Neurovisual profile in children affected by Angelman syndrome

Published:November 04, 2022DOI:



      Angelman syndrome (AS) is a rare neurogenetic disorder caused by altered expression of the maternal copy of the UBE3A gene. Together with motor, cognitive, and speech impairment, ophthalmological findings including strabismus, and ocular fundus hypopigmentation characterize the clinical phenotype. The aim of this study was to detail the neurovisual profile of children affected by AS and to explore any possible genotype-phenotype correlations.


      Thirty-seven children (23 females, mean age 102.8 ± 54.4 months, age range 22 to 251 months) with molecular confirmed diagnosis of AS were enrolled in the study. All underwent a comprehensive video-recorded neurovisual evaluation including the assessment of ophthalmological aspects, oculomotor functions, and basic visual abilities.


      All children had visual impairments mainly characterized by refractive errors, ocular fundus changes, strabismus, discontinuous/jerky smooth pursuit and altered saccadic movements, and/or reduced visual acuity. Comparing the neurovisual profiles between the deletion and non-deletion genetic subgroups, we found a significant statistical correlation between genotype and ocular fundus hypopigmentation (p = 0.03), discontinuous smooth pursuit (p < 0.05), and contrast sensitivity abnormalities (p < 0.01) being more frequent in the deletion subgroup.


      Subjects affected by AS present a wide spectrum of neurovisual impairments that lead to a clinical profile consistent with cerebral visual impairment (CVI). Moreover, subjects with a chromosome deletion show a more severe visual phenotype with respect to ocular fundus changes, smooth pursuit movements, and contrast sensitivity. Early detection of these impaired visual functions may help promote the introduction of neurovisual habilitative programs which can improve children’s visual, neuromotor, and cognitive outcomes.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Yamamoto Y.
        • Huibregtse J.M.
        • Howley P.M.
        The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.
        Genomics. 1997; 41: 263-266
        • Williams C.A.
        • Driscoli D.J.
        • Dagli A.I.
        Clinical and genetic aspects of Angelman syndrome.
        Genet Med. 2010; 12: 385-395
        • Dagli A.
        • Buiting K.
        • Williams C.A.
        Molecular and clinical aspects of Angelman syndrome.
        Mol Syndromol. 2012; 2: 100-112
        • Buiting K.
        • Williams C.
        • Horsthemke B.
        Angelman syndrome - insights into a rare neurogenetic disorder.
        Nat Rev Neurol. 2016; 12: 584-593
        • Williams C.A.
        Neurological aspects of the Angelman syndrome.
        Brain Dev. 2005; 27: 88-94
        • Duis J.
        • Nespeca M.
        • Summers J.
        • Bird L.
        • Bindels‐de Heus K.G.C.B.
        • Valstar M.J.
        • et al.
        A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.
        Mol Genet Genomic Med. 2022; 10: e1843
        • Micheletti S.
        • Vivanti G.
        • Renzetti S.
        • Martelli P.
        • Calza S.
        • Accorsi P.
        • et al.
        Imitation in Angelman syndrome: the role of social engagement.
        Sci Rep. 2020; 10
        • Williams C.A.
        • Angelman H.
        • Clayton-Smith J.
        • Driscoll D.J.
        • Hendrickson J.E.
        • Knoll J.H.M.
        • et al.
        Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation.
        Am J Med Genet. 1995; 56: 237-238
        • Michieletto P.
        • Bonanni P.
        • Pensiero S.
        Ophthalmic findings in Angelman syndrome.
        J AAPOS. 2011; 15: 158-161
        • Dickinson A.J.
        • Fielder A.R.
        • Young I.D.
        • Duckett D.P.
        Ocular findings in Angelman's (happy puppet) syndrome.
        Ophthalmic Paediatr Genet. 1990; 11: 1-6
        • Micheletti S.
        • Palestra F.
        • Martelli P.
        • Accorsi P.
        • Galli J.
        • Giordano L.
        • et al.
        Neurodevelopmental profile in Angelman syndrome: more than low intelligence quotient.
        Ital J Pediatr. 2016; 42
        • Khan N.
        • Cabo R.
        • Tan W.H.
        • Tayag R.
        • Bird L.M.
        Healthcare burden among individuals with Angelman syndrome: findings from the Angelman Syndrome Natural History Study.
        Mol Genet Genomic Med. 2019; 7: e00734
        • Saitoh S.
        • Wada T.
        • Kuno T.
        • Kim K.C.
        • Ohashi H.
        • Hashimoto K.
        • et al.
        Clinical characteristics of Angelman syndrome patients with a non-IC-deleted imprinting mutation.
        Clin Genet. 1999; 55: 277-278
        • Fazzi E.
        • Micheletti S.
        • Calza S.
        • Merabet L.
        • Rossi A.
        • Galli J.
        • et al.
        Early visual training and environmental adaptation for infants with visual impairment.
        Dev Med Child Neurol. 2021; 63: 1180-1193
        • Galli J.
        • Loi E.
        • Morandi A.
        • Scaglioni V.
        • Rossi A.
        • Molinaro A.
        • et al.
        Neurodevelopmental profile in children affected by ocular albinism.
        Neuropediatrics. 2022; 53: 007-014
        • Purpura G.
        • Bacci G.M.
        • Bargagna S.
        • Cioni G.
        • Caputo R.
        • Tinelli F.
        Visual assessment in Down Syndrome: the relevance of early visual functions.
        Early Hum Dev. 2019; 131: 21-28
        • Aghaji A.E.
        • Lawrence L.
        • Ezegwui I.
        • Onwasigwe E.
        • Okoye O.
        • Ebigbo P.
        Unmet visual needs of children with Down syndrome in an African population: implications for visual and cognitive development.
        Eur J Ophthalmol. 2013; 23: 394-398
        • Salati R.
        • Borgatti R.
        • Giammari G.
        • Jacobson L.
        Oculomotor dysfunction in cerebral visual impairment following perinatal hypoxia.
        Dev Med Child Neurol. 2002; 44: 542-550
        • Jacobson L.
        • Ygge J.
        • Flodmark O.
        Oculomotor findings in preterm children with periventricular leukomalacia. A connection between lesions in the periventricular area and eye motility disorders?.
        Acta Ophthalmol Scand. 1996; 74: 645
      1. Michieletto P, Pensiero S, Diplotti L, Ronfani L, Giangreco M, Danieli A, et al. Strabismus surgery in Angelman syndrome: More than ocular alignment. PloS one, 2020;15(11):e0242366.

