Alterations in white matter pathways in Angelman syndrome

Abstract

Aim Angelman syndrome is a neurogenetic disorder characterized by severe intellectual disability, absent speech, seizures, and outbursts of laughter. The aim of this study was to utilize diffusion tensor imaging (DTI) to examine alterations in white matter pathways in Angelman syndrome, with an emphasis on correlations with clinical severity. Method DTI was used to examine the arcuate fasciculus (AF), uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), inferior fronto‐occipital fasciculus (IFOF), and the corpus callosum (CC). We enrolled 14 children aged 8 to 17 years (mean age 10y 8mo; SD 2y 7mo) with Angelman syndrome (seven male; seven female) and 13 typically developing children, aged 8 to 17 years, for comparison (five male; eight female; mean age 12y; SD 2y 9mo). Individuals with Angelman syndrome were assessed using standardized measures of development, language, and behaviour. Results The children with Angelman syndrome exhibited lower fractional anisotropy and increased radial diffusivity values than the comparison group for the AF, UF, ILF, and CC (p<0.006 corrected for multiple comparisons). They also had lower fractional anisotropy values for the IFOF and higher radial diffusivity values for the left IFOF (p<0.006). Additionally, children with Angelman syndrome had significantly higher apparent diffusion coefficient values in the AF, CC, ILF, and the left IFOF (p<0.006). Significant correlations were noted between DTI parameters and some of the clinical assessment outcomes (e.g. language, socialization, cognition) for three of the temporal pathways (AF, UF, ILF; p<0.05). Interpretation Changes in DTI parameters in individuals with Angelman syndrome suggest decreased/delayed myelination, decreased axonal density or diameter, or aberrant axonal organization. Our findings suggest a generalized white matter alteration throughout the brain in those with Angelman syndrome; however, only the alterations in temporal white matter pathways were associated with language and cognitive and social functioning.

The Arcuate Fasciculus and Language Development in a Cohort of Pediatric Patients with Malformations of Cortical Development

“…Abnormal, though identifiable, arcuate fasciculi have been reported in a range of disorders manifesting speech delay. [37][38][39] 42 reported a small frequency of the absence of the left arcuate fasciculus in healthy patients. In our control population, by contrast, all subjects had an identifiable left arcuate fasciculus.…”

Applicability of genetic polymorphism analysis for the diagnosis of Angelman syndrome and the correlation between language difficulties and disease phenotype

“…Peters et al (2004) also reported reduced myelination in the white matter of the brain. DTI tractography studies in participants with AS have also shown abnormalities in the arcuate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, uncinate fasciculus, corticospinal tracts, and corpus callosum (Peters et al, 2011). The arcuate fasciculus is a white matter tract that connects the language comprehension region of the temporal lobe with the speech-generating region of the frontal lobe.…”

Angelman Syndrome: A Case Series Assessing Neurological Issues in Adulthood

“…They may precede the diagnosis [17,19] but are not absolutely specific [3,7,22]. Neuro-imaging studies may be normal but show global atrophy and abnormal myelination in the frontal lobes, as well as a thin corpus callosum [23,24], in approximately 60% of the cases [25]. This MRI finding is now an important feature in the evaluation and understanding of AS and may explain the language and motor difficulties observed in patients [23,25].…”

“…Epileptiform discharges tend to shift towards the frontal region [21] as observed in all cases, and reflect the functional neuro-chemical or maturational disorder of the frontal area: from a pathophysiological point of view as suggested by MRI [23,24,25,26], the mechanism could consist of delayed myelination, associated with a thin corpus callosum [23,26]. A previous study [27] using diffusion tensor imaging has demonstrated that in addition to delayed myelination, there was decreased axonal density and aberrant axonal organisation mainly in the temporal pathways, which partly explained the language, cognitive and social functioning disorders [26,27].…”