photophobia

Retinitis Pigmentosa 79

Clinical Characteristics
Ocular Features: 

As in many autosomal dominant conditions, there is considerable clinical heterogeneity and even nonpenetrance among individuals.  Onset may consist of night blindness in early childhood but many patients are not symptomatic until the 6th or 7th decade of life.  The fundus signs are characteristic for retinitis pigmentosa with bone spicule pigmentation clumps, attenuated vessels, optic disc pallor, and peripheral retinal atrophy.  Visual fields are peripherally constricted to variable degrees.   Patches of chorioretinal "degeneration" and choroidal "sclerosis" have been described.  Photophobia, decreased central acuity, and some degree of dyschromatopsia have been reported.  Progression of symptoms is highly variable but central acuity is usually affected at some point.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This autosomal dominant type of retinitis pigmentosa seems to result from heterozygous mutations in the HK1 gene (10q22.1).  Its phenotype is nonpenetrant in some individuals.   

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported but low vision aids might be helpful especially for near vision.

References
Article Title: 

A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa

Sullivan LS, Koboldt DC, Bowne SJ, Lang S, Blanton SH, Cadena E, Avery CE, Lewis RA, Webb-Jones K, Wheaton DH, Birch DG, Coussa R, Ren H, Lopez I, Chakarova C, Koenekoop RK, Garcia CA, Fulton RS, Wilson RK, Weinstock GM, Daiger SP. A dominant mutation in hexokinase 1 (HK1) causes retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2014 Sep 4;55(11):7147-58.

PubMed ID: 
25190649

Autoinflammation with Arthritis and Dyskeratosis

Clinical Characteristics
Ocular Features: 

Signs and symptoms of dry eyes are evident early in the first decade.  Punctate keratitis with photophobia are present by 5 or 6 years of age followed by corneal dyskeratosis and neovascularization.  One 16-year-old male was reported to have uveitis.

Systemic Features: 

Recurrent febrile episodes lasting 3-4 days with impaired sweating occur early in the first decade.  Small hyperkeratosis may be seen on the limbs, shoulders, and flanks.  Diffuse xerosis is evident throughout.  Keratotic lesions occur on the soles as well.   Arthritis in the lower limbs occurs by the beginning of the second decade or earlier.  Metaphyseal striations and irregular condensations may be seen in the distal femora and proximal tibial bones.

Hypereosinophilia with elevated IgE and IgA levels and reduced vitamins A and C have been reported.  Immune hemolytic anemia, thyroiditis, and abnormal B-cell profiles may be present.

Genetics

Heterozygous and homozygous mutations in the NLRP1 gene (17p13) have been associated with this condition in several families.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)

Grandemange S, Sanchez E, Louis-Plence P, Tran Mau-Them F, Bessis D, Coubes C, Frouin E, Seyger M, Girard M, Puechberty J, Costes V, Rodiere M, Carbasse A, Jeziorski E, Portales P, Sarrabay G, Mondain M, Jorgensen C, Apparailly F, Hoppenreijs E, Touitou I, Genevieve D. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis. 2016 Dec 13. pii: annrheumdis-2016-210021. doi: 10.1136/annrheumdis-2016-210021.

PubMed ID: 
27965258

Cone-Rod Dystrophy with Hearing Loss

Clinical Characteristics
Ocular Features: 

Patients note reduced vision in brightly-lit environments with onset in early adulthood and progressive central vision loss thereafter.   Nystagmus, photophobia, and dyschromatopsia may be present.  Younger individuals may complain of night blindness.  Visual fields show diffuse progressive suppression with relative sparing of selected areas such as the peripapillary region.  The ERG documents primary cone dystrophy but less involvement of the rods.  EOG testing in 4 patients showed reduced light-dark ratios.  Macular degeneration, attenuated vessels, subtle salt-and-pepper pigmentation, and spicular pigmentary deposits in the mid-periphery may be seen.

Systemic Features: 

The hearing loss is sensorineural in nature and can be progressive from its onset in childhood.

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CEPL78 (9q21.2) gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the basic condition has been reported.  Assistive hearing devices and tinted lenses could be helpful.

References
Article Title: 

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects

Nikopoulos K, Farinelli P, Giangreco B, Tsika C, Royer-Bertrand B, Mbefo MK, Bedoni N, Kjellstrom U, El Zaoui I, Di Gioia SA, Balzano S, Cisarova K, Messina A, Decembrini S, Plainis S, Blazaki SV, Khan MI, Micheal S, Boldt K, Ueffing M, Moulin AP, Cremers FP, Roepman R, Arsenijevic Y, Tsilimbaris MK, Andreasson S, Rivolta C. Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects. Am J Hum Genet. 2016 Sep 1;99(3):770-6.

