PRPH2

Macular Dystrophy, Vitelliform 3

Clinical Characteristics
Ocular Features: 

Patients generally become symptomatic (reduced vision and metamorphopsia) in the fourth and fifth decades.  Vision loss is mild as in vitelliform 1 disease and only slowly progressive in most patients.  One or sometimes more small, oval, and slightly elevated yellow lesions resembling an egg yolk may be seen in the fovea along with paracentral drusen and mild RPE changes.  The fundus changes can appear any time in adult life but little is known about their nature history.  The EOG light/dark ratio may be normal or slightly decreased and the ERG likewise can be normal or, in some cases, reveals rod and cone system abnormalities.  Optical coherence tomography shows yellowish deposits between the neurosensory retina and the RPE with foveal thinning.  Color vision has been described as normal. The visual field may show peripheral constriction or central scotomas.  Choroidal neovascularization occurs rarely.

Variability in the clinical features often leads to misdiagnosis in individual patients who are sometimes considered to have age-related macular degeneration, retinitis pigmentosa, fundus flavimaculatus, dominant drusen, butterfly macular dystrophy, and pattern dystrophy.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal dominant condition resulting from heterozygous mutations in the RDS (PRPH2) gene (6p21.1). 

The gene product of PRPH2 is active in the retina. It is important to the integrity and stability of the structures that contain light-sensitive pigments (e.g., photoreceptors).  More than 100 mutations have been identified. The resultant phenotype can be highly variable, even within members of the same family but most affected individuals have some degree of pigmentary retinopathy within the macula or throughout the posterior pole.  The altered gene product resulting from mutations in PRPH2 often leads to symptoms beginning in midlife as a result of the slow degeneration of photoreceptors.  This database contains at least 11 disorders in which PRPH2 mutations have been found.

Genotyping has identified at least 5 forms of vitelliform macular dystrophy.  In addition to the iconic Best disease (VMD2, 153700) apparently first described by Friedreich Best in 1905 and now attributed to mutations in the Best1 gene, we know of at least 4 more and specific mutations have been identified in three.  No mutation or locus has yet been identified in VMD1 (153840) but it is likely a unique condition since mutations in other genes known to cause vitelliform dystrophy have been ruled out.  Other forms are VMD3 described here, VMD4 (616151) resulting from mutations in the IMPG1 gene, and VMD5 (616152) caused by mutations in the IMPG2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known for this disorder.  Anti-VEGF and ablation therapy may be helpful in selected individuals with choroidal neovascularization.  Low vision aids may also be beneficial.

References
Article Title: 

Fundus Albipunctatus

Clinical Characteristics
Ocular Features: 

This disorder is often considered to belong to the category of retinal disease known as flecked retina syndrome.  Further, the nomenclature is not standardized and varying names have been attached to the more or less characteristic fundus picture consisting of uniformly distributed small yellow-white dots in the retina.  These tend to be concentrated in the midperiphery.  The macula usually is not involved in young people although ERG evidence suggests some worsening of cone dysfunction with age and central acuity may be decreased in midlife.  Frank macular degeneration has been seen clinically .  Delayed dark adaptation can be demonstrated with delays in recovery of rod and cone function.  Patients complain of night blindness beginning in childhood with little evidence of progression.

The disease known as retinitis punctata albescens (136880) may or may not be a unique disorder.  It is sometimes grouped with fundus albipunctatus while others consider it to be a separate entity.  Evidence for its uniqueness is based on the progressive nature of field loss and the presence of pigmentary changes and retinal vascular attenuation which are not found in fundus albipunctatus.  Further, the scotopic ERG waveforms usually do not regenerate.  More discriminating studies, especially genotyping, will likely provide additional information.  It would also be useful to have additional follow-up information on families. 

Systemic Features: 

No systemic disease is associated.

Genetics

Fundus albipunctatus is a genetically heterogeneous disorder.  Mutations in two genes, PRPH2 (6p21.1) and RDH5 (12q13.2) have been found among families.  The inheritance pattern for families with mutations in PRPH2 is consistent with autosomal dominant inheritance while mutations in RDH5 result in an autosomal recessive pattern.  Mutations in RLBP1 have also been found in some families.

