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Table of Contents    
Year : 2016  |  Volume : 64  |  Issue : 2  |  Page : 228-232

Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome

1 Department of Developmental Pediatrics, The SARAH Network of Rehabilitation Hospitals – SARAH International Center for Neurorehabilitation and Neuroscience, Brazil
2 Department of Neuroradiology, The SARAH Network of Rehabilitation Hospitals – SARAH International Center for Neurorehabilitation and Neuroscience, Brazil
3 Department of Child Neurology, Antonio Pedro University Hospital/Federal Fluminense University, Brazil
4 Department of Neurology, Antonio Pedro University Hospital/Federal Fluminense University, Brazil

Date of Web Publication3-Mar-2016

Correspondence Address:
Marcio Leyser
Avenida Arroio Pavuna, S/N. Rio de Janeiro, RJ 22775-020
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.177615

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 » Abstract 

Background: Global developmental delay, lack of speech, and severe epilepsy are the characteristic hallmarks of Angelman syndrome (AS). The purpose of this study was to explore the utility of brain magnetic resonance imaging (MRI) as an ancillary tool for the diagnosis of AS.
Material and Methods: Brain MRI images of nine laboratory-confirmed patients with AS from a neurorehabilitation center in Rio de Janeiro were reviewed. Each MRI was assessed by a set of two experienced neuroradiologists following a predefined protocol.
Results: The main neuroimaging findings revealed in our study were: Thinning of the corpus callosum in five patients; enlargement of lateral ventricles in four patients; and, cerebral atrophy with frontal and temporal predominance in one patient. All patients presented with an increased signal intensity in T2-weighted images and fluid-attenuated inversion recovery (FLAIR) sequences.
Conclusion: The lack of specific changes in the brain MRI of children with AS observed in this case series rendered brain MRI a less helpful complementary test. Thus, a definitive diagnosis of AS could only be established on molecular biology that was undertaken based on the clinical suspicion of AS.

Keywords: Angelman syndrome; magnetic resonance imaging; periventricular leukomalacia; psychomotor disorders

How to cite this article:
Leyser M, Gonsalvez Md, Vianna PE, Fernandes PA, Carvalho RS, Vasconcelos MM, Nascimento OJ. Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome. Neurol India 2016;64:228-32

How to cite this URL:
Leyser M, Gonsalvez Md, Vianna PE, Fernandes PA, Carvalho RS, Vasconcelos MM, Nascimento OJ. Scrutinizing brain magnetic resonance imaging patterns in Angelman syndrome. Neurol India [serial online] 2016 [cited 2021 Apr 18];64:228-32. Available from:

 » Introduction Top

In 1965, Harry Angelman, an English Pediatrician from Birkenhead (Cheshire), correlated a set of similar clinical and neurological findings observed in three of his patients.[1] These children shared a common and unique phenotype, characterized by intellectual disability, lack of speech, a happy demeanor and an easy excitability, frequent episodes of unprovoked laughing, the presence of limb jerkiness, and gait ataxia. They also had severe epilepsy, which constitutes one of the most troublesome comorbidities of this syndrome.[2] Only after two decades of its first report, the pathophysiology of Angelman syndrome [AS, Online Mendelian Inheritance in Man (OMIM #105830)] has became widely recognized, and has helped the medical world in heightening its awareness about the imprinting epigenetic phenomenon.[3]

AS has four main patterns of inheritance, which are already well known.[3]

The previous neurophysiological studies have been able to establish three unequivocal electroencephalogram (EEG) patterns frequently seen in this syndrome. These EEG findings are remarkably helpful in identifying the suspected cases, who merit a definitive molecular biological confirmation for the presence of AS.[4]

More recently, the scientific goals have aimed at looking deeper into the knowledge of different pathways that ultimately explain the structural or functional lack of ubiquitination and its role in protein substrate functioning, such as those for Ephexin-5 and ARC (activity-regulated cytoskeletal protein). These substrates are thought to accumulate in the brain, initiating a cascade of events that end up in unbalancing neurotrafficking and impairs the development, growth, and maintenance of dendritic spines and synaptic networks.[5],[6],[7] In addition, diffusion tensor imaging (DTI) studies are now aiming to correlate the structural changes in the brain of children with AS with the clinical findings generated by these neurometabolic mismatches.[8],[9],[10]