      2. Ye H, Lan X, Liu Q, Zhang Y, Wang S, Zheng C, et al. Ocular findings and strabismus surgery outcomes in Chinese children with Angelman syndrome: Three case reports. Medicine, 2019; 98(51):e18077.

        • Trivedi R.H.
        • Wilson M.E.
        Refractive lens exchange with intraocular lens implantation in hyperopic eyes of a patient with Angelman syndrome.
        J Cataract Refract Surg. 2010; 36: 1432-1434
        • Varela M.C.
        • Kok F.
        • Otto P.A.
        • Koiffmann C.P.
        Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects.
        Eur J Hum Genet. 2004; 12: 987-992
      3. Fazzi E, Signorini SG, La Piana R, Bertone C, Misefari W, Galli J, et al. Neuroophthalmological disorders in cerebral palsy: ophthalmological,oculomotor, and visual aspects. Dev Med Child Neurol. 2012;54(8):730–736.

        • Iodice A.
        • Galli J.
        • Molinaro A.
        • Franzoni A.
        • Micheli R.
        • Pinelli L.
        • et al.
        Neurovisual Assessment in Children with Ataxia Telangiectasia.
        Neuropediatrics. 2018; 49: 026-034
        • Galli J.
        • Loi E.
        • Molinaro A.
        • Calza S.
        • Franzoni A.
        • Micheletti S.
        • et al.
        Age-related effects on the spectrum of cerebral visual impairment in children with cerebral palsy.
        Front Hum Neurosci. 2022; 16750464
        • Teller D.Y.
        • McDonald M.A.
        • Preston K.
        • Sebris S.L.
        • Dobson V.
        Assessment of visual acuity in infants and children: the acuity card procedure.
        Dev Med Child Neurol. 1986; 28: 779-789
        • Hyvärinen L.
        • Näsänen R.
        • Laurinen P.
        New visual acuity test for preschool children.
        Acta Ophthalmol. 1980; 58: 507-511
      4. Donahue SP, Baker CN, Committee on Practice and Ambulatory Medicine, American Academy of Pediatrics, Section on Ophthalmology, American Academy of Pediatrics, et al. Procedures for the evaluation of the visual system by pediatricians. Pediatrics 2016;137(1): 10.1542/peds.2015-3597.

