choroidal neovascularization

Macular Degeneration, Early-Onset

Clinical Characteristics

Ocular Features

Onset of distorted vision has been reported as early as the fourth decade of life with clinical evidence of pigmentary changes in the macula noted in the fifth decade.  Large areas of central RPE atrophy can be seen.  In the single family reported, there is considerable clinical heterogeneity in the RPE changes in the fundus.  Acuity is variable depending upon the stage of disease.

Systemic Features

No systemic disease has been reported.

Genetics

Heterozygous mutations in the FBN2 gene, encoding Fibrillin 2, a component protein of the extracellular matrix that segregates with the macular disease. 

Treatment Options

No treatment beyond anti-VEGF therapy is available.  Low vision devices may be helpful.

References

Ratnapriya R, Zhan X, Fariss RN, Branham KE, Zipprer D, Chakarova CF, Sergeev YV, Campos MM, Othman M, Friedman JS, Maminishkis A, Waseem NH, Brooks M, Rajasimha HK, Edwards AO, Lotery A, Klein BE, Truitt BJ, Li B, Schaumberg DA, Morgan DJ, Morrison MA, Souied E, Tsironi EE, Grassmann F, Fishman GA, Silvestri G, Scholl HP, Kim IK, Ramke J, Tuo J, Merriam JE, Merriam JC, Park KH, Olson LM, Farrer LA, Johnson MP, Peachey NS, Lathrop M, Baron RV, Igo RP Jr, Klein R, Hagstrom SA, Kamatani Y, Martin TM, Jiang Y, Conley Y, Sahel JA, Zack DJ, Chan CC, Pericak-Vance MA, Jacobson SG, Gorin MB, Klein ML, Allikmets R, Iyengar SK, Weber BH, Haines JL, Léveillard T, Deangelis MM, Stambolian D, Weeks DE, Bhattacharya SS, Chew EY, Heckenlively JR, Abecasis GR, Swaroop A. Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration. Hum Mol Genet. 2014 Nov 1;23(21):5827-37.

PubMed ID: 
24899048

Hyperoxaluria, Primary, Type I

Clinical Characteristics

Ocular Features

About 30% of patients with type I develop retinopathy and about half of those have a diffuse optic atrophy.  Oxalate crystal deposition can cause a ‘fleck retina’ picture sometimes described as a crystalline retinopathy.  Retinal toxicity leads to early and progressive vision loss.  The RPE may respond with hyperpigmentation in the form of 'ringlets' in the posterior pole.  Retinal fibrosis has been described.  Some patients develop choroidal neovascularization.

Evaluation using EDI-OCT shows progressive deposition of oxalate crystals throughout the retina, pigment epiithelium, and choroid.

Systemic Features

The onset of this disease can occur any time from infancy to 25 years of age.  Failure to thrive can be a presenting sign in infants.  Most patients have glycolic aciduria and hyperoxaluria as the result of failure to transaminate glyoxylate to form glycine.  The result is deposition of insoluble oxalate crystals in various body tissues with nephrolithiasis and nephrocalcinosis often early signs.  Neurologic, cardiac, vascular, and kidney disease is often the result although oxalate crystals can be found throughout the body.  Arteriole occlusive disease may lead to gangrene, Raynaud phenomena, acrocyanosis and intermittent claudication.  Renal failure is common. 

Genetics

Hyperoxaluria type I is an autosomal recessive disorder resulting from a mutation in the alanine-glyoxylate aminotransferase gene (AGXT) located at 2q36-q37.  Failure of this liver peroxisomal enzyme to transaminate glyoxylate results in oxidation of this molecule to form oxalate.

Hyperoxaluria type II (260000) is caused by mutations in the GRHPR gene (9cen) and type III (613616) by mutations in DHDPSL (HOGA1) (10q24.2).  Urolithiasis is the only clinical feature in these types. 

Treatment Options

Some patients benefit from oral pyridoxine (B6) treatment in type I hyperoxaluria.  Renal transplantation by itself is only temporarily helpful since the enzymatic defect remains and the donor tissue becomes damaged as well.  Combined renal-liver transplantation should be considered instead because it corrects the primary metabolic error and can even reverse the accumulation of oxalate crystals. 