At present, some authors [11],[12],[13] also believe that a few brain magnetic resonance imaging (MRI) features are more commonly expected in the AS population than was formerly thought. Even after the elapsing of more than three decades since AS became a matter of worldwide scientific interest, there is little data regarding the role of brain MRI in the diagnosis and in the prognostication of this disease. The papers published by previous authors [11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21] have failed to demonstrate an irrefutable evidence regarding the diagnostic value of neuroimaging in patients with AS. The lack of classical neuroradiological signs in these studes was initially attributed to the fact that most of these studies were performed using a brain computerized tomography (CT) scan, rather than an MRI. As suggested by Dan et al.,[11] the scanty data currently present on neuroimaging makes it necessary to offer a better overview of the subject. A few studies with an adequate sample size describe the nonspecific findings of AS such as minor abnormalities in the anatomical structure of the lateral ventricles, body of the corpus callosum, frontal lobes as well as in the white matter myelination pattern.[14],[15],[16],[17],[18],[19],[20],[21]

This paper discusses the findings of brain imaging in children with AS in an attempt to explore the value of brain MRI as an investigational tool to unequivocally establish the diagnosis of AS.

 » Material and Methods Top

Ten children suffering from neurodevelopmental arrest and epilepsy from a neuro-rehabilitation center in the city of Rio de Janeiro underwent neuroimaging scans during their initial diagnostic work-up before the diagnosis of AS was finally established by using molecular biology. An analysis from the patients' charts in this study revealed a mean age of 7.8 years. The mean age at which the brain MRI was performed was 2.4 years. Four out of the 9 patients were female and five were male. The genetic molecular classes and clinical characteristics of the study group are briefly summarized in [Table 1].
Table 1: Clinical and genetic characteristics of the study group

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Eight patients underwent a brain 1.5T MRI (Siemens-Magneton Symphony; sagittal T1 [repetition time (TR): 500, echo time (TE): 14], axial T2 [TR: 4067.19, TE: 86], coronal T2 [TR: 3000, TE: 104], and axial fluid-attenuated inversion recovery (FLAIR) [TR: 9000, TE: 114, TI: 2500]. One patient underwent both a brain MRI and a brain CT (Philips – MX8000). Another patient had only a brain CT scan done. He was excluded from the analysis to better pair the technical neuroimaging standards and to avoid a potential misjudgment of the images produced by the CT scan. The MRI images were randomly assigned and assessed in a peer-review process by four experienced neuroradiologists on a two-on-one basis. The MRI findings, based on the previously published reports by other authors, such as myelination delay, thinning of the corpus callosum, enlargement of lateral ventricles, cerebral atrophy, enlargement of frontal subarachnoid space, enlargement of the Sylvian fissure, and decrease in the cerebellar volume were scrutinized. Furthermore, our analysis also aimed at searching for new brain imaging features that could correlate more specifically with the diagnosis of AS.

This predefined protocol did not entail any technical measurement of the shape and size of the Sylvian fissure using the Talaraich procedure and the Steinmetz scheme, nor did it include any measurement of the thickness of the corpus callosum. This is because reliable standardized measuring patterns and methods to assess these entities in children have not been conclusively established as yet.

 » Results Top

All brain MRI images showed a slightly ill-defined, increased signal intensity in the periventricular white matter on T2 weighted (T2WI) and FLAIR image sequences.

Our data also revealed that thinning of the corpus callosum was present in five out of 9 (56%) patients. The enlargement of lateral ventricles was observed in 4 (45%) of the cases, followed by an increase in the frontal subarachnoid space in 2 (22%) patients, and brain atrophy with frontal and temporal predominance in 1 (11%) patient in this series. No myelination delay was seen in any of the MRIs performed in these children. No gross anatomical and signal changes could be observed in the cerebellum. The neuroimages analyzed in this study did not show any unexpected or atypical features. The most frequent MRI findings found in our study are depicted in [Figure 1],[Figure 2],[Figure 3] and are highlighted in [Table 2].
Table 2: Brain MRI findings in patients with AS

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Figure 1: Brain magnetic resonance imaging: (a) Sagittal T1 spoiled gradient echo – Thinning of the corpus callosum; (b and c) Axial T2 fast spin echo images showing frontal and temporal lobe atrophy (Patient 1)

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Figure 2: Brain magnetic resonance imaging: (a) Axial and (b) coronal T2 fast spin echo showing an enlargement of the lateral ventricles with loss of periventricular white matter (Patient 2)

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Figure 3: Brain magnetic resonance imaging. (a and b) Axial fluid-attenuated inversion recovery sequences (FLAIR) showing an increased periventricular signal intensity suggesting the myelination terminal zone (Patient 3)