      5. World Health Organization [WHO]. ICD-10: International Statistical Classification of Diseases and Related Health Problems: Tenth Revision, 2nd Edn. Geneva: World Health Organization, 2021.

        • Leat S.J.
        • Wegmann D.
        Clinical testing of contrast sensitivity in children: age-related norms and validity.
        Optom Vis Sci. 2004; 81: 245-254
        • van Hof-van D.J.
        • Heersema D.J.
        • Groenendaal F.
        • Baerts W.
        • Fetter W.P.
        Visual field and grating acuity development in low-risk preterm infants during the first 2 1/2 years after term.
        Behav Brain Res. 1992; 49: 115-122
        • Kozeis N.
        • Panos G.D.
        • Zafeiriou D.I.
        • de Gottrau P.
        • Gatzioufas Z.
        Comparative study of refractive errors, strabismus, microsaccades, and visual perception between preterm and full-term children with infantile cerebral palsy.
        J Child Neurol. 2015; 30: 972-975
        • Hsieh C.J.
        • Liu J.W.
        • Huang J.S.
        • Lin K.C.
        Refractive outcome of premature infants with or without retinopathy of prematurity at 2 years of age: a prospective controlled cohort study.
        Kaohsiung J Med Sci. 2012; 28: 204-211
        • Rymer J.
        • Wildsoet C.F.
        The role of the retinal pigment epithelium in eye growth regulation and myopia: a review.
        Vis Neurosci. 2005; 22: 251-261
        • King R.A.
        • Wiesner G.L.
        • Townsend D.
        • White J.G.
        Hypopigmentation in Angelman syndrome.
        Am J Med Genet. 1993; 46: 40-44
        • Lee S.T.
        • Nicholls R.D.
        • Bundey S.
        • Laxova R.
        • Musarella M.
        • Spritz R.A.
        Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism.
        N Engl J Med. 1994; 330: 529-534
        • Low D.
        • Chen K.S.
        UBE3A regulates MC1R expression: a link to hypopigmentation in Angelman syndrome.
        Pigment Cell Melanoma Res. 2011; 24: 944-952
        • Ehrhart F.
        • Janssen K.J.M.
        • Coort S.L.
        • Evelo C.T.
        • Curfs L.M.G.
        Prader-Willi syndrome and Angelman syndrome: Visualisation of the molecular pathways for two chromosomal disorders.
        World J Biol Psychiatry. 2019; 20: 670-682
        • Delahanty R.J.
        • Zhang Y.
        • Bichell T.J.
        • Shen W.
        • Verdier K.
        • Macdonald R.L.
        • et al.
        Beyond epilepsy and autism: disruption of GABRB3 causes ocular hypopigmentation.
        Cell Rep. 2016; 17: 3115-3124
        • Chen Y.
        • Holzman P.S.
        • Nakayama K.
        Visual and cognitive control of attention in smooth pursuit.
        Prog Brain Res. 2002; 140: 255-265
        • Hoffman J.E.
        • Subramaniam B.
        The role of visual attention in saccadic eye movements.
        Percept Psychophys. 1995; 57: 787-795
        • Luna B.
        • Velanova K.
        • Geier C.F.
        Development of eye-movement control.
        Brain Cogn. 2008; 68: 293-308
        • Yoon H.M.
        • Jo Y.
        • Shim W.H.
        • Lee J.S.
        • Ko T.S.
        • Koo J.H.
        • et al.
        Disrupted functional and structural connectivity in Angelman syndrome.
        AJNR Am J Neuroradiol. 2020; 41: 889-897
        • Keute M.
        • Miller M.T.
        • Krishnan M.L.
        • Sadhwani A.
        • Chamberlain S.
        • Thibert R.L.
        • et al.
        Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.
        Mol Psychiatry. 2021; 26: 3625-3633
        • Rösblad B.
        Roles of visual information for control of reaching movements in children.
        J Mot Behav. 1997; 29: 174-182
      6. Janmohammadi S, Haghgoo HA, Farahbod M, Overton PG, Pishyareh E. Effect of a visual tracking intervention on attention and behavior of children with Attention Deficit Hyperactivity Disorder. J Eye Mov Res. 2020;12(8):10.16910/jemr.12.8.6.

