Alternative titles; symbols
SNOMEDCT: 193411004; ORPHA: 75376; DO: 0060745;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p16.1 | Doyne honeycomb degeneration of retina | 126600 | Autosomal dominant | 3 | EFEMP1 | 601548 |
A number sign (#) is used with this entry because of evidence that Doyne honeycomb retinal dystrophy (DHRD) is caused by heterozygous mutation in the EFEMP1 gene (601548) on chromosome 2p16.
Doyne honeycomb retinal dystrophy (DHRD), also known as malattia leventinese (MLVT) and autosomal dominant radial drusen, is a progressive disorder characterized by the accumulation of macular and peripapillary yellow-white deposits, termed 'drusen,' beneath the retinal pigment epithelium in the Bruch membrane. With age, drusen increase in size and number, often forming a honeycomb-like pattern. Massive drusen, geographic retinal atrophy, and macular hyperpigmentation eventually cause visual symptoms in the fifth or sixth decades of life, including decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma. Complications such as secondary choroidal neovascularization and hemorrhage can result in rapid progression (summary by Sheyanth et al., 2021).
Hulleman et al. (2011) noted that both DHRD and MLVT present with clinical and pathologic symptoms similar to age-related macular degeneration (see ARMD1, 603075), including soft drusen accumulation, loss of basolateral ruffling of the RPE, RPE vacuolization, and atrophy, with eventual neovascularization in an accelerated time frame, usually in the fourth decade of life.
Descriptions of Doyne honeycomb retinal dystrophy (DHRD) and malattia leventinese (MLVT) were independently reported (Doyne, 1899; Vogt, 1925) and initially considered to be separate entities. However, Waardenburg (1948) concluded there was little reason to make a distinction between DHRD and MLVT, and Forni and Babel (1962) found that the histopathologic features of leventinese disease were indistinguishable from those of Doyne honeycomb choroiditis. Later, a single recurrent missense mutation in the EFEMP1 gene (R345W; 601548.0001) was identified as the cause of the disorder in all such patients, whether designated DRHD, MLVT, or autosomal dominant radial drusen (Stone et al., 1999; Matsumoto and Traboulsi, 2001).
The ophthalmologist Robert Walter Doyne (1899) (1857-1916) of Oxford, England reported a disorder in which abnormal whitish spots (drusen) appeared in early adulthood in the posterior pole, involving the macula and optic disc, and progressed to being nearly confluent, such that the macula had a 'honeycomb' appearance. This description was similar to that reported by Hutchinson and Tay (1875), who gave one of the first descriptions of the constellation of clinical findings later known as age-related macular degeneration (see ARMD1, 603075). Doyne (1899) considered the abnormality to represent 'choroiditis.' However, Collins (1913) described histopathologic findings in 1 of Doyne's patients indicating that the abnormality consisted of hyaline thickening in the inner part of the Bruch membrane. Failing vision usually developed considerably later than the ophthalmologic change.
Vogt (1925) published the first description of an autosomal dominant form of familial drusen that had been observed in patients living in the Leventine valley in the Ticino canton of southern Switzerland. Waardenburg (1948) concluded there was little reason to make a distinction between 'malattia leventinese' and the condition described by Doyne (1899). Forni and Babel (1962) found that the histopathologic features of leventinese disease are indistinguishable from those of Doyne honeycomb choroiditis.
Pearce (1967) did an extensive study of 6 kindreds living near Oxford, England, of which some and possibly all may have been descendants from a common ancestor. Dominant inheritance with complete manifestation of the trait in persons surviving beyond early adult life was found. Families living elsewhere than England had also been reported (see references given by Pearce, 1968).
Piguet et al. (1995) pointed out that the drusen in families with malattia leventinese are frequently distributed in a radial pattern. Although it is unknown what fraction of late-onset macular degeneration is caused by the gene or genes involved in malattia leventinese or Doyne disease, the clinical and histopathologic features suggest the diagnosis of age-related macular dystrophy.
Gregory et al. (1996) noted that Doyne honeycomb retinal dystrophy (DHRD) and malattia leventinese are both characterized by drusen. They cited reports describing the lesions of malattia leventinese as small discrete drusen which radiate into the peripheral retina; later, confluent soft drusen develop at the macula. Histopathologic studies established that the radial deposits are continuous with or internal to the basement membrane of the retinal pigment epithelium. In DRHD, large soft drusen deposits affecting the macula and peridiscal areas are seen. Histologically these deposits are external to the basement membrane of the retinal pigment epithelium and occupy the entire thickness of the Bruch membrane. Radial drusen extending into the periphery have not been found in DHRD.
