CACNA1F

Cone-Rod Dystrophies, X-Linked

Clinical Characteristics
Ocular Features: 

Three X-linked forms of progressive cone-rod dystrophies each with mutations in different genes have been identified.  Central vision is often lost in the second or third decades of life but photophobia is usually noted before vision loss.  Cones are primarily involved but rod degeneration occurs over time.  The ERG reveals defective photopic responses early followed by a decrease in rod responses.   All three types are rare disorders affecting primarily males with symptoms of decreased acuity, photophobia, loss of color vision, and myopia.  The color vision defect early is incomplete but progressive cone degeneration eventually leads to achromatopsia.    Peripheral visual fields are usually full until late in the disease when constriction and nightblindness are evident.  The retina may have a tapetal-like sheen.  RPE changes in the macula often give it a granular appearance and there may be a bull's-eye configuration.   Fine nystagmus may be present as well.  The optic nerve often has some pallor beginning temporally.  Carrier females can have some diminished acuity, myopia, RPE changes, and even photophobia but normal color vision and ERG responses at least among younger individuals.

There is considerable variation in the clinical signs and symptoms in the X-linked cone-rod dystrophies among both affected males and heterozygous females.  Visual acuity varies widely and is to some extent age dependent.  Vision can be normal into the fourth and fifth decades but may reach the count fingers level after that. 

Systemic Features: 

None.

Genetics

Mutations in at least 3 genes on the X chromosome cause X-linked cone-rod dystrophy.

CORDX1 (304020) is caused by mutations in an alternative exon 15 (ORG15) of the RPGR gene (Xp11.4) which is also mutant in several forms of X-linked retinitis pigmentosa (300455, 300029).  These disorders are sometimes considered examples of X-linked ocular disease resulting from a primary ciliary dyskinesia (244400).

CORDX2 (300085) is caused by mutations in an unidentified gene at Xq27.  A single family has been reported.

CORDX3 (300476) results from mutations in CACNA1F.  Mutations in the same gene also cause a form of congenital stationary night blindness, CSNB2A (300071).  The latter, however, is a stationary disorder with significant nightblindness and mild dyschromatopsia, often with an adult onset, and is associated with high myopia. Aland Island Eye Disease (300600) is another allelic disorder.   

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

There is no treatment for these dystrophies but red-tinted lenses provide comfort and may sometimes improve acuity to some extent.  Low vision aids can be helpful. 

References
Article Title: 

Night Blindness, Congenital Stationary, CSNB2A

Clinical Characteristics
Ocular Features: 

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive.  However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB).  At least 10 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them.  All are caused by defects in visual signal transduction within rod photoreceptors or in defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves.  However, the photopic ERG can be abnormal to some degree as well and visual acuity may be subnormal.  In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB.  Genotyping now enables classification with unprecedented precision.

Congenital stationary night blindness disorders are primarily rod dystrophies presenting early with symptoms of nightblindness and relative sparing of central vision.  Nystagmus and photophobia are usually not features.  Dyschromatopsia and loss of central acuity can develop later as the cones eventually become dysfunctional as well but these symptoms are much less severe than those seen in cone-rod dystrophies.  The amount of pigmentary retinopathy is highly variable. 

CSNB2A, or type 2A, is associated with myopia which ranges from mild to severe.  Residual rod function is diminished but not completely absent as suggested by the presence of small b-waves.  Cone function is impacted to some degree as well.  Nystagmus and strabismus are inconsistent findings.  Retinal pigmentation is usually normal in the X-linked forms. Visual acuity ranges from 20/30 to 20/200.  Night blindness is less severe in this form than in another X-linked CSNB (CSNB1A; 310500).  Mild dyschromatopsia is present in some patients but this is primarily a disease of rods.

Systemic Features: 

No systemic disease is associated with congenital stationary night blindness.

Genetics

Congenital stationary night blindness type 2A is an X-linked disorder caused by a mutation in the CACNA1F gene located at Xp11.23.  Only males are affected and carrier females do not have clinical disease.

This disorder is allelic to Aland Island Eye Disease (300600) from which it differs by an apparent lack of progressive myopia and the presence of a normal fovea.  Aland Island Eye Disease has foveal hypoplasia as well as iris and fundus hypopigmentation.

Another allelic disorder with mutations in CACNA1F is CORDX3 (300476), a cone-rod dystrophy.

Approximately 55% of X-linked CSNB are of this type while about 45% have another X-linked form known as CSNB1A, or type 1A (310500) secondary to a mutation at Xp11.4. 

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References
Article Title: 

Aland Island Eye Disease

Clinical Characteristics
Ocular Features: 

This is an X-linked disorder in which males have a variety of ocular defects.  The fundus is hypopigmented and the fovea is incompletely developed.  The hypopigmentation is most pronounced in the posterior pole and peripapillary region.  Variable degrees of iris transillumination have also been noted.  Progressive axial myopia, nystagmus, astigmatism, defective night vision, and a protan color vision defect are additional cardinal features.  Females may be mildly affected with subtle nystagmus and color vision defects.  It is sometimes mislabeled as X-linked albinism (OA1, #300500) but differs importantly from that disorder by the lack of misrouting of optic nerve axons.  The eponymic label 'Forsius-Eriksson type ocular albinism' further adds to the confusion with ocular albinism. 

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an X-linked disorder resulting from a mutation in the CACNA1F gene located at Xp11.23.  Molecular DNA studies suggest that there may be some heterogeneity in the causative mutations but in the original family reported by Forsius and Eriksson, a 425-bp deletion in the CACNA1F gene has been found to segregate as expected in the phenotypes.  The highly variable and subtle nature of clinical manifestations in females limits their usefulness in determination of carrier status and genotyping is necessary.

The CSNB2A type of congenital stationary night blindness (300071) is caused by mutations in the same gene suggesting allelism of the two disorders.  Aland Island eye disease shares some clinical features such as night blindness and occasionally mild color vision defects but differs in the presence of progressive myopia and an abnormal fovea. 

CORDX3 (300476), a cone-rod dystrophy, is also allelic.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment is available except for correction of the myopia.

References
Article Title: 

A novel CACNA1F gene mutation causes Aland Island eye disease

Jalkanen R, Bech-Hansen NT, Tobias R, Sankila EM, M?SSntyj?SSrvi M, Forsius H, de la Chapelle A, Alitalo T. A novel CACNA1F gene mutation causes Aland Island eye disease. Invest Ophthalmol Vis Sci. 2007 Jun;48(6):2498-502. PubMed PMID:17525176.

PubMed ID: 
17525176
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