title: Ophthalmological phenotype associated with homozygous null mutation in the NEUROD1 gene.
abstract: OBJECTIVE
  NEUROD1 is a tissue-specific basic helix loop helix (bHLH) protein involved in the development and maintenance of the endocrine pancreas and neuronal elements. Loss of NEUROD1 causes ataxia, cerebellar hypoplasia, sensorineural deafness, and severe retinal dystrophy in mice. Heterozygous loss-of-function mutations in NEUROD1 have previously been described as a cause of maturity-onset diabetes of the young (MODY) and late-onset diabetes. To date, homozygous loss-of-function NEUROD1 mutations have only been detected in two patients. Both mutations caused permanent neonatal diabetes and severe neurologic defects, including visual impairment. However, a detailed ophthalmological phenotype of this novel syndrome has not yet been reported. Our aim was to characterize the ophthalmological phenotype associated with the previously reported homozygous c.427_428CT mutation in the NEUROD1 gene.
  
  
  METHODS
  The female patient was investigated on multiple occasions between 2009 (age 14) and 2014 (age 19), including visual acuity testing, automated perimetry, funduscopy, anterior-segment imaging, optical coherence tomography of the posterior pole, standard full-field electroretinography, and fundus-autofluorescence imaging.
  
  
  RESULTS
  The patient had nyctalopia, blurry vision, and visual field constriction from early childhood. Her best corrected visual acuity ranged between 20/25 and 15/25 during the investigation period. Perimetry showed concentric constriction of the visual field, sparing only the central 30 degrees in both eyes. The anterior segment did not show any morphological changes. Optical coherence tomography revealed total absence of the photoreceptor layer of the retina outside the fovea, where a discoid remnant of cone photoreceptors could be detected. Neither setting of the standard full-field electroretinography could detect any electrical response from the retina. Color fundus photos presented peripheral chorioretinal atrophy and central RPE mottling. A hyperreflective parafoveal ring was detected on fundus autofluorescent photos, a characteristic sign of hereditary retinal dystrophies.
  
  
  CONCLUSIONS
  To the best of our knowledge, this is the first report on the ophthalmological phenotype associating with a homozygous NEUROD1 null mutation in humans. Our results indicate that the loss of NEUROD1 has similar functional and anatomic consequences in the human retina as those described in mice. The present description can help the diagnosis of future cases and provide clues on the rate of disease progression.
authors: Department of Ophthalmology, University of Debrecen, Clinical Center, Debrecen, Hungary.
authors: Orsolya
authors: O
authors: Orosz
authors: Department of Ophthalmology, Jósa András Hospital, Nyíregyháza, Hungary.
authors: Miklós
authors: M
authors: Czeglédi
authors: Department of Pediatrics, Jósa András Hospital, Nyíregyháza, Hungary.
authors: Irén
authors: I
authors: Kántor
authors: Division of Clinical Genetics, Department of Laboratory Medicine, University of Debrecen, Clinical Center, Debrecen, Hungary.
authors: István
authors: I
authors: Balogh
authors: Department of Ophthalmology, University of Debrecen, Clinical Center, Debrecen, Hungary.
authors: Attila
authors: A
authors: Vajas
authors: Department of Ophthalmology, University of Debrecen, Clinical Center, Debrecen, Hungary.
authors: Lili
authors: L
authors: Takács
authors: Department of Ophthalmology, University of Debrecen, Clinical Center, Debrecen, Hungary.
authors: András
authors: A
authors: Berta
authors: Department of Ophthalmology, University of Debrecen, Clinical Center, Debrecen, Hungary.
authors: Gergely
authors: G
authors: Losonczy
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics*; D004596:Electroretinography; D005260:Female; D005584:Fovea Centralis / Q000378:metabolism / Q000473:pathology; D005654:Fundus Oculi; D006720:Homozygote; D006801:Humans; D009154:Mutation; D009755:Night Blindness / Q000235:genetics* / Q000473:pathology; D009887:Ophthalmoscopy; D010641:Phenotype; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D014794:Visual Fields; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C093970:NEUROD1 protein, human