PubMed ID: 
27588451

CEP78 is mutated in a distinct type of Usher syndrome

Fu Q, Xu M, Chen X, Sheng X, Yuan Z, Liu Y, Li H, Sun Z, Li H, Yang L, Wang K, Zhang F, Li Y, Zhao C, Sui R, Chen R. CEP78 is mutated in a distinct type of Usher syndrome. J Med Genet. 2016 Sep 14. pii: jmedgenet-2016-104166. doi: 10.1136/jmedgenet-2016-104166.

PubMed ID: 
27627988

Cone-Rod Dystrophy With Decreased Male Fertility

Clinical Characteristics
Ocular Features: 

Features of a cone dystrophy appear first followed by rod damage although the course of degeneration is variable.  Poor vision may be present in some individuals in the first years of life but has a later onset in others.  Evidence for rod dysfunction appears later in most patients.

A hyperfluorescent area centered on the fovea can often be seen although there may be patchy areas elsewhere in the fundus.  Foveal atrophy is present in individuals generally after the 5th decade of life. Full field ERG shows reduced or absent cone responses with variable rod responses with more pronounced changes in older individuals.  Variable pigmentation can be seen in the peripapillary area.

Systemic Features: 

The only systemic abnormality thus far identified is a reduction in sperm count and reduced motility.  The resulting loss of fertility, however, occurs only in male patients with truncating variants in TTLL5 and not in those with missense mutations according to the most recent studies.

Genetics

This autosomal recessive condition results from homozygous or compound heterozygous mutations in the TTLL5 gene (14q24.3).  TTLL5 is localized at the base of the spermatozoal axoneme and at the basal body of the cilia in photoreceptors.  

Interestingly, male mice with mutations in this gene have reductions in sperm motility with evident disruption in the formation of sperm tails.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility

Bedoni N, Haer-Wigman L, Vaclavik V, Tran HV, Farinelli P, Balzano S, Royer-Bertrand B, El-Asrag ME, Bonny O, Ikonomidis C, Litzistorf Y, Nikopoulos K, Yioti G, Stefaniotou M, McKibbin M, Ellingford J, Booth AP, Black G, Toomes C, Inglehearn CF, Hoyng CB, Bax N, Klaver CC, Thiadens AA, Murisier F, Schorderet DF, Ali M, Cremers FP, Andreasson S, Munier FL, Rivolta C. Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility. Hum Mol Genet. 2016 Aug 22. pii: ddw282. [Epub ahead of print].

PubMed ID: 
27554115

Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy

Sergouniotis PI, Chakarova C, Murphy C, Becker M, Lenassi E, Arno G, Lek M, MacArthur DG; UCL-Exomes Consortium, Bhattacharya SS, Moore AT, Holder GE, Robson AG, Wolfrum U, Webster AR, Plagnol V. Biallelic variants in TTLL5, encoding a tubulin glutamylase, cause retinal dystrophy. Am J Hum Genet. 2014 May 1;94(5):760-9.

PubMed ID: 
244791901

Night Blindness, Congenital Stationary, CSNB1H

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.

Night blindness in this condition can be detected in early childhood and may be congenital.   Photophobia, reduced cone sensitivity. and mild dyschromatopsia may develop in midlife.  Peripheral field constriction can be demonstrated.  Visual acuity is near normal and there is no nystagmus or high myopia as reported for some other forms of CSNB.   

Systemic Features: 

There are no systemic abnormalities.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the GNB3 gene (12p13.31).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported but the use of tinted lenses can enhance contrast and improve acuity.

References
Article Title: 

Optic Atrophy 10

Clinical Characteristics
Ocular Features: 

Low vision is noted in early childhood without systemic symptoms.  The optic nerves appear pale (age of onset uncertain).  The retinal nerve fiber layer may be reduced in thickness in all quadrants but only segmentally in some individuals.  No VEP can be recorded.  On brain MRI examination the optic tracts are thin.  The appearance of the optic nerve is consistent with mild hypoplasia in some patients.

Systemic Features: 

Some patients have ataxia, cognitive deficits, and seizures.  A brother and sister from a consanguineous Moroccan family and two unrelated individuals have been reported.  

Genetics

This autosomal recessive condition is caused by homozygous or compound heterozygous mutations in the RTN4IP1 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Angebault C, Guichet PO, Talmat-Amar Y, Charif M, Gerber S, Fares-Taie L, Gueguen N, Halloy F, Moore D, Amati-Bonneau P, Manes G, Hebrard M, Bocquet B, Quiles M, Piro-Megy C, Teigell M, Delettre C, Rossel M, Meunier I, Preising M, Lorenz B, Carelli V, Chinnery PF, Yu-Wai-Man P, Kaplan J, Roubertie A, Barakat A, Bonneau D, Reynier P, Rozet JM, Bomont P, Hamel CP, Lenaers G. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. Am J Hum Genet. 2015 Nov 5;97(5):754-60. 

