EFEMP1 – Doyne honeycomb retinal dystrophy

EFEMP1-related Doyne honeycomb retinal dystrophy (DHRD) is an autosomal dominant maculopathy characterized by early drusen formation beneath the retinal pigment epithelium and progressive loss of central vision. A hallmark is the presence of yellow-white subretinal deposits that mimic age-related macular degeneration. Functional testing often reveals decreased macular function on electroretinography.

Genetic analysis in multiple unrelated families identified a recurrent heterozygous missense variant, c.1033C>T (p.Arg345Trp), in all DHRD and Malattia Leventinese cases studied (PMID:10369267). The variant was absent in 477 control individuals and 494 age-related macular degeneration patients, confirming its specificity for DHRD. Segregation data across these kindreds support autosomal dominant inheritance.

Functional studies demonstrate that p.Arg345Trp impairs EFEMP1 secretion via disrupted disulfide bonding in epidermal growth factor-like domain 6, leading to intracellular accumulation (PMID:22031286). Proteostasis network modulation, including reduced growth temperature or translational attenuation, restores proper folding and secretion, underscoring a haploinsufficiency mechanism.

A 43-year-old man with genetically confirmed p.Arg345Trp DHRD underwent subthreshold nanopulse laser treatment, exhibiting improved visual acuity and enhanced full-field electroretinography amplitudes at 2 and 6 months post-treatment, although fundoscopic morphology remained unchanged (PMID:30626431).

Integration of robust segregation, recurrent variant identification, and concordant cellular rescue assays justify a definitive gene-disease classification. Genetic testing for EFEMP1 c.1033C>T (p.Arg345Trp) enables accurate diagnosis and informs prognosis and emerging therapeutic strategies.

Key take-home: EFEMP1 c.1033C>T (p.Arg345Trp) is a definitive biomarker for autosomal dominant Doyne honeycomb retinal dystrophy with actionable insights into proteostasis-based interventions.

References

• Nature Genetics • 1999 • A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. PMID:10369267
• Molecular biology of the cell • 2011 • Compromised mutant EFEMP1 secretion associated with macular dystrophy remedied by proteostasis network alteration. PMID:22031286
• Journal of medical case reports • 2019 • Doyne honeycomb retinal dystrophy - functional improvement following subthreshold nanopulse laser treatment: a case report. PMID:30626431

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