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 » Discussion Top

In our case-series of nine children with AS, who underwent a brain MRI during an initial work-up for the presence of a global developmental delay associated with epilepsy, the most frequent findings, in order of frequency, were periventricular increasing signal intensity in T2W and FLAIR sequences, thinning of the corpus callosum, enlargement of lateral ventricles, enlargement of frontal subarachnoid space, and cortical brain atrophy. These results are in agreement with the studies published by Harting et al.,[12] Castro-Gago et al.,[13] Leonard et al.,[21], and Buoni et al.[22]

Harting et al.,[12] have postulated the findings of myelination delay and loss of white matter volume that may potentially be misleading. The assessment of the former is usually difficult to determine in the brain MRI of infants. In our sample, Patient 1 presented with a thinning of the corpus callosum and an enlargement of the lateral ventricles, in addition to frontal and temporal cortical atrophy. Despite having received a good Apgar score, this child was born cyanotic due to the presence of umbilical cord around the neck. He also displayed transient tachypnea of the newborn. It is not unusual to observe children with neurological syndromes being born prematurely or with neonatal medical complications. The latter entities may, most likely, result in secondary white matter damage. This could also explain thinning of the corpus callosum (observed in patients 2, 3, 4, and 8) and atrophy of the periventricular white matter resulting in an ex-vacuo enlargement of the ventricles. The latter finding was seen in patients 2, 3, and 9.

An enlargement of the subarachnoid space was also noticed on MR imaging of the third and fifth patient. Although Buoni et al.,[22] have reported a moderate enlargement of the subarachnoid spaces around the cerebral cortical space in five of their patients, we have considered it as a physiological finding which may often be seen in young children who undergo a brain scanning procedure at a young age.

In our patients, the mean age at which the brain MRI was performed was 2.4 years. At this time, the terminal zone myelination may produce an increased signal intensity on T2WI and FLAIR sequences.[23] Therefore, it is impossible to be absolutely sure of whether these images actually represent terminal zone myelination or suggest a white matter injury. Although we were able to identify an ill-defined increase in the periventricular signal intensity on T2WI and FLAIR sequences in all the nine patients enrolled in our study, we suspect it to be probably related to the presence of terminal myelination zones (due to the thin curvilinear layer isointense to the cerebrospinal fluid present between the trigones of the lateral ventricles and the terminal zones).[23] Moreover, in agreement with Harting et al.,[12] and Castro-Gago et al.,[13] we believe that there might be a myelination delay in some infants suffering from AS, but the MRI findings are usually not specific enough to make one completely rely on that type of imaging test to establish the diagnosis of AS. Another important issue that requires focus is the finding of a reduction in the periventricular white matter thickness in regions where the lateral ventricles were minimally enlarged. This was demonstrable on the brain MRI of patient nine in this series. This patient was the only one with a classically evident central defect on MR imaging. Does the MR finding of diminished periventricular white matter conclusively establish the definitive diagnosis of AS? At the present state of knowledge, this question remains unanswered.

Paprocka et al.,[15] Leonard et al.,[21], and Buoni et al.,[22] have suggested that the Sylvian fissures, in a vast majority of patients with AS, were anomalously larger than usual. Contrary to the observation made by these authors, the MR images seen in our study do not suggest a significant change in the size of the Sylvian fissure or an alteration in the opercular area or the distal ramifications of the fissure. Moreover, when Leonard et al.,[21] studied this mixed group of patients having both AS and Prader–Willi syndrome, only two out of 6 patients, who were initially diagnosed to be suffering from AS, were definitively confirmed to be having that syndrome by genetic tests. The remaining patients were suspected to be suffering from AS based only on clinical judgment, a fact that might lead to a potential bias.

Peters et al.,[8] found a decrease in the cerebellar volume in one participant and a mildly foreshortened corpus callosum in five participants in a study that included 14 patients with AS who underwent a diffusion tensor imaging (DTI) tractrographic analysis. A few studies have used DTI to scrutinize the white matter tracts. They have yielded information about a potential clinical-imaging relationship between the altered white matter architecture, more specifically in the arcuate fasciculus, and the typical social and communication neurobehavior of AS patients.[8],[9],[10] Nevertheless, at present, DTI tractrography has still been used more frequently as a research tool rather than as a routine diagnostic neuroimaging option.

The brain MRI has become in general an accepted step in the work-up of children with global developmental arrest, even though its diagnostic and prognostic implications have not yet been conclusively established. In contrast, a more feasible, safer, and cheaper diagnostic tool such as a video-electroencephalogram in a non-sedated child usually yields more reliable data, upon which a high index of clinical suspicion may be raised, prior to the definitive establishment of the diagnosis by molecular biology.