Gene studies so far have not been helpful in discriminating between fundus albipunctatus and retinitis punctata albescens (136880).  For example, RLBP1 mutations have been identified among members of the same kindred having the clinical diagnosis of retinitis punctata albescens (136880) among older individuals while younger patients had features of fundus albipunctatus.  Further, the latter disorder has also been described among families with mutations in PRPH2 and RHO hinting at further genetic heterogeneity.

A similar clinical picture may be seen in Bietti crystalline corneoretinopathy (210370), Bardet-Biedl syndrome (209900), and hyperoxaluria (259900).  More information on flecked retina syndromes may be found at Flecked Retina Syndromes.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available to restore full receptor cell function.  However, high oral doses of beta-carotene may lead to an improvement in night blindness. Low vision aids could be beneficial when central acuity is damaged.

References
Article Title: 

Choroidal Dystrophy, Central Areolar

Clinical Characteristics
Ocular Features: 

The primary feature of this form of macular dystrophy is atrophy of the RPE and choriocapillaris in the central macula.  In early stages among young patients in the second decade of life, some pigment changes are seen in the parafoveal area.  Later, the central macula develops hypopigmentation followed by atrophy of the choriocapillaris.  The area is usually sharply defined but fluorescein angiography often shows multiple window defects beyond the edges.  The same region often has speckled autofluorescence.  Secondary dysfunction of the photoreceptors in this area leads to some mild degree of vision loss in adults between the ages of 30 and 60 years but this progressive disease may eventually result in legal blindness.  The ERG demonstrates a cone dystrophy. The rate of disease progression is highly variable.  Visual acuity varies considerably as does the appearance of the macula.  Older individuals may be misdiagnosed as having age-related macular degeneration. 

Systemic Features: 

There is no associated systemic disease. 

Genetics

This is a genetically heterogeneous disorder with mutations in several genes responsible.  The majority of patients have one of several mutations in the PRPH2 gene (6p21.1-cen) and the inheritance pattern seems to be autosomal recessive (CACD2).  Other family trees in which mutations in PRPH2 were excluded suggest autosomal dominant inheritance (CACD3; 613144).  CACD1 is caused by an unknown mutation localized to 17p13. 

The gene product of PRPH2 is active in the retina. It is important to the integrity and stability of the structures that contain light-sensitive pigments (e.g., photoreceptors). More than 100 mutations have been identified. The resultant phenotype can be highly variable, even within members of the same family but most affected individuals have some degree of pigmentary retinopathy within the macula or throughout the posterior pole.

The altered gene product resulting from mutations in PRPH2 often leads to symptoms beginning in midlife as a result of the slow degeneration of photoreceptors. This database contains at least 11 disorders in which PRPH2 mutations have been found.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment of the macular disease.  However, some patients can benefit from low vision aids. 

References
Article Title: 

Central areolar choroidal dystrophy

Boon CJ, Klevering BJ, Cremers FP, Zonneveld-Vrieling MN, Theelen T, Den Hollander AI, Hoyng CB. Central areolar choroidal dystrophy. Ophthalmology. 2009 Apr;116(4):771-82, 782.e1.

PubMed ID: 
19243827

Macular Dystrophy, Patterned 1

Clinical Characteristics
Ocular Features: 

Patterned dystrophies of the macula are clinically heterogeneous.  It is common for different patterns to be seen among multiple members of a single family.  They can also be different in the two eyes of the same individual.  RPE changes can often be seen in the second decade of life but visual disturbances may not be noted until a decade or two later.  The process is progressive and eventually macular function is severely depressed with vision in the range of 20/200.  The pigmentary retinopathy occurs at the level of the RPE with the typical appearance of pigment but sometimes an accumulation of white or yellowish deposits is present.  The pattern of changes may appear in a configuration resembling the wings of a butterfly, hence the name.  However, vitelliform-like lesions have also been reported.  Paracentral tritan color defects have been described.