        • Bauer C.M.
        • Merabet L.B.
        Perspectives on cerebral visual impairment.
        Semin Pediatr Neurol. 2019; 31: 1-2
        • Sakki H.E.
        • Dale N.J.
        • Sargent J.
        • Perez-Roche T.
        • Bowman R.
        Is there consensus in defining childhood cerebral visual impairment? A systematic review of terminology and definitions.
        Br J Ophthalmol. 2018; 102: 424-432
        • Philip S.S.
        • Dutton G.N.
        Identifying and characterising cerebral visual impairment in children: a review.
        Clin Exp Optom. 2014; 97: 196-208
      7. Pamir Z, Bauer CM, Bennett CR, Kran BS, Merabet LB. Visual perception supported by verbal mediation in an individual with cerebral visual impairment (CVI). Neuropsychologia. 2021;160:107982.

        • Good W.V.
        • Jan J.E.
        • DeSa L.
        • Barkovich A.J.
        • Groenveld M.
        • Hoyt C.S.
        Cortical visual impairment in children.
        Surv Ophthalmol. 1994; 38: 351-364
        • Chang M.Y.
        • Borchert M.S.
        Advances in the evaluation and management of cortical/cerebral visual impairment in children.
        Surv Ophthalmol. 2020; 65: 708-724
        • Ffytche D.H.
        • Blom J.D.
        • Catani M.
        Disorders of visual perception.
        J Neurol Neurosurg Psychiatry. 2010; 81: 1280-1287
        • Galli J.
        • Ambrosi C.
        • Micheletti S.
        • Merabet L.B.
        • Pinardi C.
        • Gasparotti R.
        • et al.
        White matter changes associated with cognitive visual dysfunctions in children with cerebral palsy: A diffusion tensor imaging study.
        J Neurosci Res. 2018; 96: 1766-1774
        • Burette A.C.
        • Judson M.C.
        • Li A.N.
        • Chang E.F.
        • Seeley W.W.
        • Philpot B.D.
        • et al.
        Subcellular organization of UBE3A in human cerebral cortex.
        Mol Autism. 2018; 9
        • Jay V.
        • Becker L.E.
        • Chan F.W.
        • Perry Sr., T.L.
        Puppet-like syndrome of Angelman: a pathologic and neurochemical study.
        Neurology. 1991; 41: 416-422
        • Kim H.
        • Kunz P.A.
        • Mooney R.
        • Philpot B.D.
        • Smith S.L.
        Maternal loss of Ube3a impairs experience-driven dendritic spine maintenance in the developing visual cortex.
        J Neurosci. 2016; 36: 4888-4894
        • Sabel B.A.
        • Flammer J.
        • Merabet L.B.
        Residual vision activation and the brain-eye-vascular triad: Dysregulation, plasticity and restoration in low vision and blindness - a review.
        Restor Neurol Neurosci. 2018; 36: 767-791
        • Cosgrove J.A.
        • Kelly L.K.
        • Kiffmeyer E.A.
        • Kloth A.D.
        Sex-dependent influence of postweaning environmental enrichment in Angelman syndrome model mice.
        Brain Behav. 2022; 12: e2468
        • Caselli M.C.
        • Casadio P.
        Il primo vocabolario del bambino: Guida all’uso del questionario MacArthur per la valutazione della comunicazione e del linguaggio nei primi anni di vita [The child’s first words: Guide to the use of the MacArthur questionnaire for assessing communication and language in the first years of life].
        Franco Angeli, Milan1995
      8. Griffiths RThe Griffiths Mental Development Scales from Birth to 2 Years Manual. The 1996 Revision Huntley: Association for Research in Infant and Child Development.

        • Sadhwani A.
        • Wheeler A.
        • Gwaltney A.
        • Peters S.U.
        • Barbieri-Welge R.L.
        • Horowitz L.T.
        • et al.
        Developmental skills of individuals with Angelman syndrome assessed using the Bayley-III.
        J Autism Dev Disord. 2021;