The importance of biochemical and genetic findings in the diagnosis of atypical Norrie disease

Ana Rodríguez-Muñoz; Gema García-García; Francisco Menor; José M. Millán; Miguel Tomás-Vila; Teresa Jaijo

doi:10.1515/cclm-2017-0226

Article

The importance of biochemical and genetic findings in the diagnosis of atypical Norrie disease

Ana Rodríguez-Muñoz , Gema García-García , Francisco Menor , José M. Millán , Miguel Tomás-Vila and Teresa Jaijo

Published/Copyright: July 25, 2017

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information

From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 56 Issue 2

Abstract

Background:

Norrie disease (ND) is a rare X-linked disorder characterized by bilateral congenital blindness. ND is caused by a mutation in the Norrie disease pseudoglioma (NDP) gene, which encodes a 133-amino acid protein called norrin. Intragenic deletions including NDP and adjacent genes have been identified in ND patients with a more severe neurologic phenotype. We report the biochemical, molecular, clinical and radiological features of two unrelated affected males with a deletion including NDP and MAO genes.

Methods:

Biochemical and genetic analyses were performed to understand the atypical phenotype and radiological findings. Biogenic amines in cerebrospinal fluid (CSF) were measured by high-performance liquid chromatography. The coding exons of NDP gene were amplified by polymerase chain reaction. Multiplex ligation-dependent probe amplification and chromosomal microarray were carried out on both affected males. Computed tomography and magnetic resonance imaging were performed on the two patients.

Results:

In one patient, the serotonin and catecholamine metabolite levels in CSF were virtually undetectable. In both patients, genetic studies revealed microdeletions in the Xp11.3 region, involving the NDP, MAOA and MAOB genes. Radiological examination demonstrated brain and cerebellar atrophy.

Conclusions:

We suggest that alterations caused by MAO deficit may remain during the first years of life. Clinical phenotype, biochemical findings and neuroimaging can guide the genetic study in patients with atypical ND and help us to a better understanding of this disease.

Keywords: brain and cerebellar atrophy; contiguous gene syndrome; monoamine oxidase; Norrie disease; psychomotor regression

Acknowledgments

We are thankful to our colleague Enrique Rodríguez Borja for his thoughtful comments on the manuscript.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Instituto de Investigación Sanitaria La Fe, Post-resident Research Program.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Suárez-Merino B, Bye J, McDowall J, Ross M, Craig IW. Sequence analysis and transcript identification within 1.5 MB of DNA deleted together with the NDP and MAO genes in atypical Norrie disease patients presenting with a profound phenotype. Hum Mutat 2001;17:523.10.1002/humu.1140Search in Google Scholar PubMed

2. Wu W-C, Drenser K, Trese M, Capone A, Dailey W. Retinal phenotype-genotype correlation of pediatric patients expressing mutations in the Norrie disease gene. Arch Ophthalmol 2007;125:225–30.10.1001/archopht.125.2.225Search in Google Scholar PubMed

3. Zhang XY, Jiang WY, Chen LM, Chen SQ. A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family. Int J Ophthalmol 2013;6:739–43.Search in Google Scholar

4. Berger W, Meindl A, van de Pol TJ, Cremers FP, Ropers HH, Döerner C, et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet 1992;2:84.10.1038/ng0692-199Search in Google Scholar PubMed

5. Chen ZY, Hendriks RW, Jobling MA, Powell JF, Breakefield XO, Sims KB, et al. Isolation and characterization of a candidate gene for Norrie disease. Nat Genet 1992;1:204–8.10.1038/ng0692-204Search in Google Scholar PubMed

6. Riveiro-Alvarez R, Trujillo-Tiebas MJ, Gimenez-Pardo A, Garcia-Hoyos M, Cantalapiedra D, Lorda-Sanchez I, et al. Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR. Mol Vis 2005;11:705–12.Search in Google Scholar

