Central Nervous System Structure
Individuals with AS are generally thought to have normal imaging studies although occasional abnormalities have been reported that probably are coincidental findings. The most common MRI or CT change, when any is detected, is mild cortical atrophy (i.e. a small decrease in the thickness of the cortex of the cerebrum) and/or mildly decreased myelination (i.e. the more central parts of the brain appear to have a slight degree of diminished white matter)[1, 2]. Several detailed microscopic and chemical studies of the brain in AS have been reported but the findings generally have been nonspecific or the number of cases has been too few to make meaningful conclusions.
A recent study using advanced neuroimaging techniques (diffusion tensor imaging [DTI], quantitative magnetic resonance imaging [MRI], and magnetization transfer ratio [MTR] imaging) revealed abnormalities in deletion positive individuals with AS [3, 4]. The DTI studies reveal significant differences between AS patients and controls for white matter pathways involving the frontal, temporal, parietal, and limbic areas. Those with AS had reduced white matter fiber density and coherence in these respective regions. Results of MTR, a measure of white matter integrity, showed differences between individuals with AS and controls in the global pallidus, thalamus, frontal white matter, and left temporal regions. Differences in these regions appear to correlate with the language, cognitive, motor, and behavioral difficulties associated with AS. Quantitative MRI study, after controlling for total brain size, showed that those with AS had reduced white matter volumes in the cerebellum, cerebrum, hippocampus, accumbens, caudate, and corpus callosum. There was also subtle cortical thinning in gray matter in temporal, frontal, and occipital regions, primarily in the left hemisphere. The same regions are associated with increased cortical folding/gyrification. Findings in these regions appear to correlate with the clinical/behavioral anomalies (e.g., reduced hippocampal volume corresponds to lower cognitive and memory skills, reduced cerebellar volume corresponds to increased stereotypic behaviors, reduced fiber density and coherence in limbic regions corresponds to impairments in social communication and play).
These findings demonstrate that deletion positive AS patients exhibit microstructural changes in white matter fiber tracts that affect the development, wiring, and targeting of axons that link affected brain regions. They also exhibit reduced volume in brain regions that appeared to contribute to the clinical phenotype observed. It has not yet been determined if these abnormalities are present in other molecular subtypes of AS but it seems reasonable to expect that they will be.
1. Harting I, Seitz A, Rating D, et al. Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol, 2008.
2. Leonard CM, Williams CA, Nicholls RD, et al. Angelman and Prader-Willi syndrome: a magnetic resonance imaging study of differences in cerebral structure. Am J Med Genet, 1993. 46(1): p. 26-33.
3. Peters SU, Bacino CA, Chu Z, et al. Inside the brain in Angelman Syndrome: Phenotypic characterization using advanced neuroimaging techniques (452). The Am Soc Hum Genet Mtg (www.ashg.org/2008meeting/abstracts/fulltext), 2008.
4. Peters SU, Bacino CA, Chu Z, et al. Neuroantomical abnormaliites and whte matter alterations predict the overall phenotype in Angelman Syndrome. Presented at the Angelman Syndrome Foundation's Scientific Symposium, Boston, 2008.