NDP – Norrie Disease

Norrie disease is a rare X-linked recessive retinal vasculopathy characterized by congenital bilateral blindness, progressive sensorineural hearing loss, and variable intellectual disability. The disorder arises from pathogenic variants in NDP, which encodes the secreted growth factor norrin that activates Wnt/β-catenin signaling through the FZD4/LRP5 receptor complex, essential for retinal vascular development and maintenance.

Inheritance and Genetic Evidence

NDP variants segregate in an X-linked recessive pattern, with hemizygous males affected and heterozygous females typically asymptomatic carriers. Over 100 male probands and at least 12 affected relatives across multiple unrelated families have been documented with segregating NDP mutations ([PMID:7993212]; [PMID:14635119]).

Variant Spectrum

Pathogenic alleles include missense changes disrupting the cysteine-knot domain, nonsense and frameshift variants causing early termination, splice-site mutations, and whole-gene deletions. A representative example is c.109C>T (p.Arg37Ter), which truncates norrin and abolishes downstream signaling ([PMID:10773814]).

Functional Evidence

Biochemical and cellular assays demonstrate that NDP loss-of-function impairs norrin-mediated Wnt/β-catenin signaling, leading to defective retinal angiogenesis. Ndp knockout mice recapitulate human ocular and auditory phenotypes, and rescue experiments confirm haploinsufficiency as the pathogenic mechanism ([PMID:22394677]).

Clinical Utility

Molecular diagnosis of NDP mutations enables definitive diagnosis, carrier testing, prenatal diagnosis, and early interventions—including prophylactic laser photocoagulation in genetically diagnosed neonates to preserve retinal structure and function ([PMID:20619898]). Genetic counseling is critical for family planning and management.

Conclusion

The NDP–Norrie disease association is classified as Definitive based on extensive genetic and functional data accrued over three decades. NDP genetic testing is essential for accurate diagnosis, prognostic assessment, and guiding emerging therapeutic strategies.

References

• Archives of ophthalmology • 1994 • Ocular findings associated with a Cys39Arg mutation in the Norrie disease gene. PMID:7993212
• Human mutation • 2003 • NDP gene mutations in 14 French families with Norrie disease. PMID:14635119
• Molecular Vision • 2010 • A novel nonsense mutation in the NDP gene in a Chinese family with Norrie disease. PMID:21179243
• Journal of AAPOS • 2000 • A novel mutation in the Norrie disease gene. PMID:10773814
• Human molecular genetics • 2012 • Norrin stimulates cell proliferation in the superficial retinal vascular plexus and is pivotal for the recruitment of mural cells. PMID:22394677
• Ophthalmology • 2010 • Laser photocoagulation at birth prevents blindness in Norrie's disease diagnosed using amniocentesis. PMID:20619898

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