7. Zhou Y, Wang Y, Tischfield M, Williams J, Smallwood PM, Rattner A, et al. Canonical Wnt signaling components in vascular development and barrier formation. J Clin Invest 2014;124:3825–46.10.1172/JCI76431Search in Google Scholar PubMed PubMed Central

8. Musada GR, Jalali S, Hussain A, Chururu AR, Gaddam PR, Chakrabarti S, et al. Mutation spectrum of the Norrie disease pseudoglioma (NDP) gene in Indian patients with FEVR. Mol Vis 2016;22:491–502.Search in Google Scholar

9. Dickinson JL, Sale MM, Passmore A, Fitzgerald LM, Wheatley CM, Burdon KP, et al. Mutations in the NDP gene: Contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clin Exp Ophthalmol 2006;34:682–8.10.1111/j.1442-9071.2006.01314.xSearch in Google Scholar PubMed

10. Payabvash S, Anderson JS, Nascene DR. Bilateral persistent fetal vasculature due to a mutation in the Norrie disease protein gene. Neuroradiol J 2015;28:623–7.10.1177/1971400915609350Search in Google Scholar PubMed PubMed Central

11. Dhingra S. Advanced bilateral persistent fetal vasculature associated with a novel mutation in the Norrie gene. Br J Ophthalmol 2006;90:1324–5.10.1136/bjo.2005.088625Search in Google Scholar PubMed PubMed Central

12. Hiraoka M, Berinstein DM, Trese MT, Shastry BS. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet 2001;46:178–81.10.1007/s100380170085Search in Google Scholar PubMed

13. Black GC, Perveen R, Bonshek R, Cahill M, Clayton-Smith J, Lloyd IC, et al. Coats’ disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet 1999;8:2031–5.10.1093/hmg/8.11.2031Search in Google Scholar PubMed

14. Lev D, Weigl Y, Hasan M, Gak E, Davidovich M, Vinkler C, et al. A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms. Am J Med Genet Part A 2007;143A:921–4.10.1002/ajmg.a.31531Search in Google Scholar

15. Collins FA, Murphy DL, Reiss AL, Sims KB, Lewis JG, Freund L, et al. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes. Am J Med Genet 1992;42:127–34.10.1002/ajmg.1320420126Search in Google Scholar

16. Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev 2008;60:1527–33.10.1016/j.addr.2008.06.002Search in Google Scholar

17. Saito M, Yamagata T, Matsumoto A, Shiba Y, Nagashima M, Taniguchi S, et al. MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus. Brain Dev 2014;36:64–9.10.1016/j.braindev.2013.01.004Search in Google Scholar

18. Staropoli JF, Xin W, Sims KB. Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.4. J Med Genet 2010;47:786–90.10.1136/jmg.2010.079301Search in Google Scholar

19. Whibley A, Urquhart J, Dore J, Willatt L, Parkin G, Gaunt L, et al. Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements. Eur J Hum Genet 2010;18:1095–9.10.1038/ejhg.2010.41Search in Google Scholar

20. Yamada K, Limprasert P, Ratanasukon M, Tengtrisorn S, Yingchareonpukdee J, Vasiknanonte P, et al. Two Thai families with Norrie disease (ND): association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier. Am J Med Genet 2001;100:52–5.10.1002/1096-8628(20010415)100:1<52::AID-AJMG1214>3.0.CO;2-BSearch in Google Scholar

21. Zaremba J, Feil S, Juszko J, Myga W, van Duijnhoven G, Berger W. Intrafamilial variability of the ocular phenotype in a Polish family with a missense mutation (A63D) in the Norrie disease gene. Ophthalmic Genet 1998;19:157–64.10.1076/opge.19.3.157.2184Search in Google Scholar

Received: 2017-03-14

Accepted: 2017-06-25

Published Online: 2017-07-25

Published in Print: 2018-01-26

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/cclm-2017-0226

Keywords for this article

brain and cerebellar atrophy; contiguous gene syndrome; monoamine oxidase; Norrie disease; psychomotor regression