Malattia Leventinese

Characteristically small round white spots (drusen) involving the posterior pole of the eye, including the areas of the macula and optic disc, appear in early adult life. Progression to form a mosaic pattern which Doyne (1899) aptly termed 'honeycomb' occurs thereafter. Doyne considered it to represent 'choroiditis.' However, Collins (1913) showed that the changes consisted of swelling in the inner part of Bruch membrane. Failing vision usually developed considerably later than the ophthalmologic change. Robert Walter Doyne (1857-1916) was an ophthalmologist in Oxford, England. Pearce (1967) did an extensive study of 6 kindreds living near Oxford. 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 have been reported (see references given by Pearce, 1968).Maumenee (1982) suggested that this may be fundamentally the same disorder as drusen of Bruch membrane (126700).

Hutchinson and Tay (1875) gave one of the first descriptions of the constellation of clinical findings later known as age-related macular degeneration. Three of the 10 patients they described were sisters affected with whitish spots (drusen) in the macula. Doyne (1899) reported a similar disorder in which the abnormal spots were nearly confluent, such that the macula had a 'honeycomb' appearance. Collins (1913) described histopathologic findings indicating that the abnormality in one of Doyne's patients consisted of hyaline thickenings of Bruch membrane. Vogt (1925) published the first description of the ophthalmoscopic appearance of a form of familial drusen that had been observed in patients living in the Leventine valley in the Ticino canton of southern Switzerland. The autosomal dominant inheritance was established. 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.

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.

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.

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 to DNA markers from 2p21-p16. They studied a large American kindred with 2 extensively affected branches and 3 kindreds from the Leventine. 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) reported the results of linkage studies in a large British pedigree with this disorder. They noted that Doyne honeycomb retinal dystrophy (referred to as DHRD by them) and malattia leventinese are both characterized by drusen. Malattia leventinese, which is sometimes considered to be distinct from DHRD because of differences in drusen composition and distribution, was recently mapped to chromosome 2p21-p16 by Heon et al. (1996)Gregory et al. (1996) cited reports noting that in malattia leventinese there are small discrete drusen seen 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. Large soft drusen deposits affecting the macula and peridiscal areas are seen in DHRD. 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. The pedigree selected for linkage studies by Gregory et al. (1996) were members of the DHRD pedigree originally described by Doyne (1910) and Pearce (1968)Gregory et al. (1996)established linkage of the DHRD locus to chromosome 2p by genotyping 9 markers. 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 5 families with Doyne honeycomb retinal dystrophy, Stone et al. (1999) found an arg345-to-trp (R345W) mutation in EGF-containing fibulin-like extracellular matrix protein-1 (EFEMP1;601548.0001). 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. Of the 3 families without an EFEMP1 mutation, 2 were linked to 2p16. Haplotype data in the family not linked to 2p16 suggested possible linkage to a locus at 6q14.

In a Swiss-Italian family in which 7 members in 3 generations had Doyne honeycomb retinal dystrophy, Toto et al. (2002) excluded linkage of the disorder to both the EFEMP1 and the EFEMP2 (604633) genes.

CLINICAL SYNOPSIS

Eyes :

  • Honeycomb retinal degeneration
  • Small round white retinal spots
  • Failing vision

Inheritance :

  • Autosomal dominant

Source: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?126600#TEXT