Subfoveal choroidal neovascularization can occur.

While the ERG may show some diffuse photoreceptor dysfunction in the presence of normal vision, there is little to suggest a primary rod or cone abnormality. Dark adaptation is normal.  Visual fields can reveal a small central scotoma and fluorescein angiography often shows window defects in the posterior pole. 

Systemic Features: 

Simple patterned macular dystrophy is not associated with systemic disease. 

Genetics

Pattern macular dystrophies are usually inherited as autosomal dominant conditions.  Several mutations in separate genes have been linked to these disorders suggesting that this group is genetically as well as clinically heterogeneous. 

Some families have mutations in the photoreceptor peripherin gene (PRPH2) at 6p21.1-cen (169150) whose gene product is active in the retina. It is important to the integrity and stability of the structures that contain light-sensitive pigments (e.g., photoreceptors). More than 100 mutations have been identified. The resultant phenotype can be highly variable, even within members of the same family but most affected individuals have some degree of pigmentary retinopathy within the macula or throughout the posterior pole.  The altered gene product coded by mutations in PRPH2 often leads to symptoms beginning in midlife as a result of the slow degeneration of photoreceptors. This database contains at least 11 disorders in which PRPH2 mutations have been found.

A locus at 5q21.2-q33.2 containing heterozygous CTNNA1 mutations has been linked to a pattern dystrophy (Macular Dystrophy, Patterned 2) (608970). 

As many as 25% of patients with myotonic dystrophy 1 (160900) and myotonic dystrophy 2 (602668) have a patterned pigmentary maculopathy.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the macular disease but low vision aids should be considered for appropriate individuals. 

Surveillance is useful for the detection of choroidal neovascularization and prompt treatment with ranibizumab injections can be useful in the elimination of this complication.

References
Article Title: 

Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections

Vaclavik V, Tran HV, Gaillard MC, Schorderet DF, Munier FL. Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections. Retina. 2012 Oct;32(9):1942-9.

PubMed ID: 
22466463

Leber Congenital Amaurosis

Clinical Characteristics
Ocular Features: 

Leber congenital amaurosis is a collective term applied to multiple recessively inherited conditions with early-onset retinal dystrophy causing infantile or early childhood blindness.  There are no established diagnostic criteria.  First signs are usually noted before the age of 6 months.  These consist of a severe reduction in vision accompanied by nystagmus, abnormal pupillary responses, and photophobia.  Ametropia in the form of hyperopia is common.  Keratoconus (and keratoglobus) is frequently found in older children but it is uncertain if this is a primary abnormality or secondary to eye rubbing as the latter is commonly observed.  Repeated pressure on the eye may also be responsible for the relative enophthalmos often seen in these patients.  The ERG is reduced or absent early and permanently.  Final visual acuity is seldom better than 20/400 and perhaps one-third of affected individuals have no light perception.  Some individuals experience a period of vision improvement.

The retina usually has pigmentary changes but these are not diagnostic.  Retinal vessels are generally attenuated.  The RPE may have a finely granulated appearance or, in some cases, whitish dots, and even 'bone spicules'.

Systemic Features: 

A variety of metabolic and physical abnormalities have been reported with LCA but many publications are from the pre-genomic era and the significance of such associations remains uncertain.  Most extraocular signs result from delays in mental development but it is uncertain what role, if any, that visual deprivation plays.  Perhaps 20% of patients are mentally retarded or have significant cognitive deficits.

Genetics

Leber congenital amaurosis is genetically heterogeneous with at least 18 known gene mutations associated with the phenotype.  It is also clinically heterogeneous both within and among families and this is the major obstacle to the delineation of individual clinicogenetic entities.  As more patients are genotyped, it is likely that more precise genotype-phenotype correlations will emerge.  At the present time, however, it is not possible to use clinical findings alone to distinguish individual conditions.

Below are links to the genotypic and phenotypic features of the 18 known types of LCA.  All cause disease in the homozygous or compound heterozygous state. 