References

Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med. 2013 Aug 15;369(7):649-58. Review.

PubMed ID: 
23944302

Roth BM, Yuan A, Ehlers JP. Retinal and Choroidal Findings in Oxalate Retinopathy Using EDI-OCT. Ophthalmic Surg Lasers Imaging. 2012 Nov 1;43(6):S142-4. doi: 10.3928/15428877-20121001-05.

PubMed ID: 
23357321

Beck BB, Hoyer-Kuhn H, Göbel H, Habbig S, Hoppe B. Hyperoxaluria and systemic oxalosis: an update on current therapy and future directions. Expert Opin Investig Drugs. 2012 Nov 21. [Epub ahead of print].

PubMed ID: 
23167815

Theodossiadis PG, Friberg TR, Panagiotidis DN, Gogas PS, Pantelia EM, Moschos MN. Choroidal neovascularization in primary hyperoxaluria. Am J Ophthalmol. 2002 Jul;134(1):134-7.

PubMed ID: 
12095827

Cochat P, Koch Nogueira PC, Mahmoud MA, Jamieson NV, Scheinman JI, Rolland MO. Primary hyperoxaluria in infants: medical, ethical, and economic issues. J Pediatr. 1999 Dec;135(6):746-50.

PubMed ID: 
10586179

Small KW, Letson R, Scheinman J. Ocular findings in primary hyperoxaluria. Arch Ophthalmol. 1990 Jan;108(1):89-93.

PubMed ID: 
2297338

Macular Dystrophy, North Carolina

Clinical Characteristics

Ocular Features

North Carolina macular dystrophy is characterized by central macular defects that are present at birth but rarely progress. The fundus findings are highly variable and are usually more dramatic than expected from the visual acuity, which ranges from 20/40 to 20/200, with an average around 20/50. The clinical findings have been classified into different grades: In Grade I, fine drusen-like lesions at the level of the retinal pigmented epithelium are found in the central macular area. Grade II exhibits central confluent drusen with or without pigmentary changes, retinal pigment epithelium atrophy, disciform scar formation or neovascularization. Grade III is characterized by a well-delineated chorioretinal degeneration with hyperpigmentation at the border of the lesion. A central crater-like lesion that affects all retinal layers, as well as the deep choroidal tissue, is a typical finding. It is surrounded by an elevated ridge, which is 3-4 disc diameter is diameter. Color vision and electrophysiological testing are usually normal.

Although first described in a 4 generation North Carolina family, it has since been found in a variety of ethnic groups and geographic locations.

Systemic Features

No general systemic manifestations are associated with North Carolina macular dystrophy.

Genetics

North Carolina macular dystrophy is an autosomal dominant disorder with high penetration. The genetic locus for the disorder is designated MCDR1, for macular degeneration locus 1, and has been mapped to 6q14-q16.2. Candidate genes in this region have been screened for disease causing mutations, but none have been identified so far. The disorder was initially described in a family of Irish descent in North Carolina, and affected individuals have been identified in European, Asian and South American families as well.

Treatment Options

For patients with Grade II disease with choroidal neovascularization, standard treatment for neovascularization may be used. Low vision aids can be useful for other forms of the disorder with decreased visual acuity.

References

Khurana RN, Sun X, Pearson E, Yang Z, Harmon J, Goldberg MF, Zhang K. A reappraisal of the clinical spectrum of North Carolina macular dystrophy. Ophthalmology. 2009 Oct;116(10):1976-83.

PubMed ID: 
19616854

Yang Z, Tong Z, Chorich LJ, Pearson E, Yang X, Moore A, Hunt DM, Zhang K. Clinical characterization and genetic mapping of North Carolina macular dystrophy. Vision Res. 2008 Feb;48(3):470-7.

PubMed ID: 
17976682

Small KW. North Carolina macular dystrophy, revisited. Ophthalmology. 1989 Dec;96(12):1747-54.

PubMed ID: 
2622620

Lefler, W. H., Wadsworth, J. A. C., Sidbury, J. B., Jr. Hereditary macular dystrophy and amino-aciduria. Am. J. Ophthal. 71 (suppl.): 224-230, 1971.

PubMed ID: 
5100467