cone dystrophy

Macular Dystrophy with Central Cone Involvement

Clinical Characteristics
Ocular Features: 

This is primarily a cone dystrophy but there is evidence of some rod damage in older patients.  A mild decrease in central acuity is noted by individuals in the third to sixth decades.  Slight pigmentary changes and color vision abnormalities can be documented with the onset of these symptoms and a bull's eye maculopathy and severe atrophy of the central fovea may be present. An enlarging central scotoma with normal periphery can sometimes be identified.  Other patients have an atrophic appearance to the peripapillary area with a pale optic disc.  ERG responses to full-field testing are normal but multifocal studies reveal severely reduced central responses.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Compound heterozygosity for a missense mutation and a nonsense mutation in the MFSD8 gene (4q28.2) has been found among members of a Dutch sibship suggesting autosomal recessive inheritance.       

The same mutant gene has been identified in some patients with late infantile or early juvenile onset lysosomal storage disease known as neuronal ceroid lipofuscinoses (610951) in which there may be optic atrophy, attenuated retinal vessels, a pigmentary retinopathy, and severe vision loss.   However, it is of note that no members of the Dutch family with the macular cone dystrophy described here had extraocular manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Retinal Cone Dystrophy 3B

Clinical Characteristics
Ocular Features: 

This is a degenerative disorder in which patients have a progressive deterioration of visual acuity and color vision.  Most patients have significant myopia.  Visual difficulties begin in early childhood with acuity of 20/100 or worse by the second decade of life.  Color vision deficits can be detected in the second decade but nyctalopia occurs later in young adults.  Photophobia is a prominent symptom.  The ERG shows reduced and delayed cone responses.  Rod responses to low intensity flashes are undetectable but increased stimulus intensity leads to an abrupt increase in amplitude, often exceeding the upper limits of normal.

The fundus appears normal in some patients but foveal or parafoveal atrophy, a macular bull’s eye, hyperfluorescence anomalies, and a generalized fine pigmentary retinopathy have been reported.  There may be some temporal pallor in the optic nerves.  Nystagmus and strabismus may be present.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the KCNV2 gene (9p24.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this dystrophy.  Low vision aids and tinted lenses may be helpful.

References
Article Title: 

Choroidal Dystrophy, Central Areolar 1

Clinical Characteristics
Ocular Features: 

The primary feature of this form of macular dystrophy is atrophy of the RPE and choriocapillaris centralized to the 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

CACD1 is caused by a hterozygous mutations in GUCY2D gene localized to 17p13.  One large three generation Irish family has been reported.

For a somewhat similar disorder see choroidal dystrophy, central areolar 2 (613105).

CACD 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).  However, other family trees in which mutations in PRPH2 were excluded suggest autosomal dominant inheritance (CACD3; 613144) suggesting genetic heterogeneity such as the CACD1 condition described here.   

 

Pedigree: 
Autosomal dominant
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

Cone Dystrophy 3

Clinical Characteristics
Ocular Features: 

The evidence for the existence of pure cone dystrophies is inconclusive.  Certainly some patients at least early in the disease seem to have pure cone dysfunction but eventually rod involvement becomes apparent.  Loss of central acuity and color vision occurs in young adults between the ages of 20 and 40 years.   Symptoms usually worsen with age and most patients eventually are legally blind.  Photophobia is common.  Pigmentary mottling in the retina may be evident before symptoms appear.  Thinning of the retina, especially the macula, is seen late in the disease.  Peripheral visual fields and rod function are often normal for many years although scotopic responses on the ERG eventually become attenuated. 

Systemic Features: 

No systemic disease is associated with cone dystrophies. 

Genetics

There is considerable genetic and clinical heterogeneity in photoreceptor disease.  Heterozygous mutations in the GUCA1A (GCAP1) gene located at 6p21.1 seem to be responsible for this form of cone dystrophy, and inheritance therefore follows an autosomal dominant pattern.  However, mutations in the same gene are also associated with macular dystrophy.  The same region contains the RDS (PRPH2) gene which is also known to cause retinitis pigmentosa (608133) and fundus albipunctatus (136880).  RDS (PRPH2) mutations have also been reported in some cases of so-called adult-onset vitelliform macular dystrophy (AVMD)(608161).

Another autosomal dominant cone dystrophy, RCD1, has been linked to a locus at 6q25-q26 but the gene has not yet been identified (180020).  There is also a cone dystrophy with primarily peripheral involvement (609021). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the disease is available but low vision aids can be helpful in selected patients.  Red tinted lenses may provide comfort in bright light. 

References
Article Title: 

Cone Dystrophy, Peripheral

Clinical Characteristics
Ocular Features: 

Several families have been reported in which rod function was normal while cone function was impaired, more so peripherally than centrally.  Visual acuity ranges from normal to 20/200.  Color vision may be normal in some patients while others have some degree of dyschromatopsia.  Full-field ERG cone responses are reduced significantly but focal macular cone ERGs are normal.   Visual fields are normal except for small paracentral scotomas.  Temporal pallor has been noted in the optic discs of 2 patients.  Cone responses on ERG were demonstrated to decrease in one patient during a 4 year interval.  Photophobia as commonly seen in cone-rod dystrophies was not reported.  No abnormalities are seen on fundus examination or fluorescein angiography. 

Systemic Features: 

No systemic disease has been reported. 

Genetics

No responsible mutation has been reported.  Two of the three reported patients were siblings born to presumably unaffected parents, compatible with autosomal recessive inheritance. 

It is questionable whether a 'pure' cone dystrophy exists as most patients have evidence (at least eventually) of both rod and cone disease.  However, an autosomal dominant form of cone dystrophy (602093) has been reported in which cone dysfunction predominates and evidence of rod damage occurs much later.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available but visual function can be enhanced with low vision aids.  

References
Article Title: 

Peripheral cone disease

Pinckers A, Deutman AF. Peripheral cone disease. Ophthalmologica. 1977;174(3):145-50.

PubMed ID: 
854266

Colorblindness-Achromatopsia 5

Clinical Characteristics
Ocular Features: 

Poor visual acuity and congenital nystagmus are characteristic of ACHM5 and may be seen in infancy.  Vision loss can be progressive for those who have a milder form of colorblindness or incomplete achromatopsia.  Such patients have a somewhat later onset and may not have nystagmus or photophobia.  Cone responses are usually absent in the ERG whereas rod responses are often normal.  However, in the incomplete form there may be reduced but measureable cone responses.  There may be some reduction in rod responses with disease progression.  Myopia has been found in some patients.  Atrophy of the RPE in the posterior pole characteristic of progressive cone dystrophies may be seen. 

Systemic Features: 

No systemic abnormalities are found in this disorder. 

Genetics

This is an autosomal recessive disorder resulting from mutations in the PDE6C gene located at 10q24.  This condition is sometimes called cone dystrophy 4.

Other forms of achromatopsia are ACHM3 caused by mutations in CNGB3 (262300), ACHM2 caused by mutations in CNGA3 (216900), and ACHM4 by mutations in GNAT2 (139340).

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the cone dystrophy but dark glasses and red colored contact lenses are helpful in reducing the photophobia and can improve acuity to some extent.  Low vision aids can also be helpful. 

References
Article Title: 

A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia

Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Bolz S, van Genderen MM, Riemslag FC; the European Retinal Disease Consortium, Lukowski R, den Hollander AI, Cremers FP, De Baere E, Hoyng CB, Wissinger B. A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia. Am J Hum Genet. 2012 Sep 7; 91(3) :527-32.

PubMed ID: 
22901948

Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders

Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009 Aug;85(2):240-7.

PubMed ID: 
19615668
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