 » Conclusion Top

In our case series of nine patients with AS, we could not discover a brain pattern on the MRI that would be specific enough to support a definitive diagnosis of AS. Moreover, slight cortical atrophy, white matter signal abnormality, and volume reduction are not only non-specific, but could also be a by-product of secondary white matter brain injury in some patients.

Even considering the limitations of our small sample size, we believe that the lack of specific changes in the brain MRIs of children with AS makes it a less helpful complementary test and a definitive diagnosis of this syndrome may only be established based on a screening EEG and molecular biology.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Angelman H. “Puppet children”: A report on three cases. Dev Med Child Neurol 1965;7:681-8.  Back to cited text no. 1
Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, et al. Angelman syndrome 2005: Updated consensus for diagnostic criteria. Am J Med Genet A 2006;140:413-8.  Back to cited text no. 2
Chamberlain SJ, Lalande M. Angelman syndrome, a genomic imprinting disorder of the brain. J Neurosci 2010;30:9958-63.  Back to cited text no. 3
Leyser M, Penna PS, de Almeida AC, Vasconcelos MM, Nascimento OJ. Revisiting epilepsy and the electroencephalogram patterns in Angelman syndrome. Neurol Sci 2014;35:701-5.  Back to cited text no. 4
Scheiffele P, Beg AA. Neuroscience: Angelman syndrome connections. Nature 2010;468:907-8.  Back to cited text no. 5
Philpot BD, Thompson CE, Franco L, Williams CA. Angelman syndrome: Advancing the research frontier of neurodevelopmental disorders. J Neurodev Disord 2011;3:50-6.  Back to cited text no. 6
Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: Insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci 2011;34:293-303.  Back to cited text no. 7
Peters SU, Kaufmann WE, Bacino CA, Anderson AW, Adapa P, Chu Z, et al. Alterations in white matter pathways in Angelman syndrome. Dev Med Child Neurol 2011;53:361-7.  Back to cited text no. 8
Wilson BJ, Sundaram SK, Huq AH, Jeong JW, Halverson SR, Behen ME, et al. Abnormal language pathway in children with Angelman syndrome. Pediatr Neurol 2011;44:350-6.  Back to cited text no. 9
Tiwari VN, Jeong JW, Wilson BJ, Behen ME, Chugani HT, Sundaram SK. Relationship between aberrant brain connectivity and clinical features in Angelman Syndrome: A new method using tract based spatial statistics of DTI color-coded orientation maps. Neuroimage 2012;59:349-55.  Back to cited text no. 10
Dan B, Pelc K, Christophe C. What would the brain look like in Angelman syndrome? Eur J Paediatr Neurol 2009;13:269-70.  Back to cited text no. 11
Harting I, Seitz A, Rating D, Sartor K, Zschocke J, Janssen B, et al. Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2009;13:271-6.  Back to cited text no. 12
Castro-Gago M, Gómez-Lado C, Eirís-Puñal J, Rodríguez-Mugico VM. Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2010;14:292.  Back to cited text no. 13
Williams CA. Neurological aspects of the Angelman syndrome. Brain Dev 2005;27:88-94.  Back to cited text no. 14
Paprocka J, Jamroz E, Szwed-Bialozyt B, Jezela-Stanek A, Kopyta I, Marszal E. Angelman syndrome revisited. Neurologist 2007;13:305-12.  Back to cited text no. 15
Guerrini R, Carrozzo R, Rinaldi R, Bonanni P. Angelman syndrome: Etiology, clinical features, diagnosis, and management of symptoms. Paediatr Drugs 2003;5:647-61.  Back to cited text no. 16
Dörries A, Spohr HL, Kunze J. Angelman (”happy puppet”) syndrome – Seven new cases documented by cerebral computed tomography: Review of the literature. Eur J Pediatr 1988;148:270-3.  Back to cited text no. 17
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Leonard CM, Williams CA, Nicholls RD, Agee OF, Voeller KK, Honeyman JC, et al. Angelman and Prader-Willi syndrome: A magnetic resonance imaging study of differences in cerebral structure. Am J Med Genet 1993;46:26-33.  Back to cited text no. 21
Buoni S, Grosso S, Pucci L, Fois A. Diagnosis of Angelman syndrome: Clinical and EEG criteria. Brain Dev 1999;21:296-302.  Back to cited text no. 22
Barkovich AJ, Raybaud C. Pediatric Neuroimaging. 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams and Wilkins; 2012.  Back to cited text no. 23


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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