Zech et al. (1999) provided a 25-year follow-up of a woman diagnosed with malattia leventinese at the age of 30 years. At that time, her vision was 20/20. Eight years later, subfoveal neovascularization led to an irreversible decrease in visual acuity in her right eye, down to 20/1,000. Twenty-three years later, a dense right vitreous hemorrhage led to a further decrease in visual acuity. At that time, the left eye had a visual acuity of 20/30, and fundus examination revealed a macula identical to that of the right eye, without complication.
Fu et al. (2007) studied a consanguineous Indian family in which a mother and father and their 2 sons had macular degeneration. The 2 sons exhibited significantly more severe phenotypes than either parent, particularly the older son whose retina demonstrated drusen extending beyond the posterior pole, with associated retinal degeneration.
Zhang et al. (2018) reported a Chinese family in which a mother and 2 children had DHRD and the recurrent R345W mutation in the EFEMP1 gene. The proband was a 28-year-old woman with a 10-year history of blurred vision, in whom the best corrected visual acuity (BCVA) was 20/20 and 20/15. Funduscopy showed diffuse drusen-like yellow-white speckling of the posterior fundus, with varying degrees of chorioretinal atrophy around a normal-appearing optic disc. Optical coherence tomography (OCT) showed extensive hyperreflective thickening beneath the RPE, and fundus fluorescein angiography (FFA)/indocyanine green angiography (ICGA) revealed a 'honeycomb' appearance. Visual field testing showed bilateral temporal defects, whereas electrophysiologic results, including electroretinography, electrooculography, and visual evoked potentials, were normal. The proband's 22-year-old brother had a BCVA of 20/20, and also showed diffuse pinpoint yellow-white deposits throughout the macular and peripapillary area with honeycomb-like pigmentary changes around the optic disc. OCT showed hyperreflective thickening beneath the RPE, with wavy uplift. Their 54-year-old mother reported poor visual acuity for at least 20 years, especially at night, and had a BCVA of 20/200 on the left and finger-counting at 10 cm on the right. Bilateral corneal opacities prevented clear observation of the fundus. Corneal scan by OCT showed granular cloudiness with corneal endothelium detachment peripherally. Doppler ultrasonography of the globes showed bilateral thickening of the posterior wall. Their father had no history of ocular problems, and declined examination.
Vaclavik et al. (2020) reported a Swiss woman with the R345W mutation in EFEMP1 who presented at age 26 years with reading difficulty. Visual acuity was 20/25 bilaterally, and fundus examination showed multiple drusen deposits at the posterior pole and nasal to the optic disc in both eyes. The drusen were hyperautofluorescent, and OCT revealed diffuse hyperreflective material under the RPE, corresponding with the large and small drusen. Follow-up OCT 6 years later showed resorption of some large drusen, temporal to the fovea.
Sheyanth et al. (2021) reported a 57-year-old Danish woman with DHRD and the R345W mutation in the EFEMP1 gene. She presented at age 47 with vision loss and distorted vision. Metamorphopsia of the left eye was detected using an Amsler grid. BCVA was 20/25 and 20/40, and funduscopy showed bilateral radially oriented massive hard partially coalescent drusen in the macular region and nasal to the disc, as well as macular hyperpigmentation. OCT revealed foveal drusen bilaterally and retinal atrophy of the left eye. No secondary choroidal neovascularization was seen on FFA/ICGA. At follow-up 10 years later, BCVA was 20/100 and 20/30, and increased atrophy with subretinal fluid was observed. FFA/ICGA showed secondary choroidal neovascularization bilaterally. The authors stated that this was the first Scandinavian case of genetically verified DHRD.
The transmission pattern of DHRD in the families reported by Doyne (1899), Vogt (1925), and Stone et al. (1999) was consistent with autosomal dominant inheritance.
Both forms of dominant drusen (malattia leventinese and Doyne retinal degeneration) are characterized by slowly progressive loss of central visual acuity. However, the clinical course may change to one of very rapid progression and severe visual loss if choroidal neovascularization invades the subretinal space. Dantas et al. (2002) found that photodynamic therapy using verteporfin closed the neovascular membrane and prevented severe visual loss. They proposed that photodynamic therapy be considered as a possible treatment in patients with malattia leventinese who develop classic choroidal neovascularization.