LCA type               OMIM#                 Locus              Gene Symbol   

LCA 1                    204000                 7p13.1                 GUCY2D

LCA 2                    204100                 1p31                    RPE65**

LCA 3                    604232                 14q31.3               SPATA7

LCA 4                    604393                 17p13.1               AIPL1

LCA 5                    604537                 6q14.1                 LCA5

LCA 6                    613826                 14q11                  RPGRIP1

LCA 7                    613829                19q13.1                CRX*

LCA 8                    613835                 1q31-q32             CRB1

LCA 9                    608553                 1p36                    NMNAT1

LCA 10                  611755                 12q21                  CEP290

LCA 11                  613837                 7q31.3-q332        IMPDH1

LCA 12                  610612                 1q32.3                 RD3

LCA 13                  612712                 14q24.1               RDH12

LCA 14                  613341                 4q31                    LRAT

LCA 15                  613843                 6p21-31              TULP1

LCA 16                  614186                 2q37                    KCNJ13

LCA 17                  615360                 8q22.1                 GDF6

LCA 18                  608133                 6p21.1                 PRPH2***

It is likely that more mutant genes will be identified since these are found in only about half of patients studied in large series.  

*(Heterozygous mutations in CRX may also cause a cone-rod dystrophy).

**(Mutations in RPE65 has been described as also causing retinitis pigmentosa (RP20; 613794)  with choroidal involvement.)

***Mutations in PRPH2 (RDS) has also been reported to cause retinitis pigmentosa 7, choroidal dystrophy, and vitelliform macular dystrophy (179605) among others.

Mutations in the GUCY2D gene seem to be the most common being present in about 21% of LCA patients with CRB1 next at 10%.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Until recently, no treatment was available for LCA.  However, results from early clinical trials with adeno-associated virus vector mediated gene therapy for RPE65 mutations in LCA 2 show promise.  Subretinal placement of recombinant  adeno-virus carrying RPE65 complementary DNA results in both subjective and objective improvements in visual function.  Patients generally report subjective improvement in light sensitivity and visual mobility.  Some recovery of rod and cone photoreceptor function has been documented.  Studies have also documented an improvement in visual acuity, size of visual field, pupillary responses, and in the amouunt of nystagmus.  More than 230 patients have now  been treated and improvements seem to be maintained for at least 3 or more years.  However, we have also learned that along with the enzymatic dysfunction of RPE65 that disrupts the visual cycle, there is also degeneration of photoreceptors which continues after treatment and the long term prognosis remains guarded. Multiple phase I clinical trials have demonstrated the safety of this approach and phase III trials are now underway.

It is crucial for patients to be enrolled early in sensory stimulation programs to ensure optimum neural development.  For patients with residual vision, low vision aids can be beneficial.  Vocational and occupational therapy should be considered for appropriate patients.

References
Article Title: 

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease

Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y,
Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan
CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare
Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid
Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R.
Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease
pathway for retinal degeneration
. Nat Genet. 2012 Jul 29.
 

PubMed ID: 
22842230

A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement

Bowne SJ, Humphries MM, Sullivan LS, Kenna PF, Tam LC, Kiang AS, Campbell M, Weinstock GM, Koboldt DC, Ding L, Fulton RS, Sodergren EJ, Allman D, Millington-Ward S, Palfi A, McKee A, Blanton SH, Slifer S, Konidari I, Farrar GJ, Daiger SP, Humphries P. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011 Oct;19(10):1074-81. Erratum in: Eur J Hum Genet. 2011 Oct;19(10):1109.

PubMed ID: 
21654732

Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial

Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90.

PubMed ID: 
18774912

Effect of gene therapy on visual function in Leber's congenital amaurosis

Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9.

PubMed ID: 
18441371

Leber congenital amaurosis

Perrault I, Rozet JM, Gerber S, Ghazi I, Leowski C, Ducroq D, Souied E, Dufier JL, Munnich A, Kaplan J. Leber congenital amaurosis. Mol Genet Metab. 1999 Oct;68(2):200-8. Review.

PubMed ID: 
10527670
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