Auditory Interhemispheric Transfer Deficits, Hearing Difficulties, and Brain Magnetic Resonance Imaging Abnormalities in Children With Congenital Aniridia Due to PAX6 Mutations

University of Connecticut, Storrs, Connecticut, United States
Archives of Pediatrics and Adolescent Medicine (Impact Factor: 5.73). 06/2007; 161(5):463-9. DOI: 10.1001/archpedi.161.5.463
Source: PubMed


To assess auditory processing, hearing difficulties, and brain magnetic resonance (MR) imaging abnormalities in children with panocular developmental aniridia due to PAX6 mutations.
Case-control study.
Great Ormond Street Hospital and Institute of Child Health.
Eleven case subjects with PAX6 mutations and 11 age-matched and sex-matched healthy control subjects.
All subjects completed a structured hearing questionnaire, baseline audiometry, and central auditory tests (dichotic speech tests, frequency and duration pattern tests, and gaps-in-noise test). Case subjects underwent brain MR imaging with volumetry, and the results were compared with those of age-matched and sex-matched healthy control subjects randomly selected from the Radiology and Physics Unit database.
Brain MR imaging, central auditory test results, and questionnaire scores.
The corpus callosum area was significantly smaller on brain volumetry in the cases compared with the controls. The anterior commissure was small in 7 cases and was normal in 3 cases on visual inspection of brain MR images (conducted in 10 of 11 cases). Audiograms showed no abnormalities in any of the children. Central auditory test results were normal in all the controls and were abnormal in all the cases except for 1 case with a pattern of abnormalities consistent with reduced auditory interhemispheric transfer. The cases had greater difficulty localizing sound and understanding speech in noise than the controls.
Despite normal audiograms, children with PAX6 mutations may experience auditory interhemispheric transfer deficits and have difficulty localizing sound and understanding speech in noise. In view of their additional visual difficulties, thorough audiological evaluation of these children is indicated to initiate appropriate management.

Download full-text


Available from: Veronica Van Heyningen
  • Source
    • "Similarly, another category ( " integration category " ) links difficulties integrating auditory and other types of information, such as that from visual stimuli (Stecker, 1998) to expected lesions in the corpus callosum or the angular gyrus (Katz, 1992). These sorts of theoretical models and their associated lesion studies (Musiek and Sachs, 1980; Bamiou et al., 2007; Boscariol et al., 2010) take important steps in forming a basis for our understanding the role of the CNS in (central) auditory processing. However, requiring or presupposing links between the observed dysfunctions in behavior specifically to brain lesions may be less informative than links to a broader class of neural dysfunction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Magnetoencephalography (MEG) provides a direct, non-invasive view of neural activity with millisecond temporal precision. Recent developments in MEG analysis allow for improved source localization and mapping of connectivity between brain regions, expanding the possibilities for using MEG as a diagnostic tool. In this paper, we first describe inverse imaging methods (e.g., minimum-norm estimation) and functional connectivity measures, and how they can provide insights into cortical processing. We then offer a perspective on how these techniques could be used to understand and evaluate auditory pathologies that often manifest during development. Here we focus specifically on how MEG inverse imaging, by providing anatomically based interpretation of neural activity, may allow us to test which aspects of cortical processing play a role in (central) auditory processing disorder [(C)APD]. Appropriately combining auditory paradigms with MEG analysis could eventually prove useful for a hypothesis-driven understanding and diagnosis of (C)APD or other disorders, as well as the evaluation of the effectiveness of intervention strategies.
    Full-text · Article · Mar 2014 · Frontiers in Human Neuroscience
  • Source
    • "For example, one of the novel targets, FOXP2, is a protein known to play a key role in language and speech functions (Fisher and Scharff 2009). Interestingly, PAX6 haploinsufficiency has been associated with structural and functional brain anomalies and learning disability (Heyman et al. 1999; Sisodiya et al. 2001; Bamiou et al. 2007; Graziano et al. 2007; Maekawa et al. 2009) and with behavioral and functional brain changes in rodents, too (Tuoc et al. 2009; Umeda et al. 2010). Another of the targets, TCF7L2, is associated with Type 2 diabetes (Grant et al. 2006; Helgason et al. 2007; Scott et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The characterization of transcriptional networks (TNs) is essential for understanding complex biological phenomena such as development, disease, and evolution. In this study, we have designed and implemented a procedure that combines in silico target screens with zebrafish and mouse validation, in order to identify cis-elements and genes directly regulated by Pax6. We chose Pax6 as the paradigm because of its crucial roles in organogenesis and human disease. We identified over 600 putative Pax6 binding sites and more than 200 predicted direct target genes, conserved in evolution from zebrafish to human and to mouse. This was accomplished using hidden Markov models (HMMs) generated from experimentally validated Pax6 binding sites. A small sample of genes, expressed in the neural lineage, was chosen from the predictions for RNA in situ validation using zebrafish and mouse models. Validation of DNA binding to some predicted cis-elements was also carried out using chromatin immunoprecipitation (ChIP) and zebrafish reporter transgenic studies. The results show that this combined procedure is a highly efficient tool to investigate the architecture of TNs and constitutes a useful complementary resource to ChIP and expression data sets because of its inherent spatiotemporal independence. We have identified several novel direct targets, including some putative disease genes, among them Foxp2; these will allow further dissection of Pax6 function in development and disease.
    Full-text · Article · Jun 2011 · Genome Research
  • Source
    • "Brain imaging (magnetic resonance imaging [MRI]) performed in patients heterozygous for PAX6 mutations often reveals various malformations as well. Absence of the brain anterior or posterior commissure, absence of the pineal gland, and a present but reduced in size corpus callosum have all been reported [10-14]. These anomalies involve the brain interhemispheric fibers and can thus affect the auditory functions that depend on these fibers [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To report the clinical and genetic study of patients with autosomal dominant aniridia. We studied ten patients with aniridia from three families of Egyptian origin. All patients underwent full ophthalmologic, general and neurological examination, and blood drawing. Cerebral magnetic resonance imaging was performed in the index case of each family. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of the Paired Box gene 6 (PAX6) was performed after PCR amplification. Phenotype description, including ophthalmic and cerebral anomalies, mutation detection in PAX6 and phenotype-genotype correlation was acquired. Common features observed in the three families included absence of iris tissue, corneal pannus with different degrees of severity, and foveal hypoplasia with severely reduced visual acuity. In Families 2 and 3, additional findings, such as lens dislocation, lens opacities or polar cataract, and glaucoma, were observed. We identified two novel (c.170-174delTGGGC [p.L57fs17] and c.475delC [p.R159fs47]) and one known (c.718C>T [p.R240X]) PAX6 mutations in the affected members of the three families. Systemic and neurological examination was normal in all ten affected patients. Cerebral magnetic resonance imaging showed absence of the pineal gland in all three index patients. Severe hypoplasia of the brain anterior commissure was associated with the p.L57fs17 mutation, absence of the posterior commissure with p.R159fs47, and optic chiasma atrophy and almost complete agenesis of the corpus callosum with p.R240X. We identified two novel PAX6 mutations in families with severe aniridia. In addition to common phenotype of aniridia and despite normal neurological examination, absence of the pineal gland and interhemispheric brain anomalies were observed in all three index patients. The heterogeneity of PAX6 mutations and brain anomalies are highlighted. This report emphasizes the association between aniridia and brain anomalies with or without functional impact, such as neurodevelopment delay or auditory dysfunction.
    Full-text · Article · Oct 2009 · Molecular vision
Show more