Nicolo et al. (2003) assayed surgically-excised human choroidal neovascular membranes for the fibronectin isoform containing extradomain B, a marker-protein for angiogenesis, to determine whether it could be used as a therapeutic target for specific antibody-photosensitizer immunoconjugates. They found that extradomain B was abundantly expressed in choroidal neovascular membranes and were hopeful it could be used to enhance the selectivity of photodynamic therapy for newly developed vessels.
Heon et al. (1996) demonstrated linkage of the autosomal dominant radial drusen (malattia leventinese) to DNA markers from 2p21-p16. They studied a large American kindred with 2 extensively affected branches and 3 kindreds from the Leventine valley. The maximum 2-point lod score observed for all 4 families combined was 10.5 and was obtained with the marker D2S378. Multipoint analysis yielded a maximum lod score of 12 centered on this same marker. The disease interval defined by observed recombinants was 14 cM. Heon et al. (1996) pointed out that beta-fodrin (182790) maps to 2p21 and is a promising candidate for the site of the mutation in this disorder.
Gregory et al. (1996) genotyped 9 markers in members of the DHRD pedigree originally described by Doyne (1910) and Pearce (1968) and established linkage to chromosome 2p. Haplotypes across the linked region were constructed for all family members and analysis of recombinants localized the DHRD gene to a 5-cM interval between D2S2316 and D2S378. These results established that DHRD maps to chromosome 2p16. Gregory et al. (1996) noted that the 14-kb region to which the malattia leventinese locus was mapped by Heon et al. (1996) encompasses the DHRD locus. They also stated that macular drusen are an important feature of age-related macular degeneration (ARMD; see 153800) and that the chromosome 2p21-p16 region should be considered as a candidate region for disease susceptibility in ARMD,
Kermani et al. (1999) used sequence tagged sites (STSs), expressed sequence tags (ESTs), and polymorphic markers within the DHRD region to identify 18 YACs encompassing the DHRD locus and spanning approximately 3 Mb. The YAC contig was constructed by STS content mapping of these YACs and incorporated 13 STSs, including 4 genes and 6 polymorphic marker loci. They also reported the genetic mapping of 2 families with a dominant drusen phenotype to the DHRD locus, and genetic refinement of the disease locus to a critical interval flanked by microsatellite marker loci D2S2352 and D2S2251, a distance of approximately 700 kb. These studies excluded a number of candidate genes and provided a resource for construction of a transcription map of the region, as a prerequisite for identification of the DHRD gene and genes for other diseases mapping in the region, such as malattia leventinese and Carney complex (160980).
Taymans et al. (1999) described radiation hybrid mapping of the region where both Carney complex and Doyne honeycomb retinal dystrophy map.
In affected members from 5 families diagnosed with malattia leventinese (MLVT), Stone et al. (1999) found an arg345-to-trp (R345W; 601548.0001) mutation in the EFEMP1 gene. The authors then screened 162 affected individuals from 37 families diagnosed with MLVT or Doyne honeycomb retinal dystrophy (DHRD) and found that all but 1 harbored the R345W-associated SSCP shift in exon 10 of the EFEMP1 gene; reexamination of retinal photographs from the discordant individual showed a phenotype more typical of common age-related macular degeneration (ARMD). The SSCP shift was not detected in 494 unrelated patients with ARMD or in 477 controls, and sequence analysis of 1 affected individual from each of the 37 families confirmed that all carried the R345W mutation. In addition, the authors investigated samples from 2 nuclear families, 1 from Northern Ireland and 1 from England, with genealogic evidence for a relationship with the original family reported by Doyne (1899), and found that affected individuals from both families harbored the R345W variation. Noting the absence of de novo R345W mutations in these 39 families, and the complete sharing of alleles of 4 intragenic EFEMP1 polymorphisms among the families, Stone et al. (1999) suggested that the R345W mutation occurred only once, in a common ancestor of every affected patient in their study.
Matsumoto and Traboulsi (2001) reported a North American family with dominant radial drusen due to the R345W mutation in the EFEMP1 gene.
Tarttelin et al. (2001) identified the R345W mutation in the EFEMP1 gene (601548.0001) in 7 of 10 families with Doyne honeycomb retinal dystrophy and 1 of 17 sporadic patients. No other mutations were identified.
