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 (a father and his 4 sons), 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 this presumably autosomal dominant macular disease have been reported. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

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

References
Article Title: 

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration.

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, Leveillard 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.  There is wide variation in the retinal phenotype.  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. 

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

Primary hyperoxaluria in infants

Jellouli M, Ferjani M, Abidi K, Zarrouk C, Naija O, Abdelmoula J, Gargah T. Primary hyperoxaluria in infants. Saudi J Kidney Dis Transpl. 2016 May-Jun;27(3):526-32.

PubMed ID: 
27215245

Primary hyperoxaluria

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

PubMed ID: 
23944302

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 diameters size.  Color vision and electrophysiological testing are usually normal.

Some patients have choroidal neovascularization that may be responsive to anti-vascular endothelial growth factor treatment. 

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.  One locus for the disorder, designated MCDR1 and containing a DNase 1 hypersensitivity site, has been mapped to 6q14-q16.2 and adversely impacts the retinal transcription factor gene PRDM13.  Multiple variants in this area have been identified.  However, other forms including MCDR2 (608051) resulting from mutations in PROM1 (4p15) and MCDR3 (608850) (linked to a locus at 5p13-p15) have been reported. 

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.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

For patients 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
Article Title: 
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