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Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature

  • Genetics
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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.

Purpose

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.

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Acknowledgments

The authors are indebted to the patients and their family for the participation in this study.

Compliance with ethical standards

ᅟ

Funding

AEV provided financial support in the form of “Bausteinförderung 3.2” funding by the Medical Faculty of the University of Ulm. The sponsor had no role in the design or conduct of this research.

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, University Hospital Cologne, Joseph Stelzmann Str.9, D-50931, Cologne, Germany

    A. Hedergott, J. Fricke & A. Neugebauer

  2. Institute of Human Genetics, Ulm University, 89081, Ulm, Germany

    A. E. Volk & C. Kubisch

  3. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany

    A. E. Volk & C. Kubisch

  4. Department of Paediatrics, University Hospital Cologne, 50931, Cologne, Germany

    P. Herkenrath

  5. Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany

    H. Thiele, J. Altmüller & P. Nürnberg

  6. Institute of Human Genetics, University Hospital Cologne, 50931, Cologne, Germany

    J. Altmüller

  7. University of Cologne, Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany

    P. Nürnberg

  8. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931, Cologne, Germany

    P. Nürnberg

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  1. A. Hedergott
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  4. H. Thiele
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  8. C. Kubisch
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  9. A. Neugebauer
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Corresponding author

Correspondence to A. Hedergott.

Additional information

A. Hedergott and A. E. Volk are equally contributing first authors.

C. Kubisch and A. Neugebauer are equally contributing last authors.

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Hedergott, A., Volk, A.E., Herkenrath, P. et al. Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature. Graefes Arch Clin Exp Ophthalmol 253, 2239–2246 (2015). https://doi.org/10.1007/s00417-015-3174-0

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  • DOI: https://doi.org/10.1007/s00417-015-3174-0

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