Fu et al. (2007) analyzed the EFEMP1 gene in a branch of 1 of the DHRD families originally described by Stone et al. (1999) and in a consanguineous Indian family with early-onset macular degeneration, and identified the R345W mutation in affected members of both families. The sons of the Indian family, who were more severely affected than their parents, were found to be homozygous for the mutation. The haplotype of the first family was identical to all previously reported haplotypes associated with the R345W mutation, whereas the disease haplotype in the Indian family was distinctly different, suggesting that the mutation arose independently.
In a Chinese family in which a sister and brother and their mother had DHRD/MLVT, Zhang et al. (2018) sequenced the EFEMP1 gene and identified heterozygosity for the recurrent R345W mutation. The authors stated that there were phenotypic differences in the affected sibs compared to previously reported cases, including well-preserved visual acuity; clustered drusen reaching the equator of the fundus with no choroidal neovascularization in the macula, in contrast to previous patients with drusen localized to the macular region; and large dark gray areas representing chorioretinal atrophy in the posterior pole, which was not mentioned in earlier reports.
In a 32-year-old Swiss woman with MLVT, Vaclavik et al. (2020) identified heterozygosity for a de novo occurrence of the recurrent R345W mutation. The authors concluded that R345W represents a hot spot mutation rather than a founder mutation.
In a 57-year-old Danish woman with DHRD, Sheyanth et al. (2021) sequenced 7 genes associated with flecked retina and identified heterozygosity for the R345W mutation in EFEMP1. No pathogenic variants were found in the remaining genes. Analysis of microsatellite markers and intragenic SNPs indicated a different haplotype compared to the original study by Stone et al. (1999), suggesting that the mutation arose independently.
Exclusion Studies
Tarttelin et al. (2001) reported 3 families with DHRD and no mutation in the EFEMP1 gene. Two of the families showed linkage to chromosome 2p16, and haplotype analysis in the remaining family suggested possible linkage to a locus at 6q14.
Toto et al. (2002) sequenced exon 10 of the EFEMP1 gene in 5 affected individuals over 3 generations of a family of Swiss origin with MLVT. Although this report stated that the R345W mutation was not found in any of these individuals, in an erratum the authors stated that analysis of different samples led to the identification of the R345W mutation in 2 individuals (I.1 and II.2). These results were in agreement with linkage analysis that showed transmission of chromosome 2 markers from I.1 to II.2 and to none of the other family members. One patient (II.6) shared the same phenotypic features as I.1 and II.2 but did not carry the R345W mutation. Fundus examination revealed the presence of drusen in the 2 remaining patients. The authors concluded that their observations still support the possible genetic heterogeneity of MLVT.
Marmorstein et al. (2002) showed that wildtype EFEMP1 is a secreted protein, whereas mutant EFEMP1 is misfolded, secreted inefficiently, and retained within cells. In normal eyes, EFEMP1 is not present at the site of drusen formation. However, in MLVT eyes, EFEMP1 accumulates within the RPE cells and between the RPE and drusen, but does not appear to be a major component of drusen. Furthermore, in ARMD eyes, EFEMP1 is found to accumulate beneath the RPE immediately overlying drusen, but not in the region where there is no apparent retinal pathology. Marmorstein et al. (2002) interpreted these data as evidence that folding and aberrant accumulation of EFEMP1 may cause drusen formation and cellular degeneration and play an important role in the etiology of both MLVT and ARMD.
Fu et al. (2007) generated Efemp1-R345W knockin mice and observed the development of deposits of material between the Bruch membrane and the retinal pigment epithelium (RPE) that resembled basal deposits in patients with age-related macular degeneration. Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice. Fu et al. (2007) concluded that the R345W mutation in EFEMP1 is pathogenic, and suggested that alterations in the extracellular matrix may stimulate complement activation and represent a connection between these 2 etiologic factors in macular degeneration.
Marmorstein et al. (2007) generated knockin mice carrying the R345W mutation and found that small isolated sub-RPE deposits developed as early as 4 months of age in both R345W heterozygous and homozygous mice. Over time, these deposits increased in size and number, eventually becoming continuous sheets. In older mice, membranous debris was observed within the deposits and within the Bruch membrane, and was accompanied by general RPE and choroidal abnormalities including degeneration, vacuolation, loss or disruption of the RPE basal infoldings, choroidal atrophy, and focal thickening of and invasion of cellular processes into the Bruch membrane. Fibulin-3 (Efemp1) was found to accumulate in the sub-RPE deposits.
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