PubMed ID: 
26593267

Albinism, Oculocutaneous, Type V

Clinical Characteristics
Ocular Features: 

The phenotype in the two families studied includes photophobia, nystagmus, foveal hypoplasia and decreased visual acuity.  The fundus is hypopigmented.

Systemic Features: 

The hair is golden-colored and the skin is described as white. 

Genetics

The specific gene causing this form of oculocutaneous albinism has not been identified.  However, an area of homozygosity in the region of 4q24 has been identified in 6 members in two families belonging to a large consanguineous Pakistani pedigree in which it segregates with the OCA5 phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for oculocutaneous albinism but appropriately tinted glasses could be beneficial.

References
Article Title: 

Increasing the complexity: new genes and new types of albinism

Montoliu L, Gronskov K, Wei AH, Martinez-Garcia M, Fernandez A, Arveiler B, Morice-Picard F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg T, Li W. Increasing the complexity: new genes and new types of albinism. Pigment Cell Melanoma Res. 2014 Jan;27(1):11-18. Review.

PubMed ID: 
24066960

Retinal Dystrophy with Inner Retinal Abnormalities

Clinical Characteristics
Ocular Features: 

Otherwise healthy individuals note onset of light sensitivity between 25 and 40 years of age.  Central vision is progressively lost with average vision levels of 20/50.  In some patients vision is 20/400 but peripheral vision remains normal on visual field testing.  Small central and centrocecal scotomas can be demonstrated.  There is general hyper-reflectivity of the ganglion cell and nerve fiber layers with the latter decreased in thickness especially in the foveal area of all patients.  The optic nerve is often pale.  The ERG recordings are consistent with inner retinal dysfunction with an absent b-wave and a normal a-wave response.  Older patients have additional photopic response abnormalities and delayed implicit times.  Color vision in younger individuals was reported to be normal but older persons had mild deuteranopia.

Systemic Features: 

No systemic disease was noted in the single reported family.  Specifically, no dementia was present in affected individuals (vida infra).

Genetics

This condition has been identified in a single large 3-generation family.  A missense heterozygous mutation in the ITM2B gene (13q14.2) is responsible.  The gene product localizes to the inner nuclear and ganglion cell layers in the eye and co-localizes with the amyloid beta precursor protein of Alzheimer disease in cerebral tissue.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the retinal disease is available but photosensitive individuals may benefit from tinted lenses.  Low vision aid can be useful for near vision.

References
Article Title: 

The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family

Audo I, Bujakowska K, Orhan E, El Shamieh S, Sennlaub F, Guillonneau X, Antonio A, Michiels C, Lancelot ME, Letexier M, Saraiva JP, Nguyen H, Luu TD, Leveillard T, Poch O, Dollfus H, Paques M, Goureau O, Mohand-Said S, Bhattacharya SS, Sahel JA, Zeitz C. The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Hum Mol Genet. 2014 Jan 15;23(2):491-501..

PubMed ID: 
24026677

Albinism, Oculocutaneous, Type VI

Clinical Characteristics
Ocular Features: 

Nystagmus is usually present from birth and visual acuity is in the range of 20/100.  There is marked hypopigmentation in the retina and the iris often transilluminates.  OCT usually shows foveal flattening consistent with hypoplasia.  Most patients experience severe photophobia and many have strabismus.

Systemic Features: 

There is usually complete loss or a severe reduction of melanin in skin, hair, and eyes.  Hair color is blond but may become tinged with brown in older individuals.  The skin may have pigmented nevi and has a tendency to tan in some patients.

Genetics

This is an autosomal recessive disorder resulting from mutations in SLC24A5 (15q21.1).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Visual function can be improved with low vision aids.

References
Article Title: 

SLC24A5 Mutations are Associated with Non-Syndromic Oculocutaneous Albinism

Morice-Picard F, Lasseaux E, Fran?ssois S, Simon D, Rooryck C, Bieth E, Colin E, Bonneau D, Journel H, Walraedt S, Leroy BP, Meire F, Lacombe D, Arveiler B. SLC24A5 Mutations are Associated with Non-Syndromic Oculocutaneous Albinism. J Invest Dermatol. 2013 Aug 28. [Epub ahead of print] PubMed PMID: 23985994.

PubMed ID: 
23985994

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: 

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