The neuroanatomy of genetic subtype in Prader–Willi syndrome

Department of Neurology, University of Kansas School of Medicine, Kansas City, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 03/2012; 159B(2):243-53. DOI: 10.1002/ajmg.b.32022
Source: PubMed


Despite behavioral differences between genetic subtypes of Prader-Willi syndrome (PWS), no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of PWS [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)]. Fifteen individuals with PWS due to a typical deletion [(DEL) type I; n = 5, type II; n = 10], eight with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume (WMV) between groups, covarying for age, sex, and body mass index (BMI). Overall, compared to HWC, PWS individuals had lower gray matter volumes (GMV) that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower WMVs in the brain stem, cerebellum, medial temporal, and frontal cortex. Compared to UPD, the DEL subtypes had lower GMV primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and WMVs in the orbitofrontal and limbic cortices compared to HWC. These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes.

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    • "Key symptoms indicate that the central nervous system (CNS) is adversely affected in PWS. To date, only two quantitative structural magnetic resonance imaging (MRI) studies have been performed in adults with PWS, which reported smaller grey matter volumes in the frontal, temporal, and parietal [14,15] lobes, and smaller white matter volumes in the frontal and temporal cortices, brainstem, and cerebellum [15]. An MRI qualitative study reported enlarged ventricles, decreased parieto-occipital lobar volume, and sylvian fissure abnormalities in adults with PWS [16]. "
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    ABSTRACT: Prader--Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD.
    Journal of Neurodevelopmental Disorders 10/2013; 5(1):31. DOI:10.1186/1866-1955-5-31 · 3.27 Impact Factor
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    • "The phenotype includes intellectual disabilities, compulsivity, hyperphagia, and increased risks of life-threatening obesity [3,4]. Several studies have examined possible phenotypic differences in PWS across these two major genetic subtypes in neuroanatomy [5], cognitive performance and adaptive skills [6-8], food-related behaviors [9,10], and behavioral problems and psychiatric illness [11-15]. "
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    ABSTRACT: Background People with Prader-Willi syndrome (PWS) demonstrate social dysfunction and increased risk of autism spectrum disorder, especially those with the maternal uniparental disomy (mUPD) versus paternal deletion genetic subtype. This study compared the neural processing of social (faces) and nonsocial stimuli, varying in emotional valence, across genetic subtypes in 24 adolescents and adults with PWS. Methods Upright and inverted faces, and nonsocial objects with positive and negative emotional valence were presented to participants with PWS in an oddball paradigm with smiling faces serving as targets. Behavioral and event-related potential (ERP) data were recorded. Results There were no genetic subtype group differences in accuracy, and all participants performed above chance level. ERP responses revealed genetic subtype differences in face versus object processing. In those with deletions, the face-specific posterior N170 response varied in size for face stimuli versus inverted faces versus nonsocial objects. Persons with mUPD generated N170 of smaller amplitude and showed no stimulus differentiation. Brain responses to emotional content did not vary by subtype. All participants elicited larger posterior and anterior late positive potential responses to positive objects than to negative objects. Emotion-related differences in response to faces were limited to inverted faces only in the form of larger anterior late positive potential amplitudes to negative emotions over the right hemisphere. Detection of the target smiling faces was evident in the increased amplitude of the frontal and central P3 responses but only for inverted smiling faces. Conclusion Persons with the mUPD subtype of PWS may show atypical face versus object processes, yet both subtypes demonstrated potentially altered processing, attention to and/or recognition of faces and their expressions.
    Journal of Neurodevelopmental Disorders 03/2013; 5(1):7. DOI:10.1186/1866-1955-5-7 · 3.27 Impact Factor
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    ABSTRACT: Prader Willi syndrome (PWS) is a genetic disorder (15q11-q13) characterized by short stature, hypogonadism leading to osteoporosis, delayed puberty, central hypocorticism and the most life threatening, excessive appetite which is followed by morbid obesity. Patients with PWS present reduced GH secretion, hypogonadotropic hypogonadism, abnormal appetite control and high pain threshold suggesting hypothalamic-pituitary dysfunction. However, all high resolution imaging studies are normal; due to changes in Chr 15, the hypothalamic function is disrupted. All patients with PWS show severe disturbances in appetite control resulting in hyperphagia and obesity. Peptides involved in hypothalamic appetite control as ghrelin. leptin, NPY/AGRP, POMC, and their cognate receptors, are involved in developmental processes, determine the threshold for signals of body fat below which increases in energy intake and reductions in energy expenditure. In addition, low GH and IGF1 level, central hypothyroidism, delayed puberty and central hypogonadism may impact upon the body composition. Despite the detailed knowledge about obesity mechanisms regulated at hypothalamic level, the pharmacological intervention is limited currently to substitution of proven endocrine deficiencies and GH treatment. The PWS brain seems "wired" for a positive energy balance, and very few pathways can counterbalance this genetic imprinting
    Choroid Plexus - Pineal Gland Correlations Medical Anthropology - Computed Tomography Studies Intracranial Physiological Calcification 01/2012; 8(1-1):99-105. DOI:10.4183/aeb.2012.99 · 0.27 Impact Factor
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