ( P = .03 and P = .04, respectively). In conclusion, abnormal language area protein synthesis in developmentally delayed children may be related to pervasive symptoms.

BACKGROUND AND PURPOSE: One of the neurologic substrates of poor language in children with DD is the abnormal development of perisylvian language networks. We sought to determine whether this manifests as aberrant regional changes in diffusivity or geometry of the left AF. MATERIALS AND METHODS: We performed DTI studies in 16 young (age, 55.4 ± 18.95 months) patients with DD and 11 age- and sex-matched TD children (age, 60.09 ± 21.27 months). All children were right-handed. To detect the malformation of left AF structure in native or standard space, we proposed new methodology consisting of 2 complementary approaches, principal fiber orientation quantification in color-coded anisotropic maps and tract-based morphometry analysis. RESULTS: Patients with DD did not show the typical pattern of age-related maturity of the AP and ML pathways passing through the left AF (R² of the AP pathway: DD versus TD = 0.002 versus 0.4542; R² of the ML pathway: DD versus TD = 0.002 versus 0.4154). In addition, the patients with DD showed significantly reduced FA in the temporal portion of the AF (mean FA of DD versus TD = 0.37 ± 0.11 versus 0.48 ± 0.06, P < .001), and the AF showed higher curvatures in the parietotemporal junction, resulting in sharper bends to the Wernicke area (mean curvature of DD versus TD = 0.12 ± 0.03 versus 0.06 ± 0.02, P < .001). CONCLUSIONS: The proposed methods successfully revealed regional abnormalities in the axonal integrity of the left AF in the patients with DD. These abnormalities support the notion that the perisylvian language network is malformed in children with DD.

To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 ± 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 ± 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.