title: Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature.
abstract: BACKGROUND
  Leber congenital amaurosis (LCA) is a severe retinal dystrophy, typically manifesting in the first year of life. Mutations in more than 18 genes have been reported to date. In recent studies, biallelic mutations in NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 have been found to cause LCA.
  
  
  OBJECTIVE
  To broaden the knowledge regarding the phenotype of NMNAT1-associated LCA.
  
  
  METHODS
  Clinical ophthalmologic examinations were performed in two sisters with LCA. Whole exome sequencing was performed in one of the affected girls, with subsequent segregation analysis in the affected sister and unaffected parents. The literature was reviewed for reports of NMNAT1-associated LCA.
  
  
  RESULTS
  Exome sequencing revealed the known NMNAT1 mutation c.25G>A (p.Val9Met) in a homozygous state. Segregation analysis showed the same homozygous mutation in the affected younger sister. Both parents were found to be heterozygous carriers of the mutation. The two girls both presented with severe visual impairment, nystagmus, central atrophy of the pigment epithelium, and pigment clumping in the periphery before the age of 6 months. Retinal vessels were attenuated. Both children were hyperopic. In the older sister, differential diagnosis included an inflammatory origin, but electrophysiology in her as well as her sister confirmed a diagnosis of LCA. Pallor of the optic nerve head was not present at birth but developed progressively.
  
  
  CONCLUSIONS
  We confirmed a diagnosis of NMNAT1-associated LCA in two siblings through identification of the mutation (c.25G>A [p. Val9Met]) in a homozygous state. In infants with non-detectable electroretinogram (ERG), along with severe congenital visual dysfunction or blindness and central pigment epithelium atrophy with pigment clumping resembling scarring due to chorioretinitis, LCA due to NMNAT1 mutations should be considered.
authors.affiliation: Department of Ophthalmology, University Hospital Cologne, Joseph Stelzmann Str.9, D-50931, Cologne, Germany. a.schild@gmx.de.
authors.forename: A
authors.initials: A
authors.lastname: Hedergott
authors.affiliation: Institute of Human Genetics, Ulm University, 89081, Ulm, Germany.|Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: A E
authors.initials: AE
authors.lastname: Volk
authors.affiliation: Department of Paediatrics, University Hospital Cologne, 50931, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Herkenrath
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Department of Ophthalmology, University Hospital Cologne, Joseph Stelzmann Str.9, D-50931, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Fricke
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.|Institute of Human Genetics, University Hospital Cologne, 50931, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.|University of Cologne, Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Human Genetics, Ulm University, 89081, Ulm, Germany.|Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Department of Ophthalmology, University Hospital Cologne, Joseph Stelzmann Str.9, D-50931, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Neugebauer
mesh_terms: D001483:Base Sequence; D001766:Blindness / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005074:Evoked Potentials, Visual / Q000502:physiology; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics*; D010375:Pedigree; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology
chemical_list: C484007:NMNAT1 protein, human; D009612:Nicotinamide-Nucleotide Adenylyltransferase
keywords: LCA; Macular atrophy; NMNAT1; Whole exome sequencing