night blindness

Retinitis Pigmentosa 47

Clinical Characteristics
Ocular Features: 

Onset of night blindness and field constriction symptoms occur during the 4th and 5th decades of life.  Pigmentary abnormalities of the retina are the hallmark of this condition.  Retinal thinning, bone spicule pigmentation, vascular attenuation, optic disc pallor, and pigmentary atrophy have all been noted.

In patients with the autosomal dominant form of this disease, rod function is severely impaired or absent as evidenced by ERG studies.  Cone responses are often reduced on an age-related basis and in the range of 85-95% below normal.  As expected, dark-adapted visual thresholds are elevated and visual fields are restricted peripherally.  Loss of vision is age-related but some individuals can retain acuities of 20/35 to 20/40 into their sixth decade.  It is more common for acuities to be in the range of 20/200 to 20/400 later in life.

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

Mutations in the SAG gene (2q37) are responsible for this form of RP.  Both autosomal recessive and autosomal dominant modes of inheritance have been reported.

In one family with homozygous mutations a sib had features of Oguchi disease which also results from homozygous mutations in SAG.

Among Hispanic families in the southwestern US, heterozygous mutations in SAG are a common cause of autosomal dominant retinitis pigmentosa.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this disorder.

References
Article Title: 

A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States

Sullivan LS, Bowne SJ, Koboldt DC, Cadena EL, Heckenlively JR, Branham KE, Wheaton DH, Jones KD, Ruiz RS, Pennesi ME, Yang P, Davis-Boozer D, Northrup H, Gurevich VV, Chen R, Xu M, Li Y, Birch DG, Daiger SP. A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2774-2784.

PubMed ID: 
28549094

Retinitis Pigmentosa 78

Clinical Characteristics
Ocular Features: 

Onset of visual complaints is in the third or fourth decades with night blindness and visual field defects.  These symptoms are progressive with the oldest of three reported patients having 20/1250 vision at 51 years of age.  Classic signs of retinitis pigmentosa are usually present including disc pallor, pigment clumping, peripheral field constriction, and attenuated retinal vessels.  Intraretinal cysts may be detected with optical coherence tomography.  The full-field ERG shows general photoreceptor dysfunction with the rods most severely involved while pattern ERGs shows variable macular involvement.

Systemic Features: 

No systemic disease has been detected in the three reported individuals.

Genetics

Three unrelated individuals have been reported with homozygous or compound heterozygous mutations in the ARHGEF18 gene (19p13.2).   Five different mutant alleles were found among these patients.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

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

References
Article Title: 

Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Arno G, Carss KJ, Hull S, Zihni C, Robson AG, Fiorentino A; UK Inherited Retinal Disease Consortium., Hardcastle AJ, Holder GE, Cheetham ME, Plagnol V; NIHR Bioresource - Rare Diseases Consortium., Moore AT, Raymond FL, Matter K, Balda MS, Webster AR. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration. Am J Hum Genet. 2017 Feb 2;100(2):334-342.

PubMed ID: 
28132693

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

Retinitis Pigmentosa 77

Clinical Characteristics
Ocular Features: 

The onset of nyctalopia apparently varies from early childhood to 20 years of age and is usually the presenting symptom.  The loss of acuity is progressive (20/30 to 20/400) with older patients generally having more severe loss but there is little direct correlation with age.  Peripheral fields are progressively constricted, ranging from 10 to 30 degrees.  Some patients develop posterior subcapsular cataracts.  Retinal pigmentation is often mottled but 'bone spicules' are seen in about half of individuals.  Retinal vessels are narrowed.  The ERG shows generalized rod-cone dystrophy.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Homozygous or compound heterozygous mutations in the REEP6 gene (19p13.3) are responsible for this disorder.  Five unrelated families have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported although cataract removal may be visually beneficial.  

References
Article Title: 

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Arno G, Agrawal SA, Eblimit A, Bellingham J, Xu M, Wang F, Chakarova C, Parfitt DA, Lane A, Burgoyne T, Hull S, Carss KJ, Fiorentino A, Hayes MJ, Munro PM, Nicols R, Pontikos N, Holder GE; UKIRDC., Asomugha C, Raymond FL, Moore AT, Plagnol V, Michaelides M, Hardcastle AJ, Li Y, Cukras C, Webster AR, Cheetham ME, Chen R. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. Am J Hum Genet. 2016 Dec 1;99(6):1305-1315.

PubMed ID: 
27889258

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: 

Retinitis Pigmentosa 75

Clinical Characteristics
Ocular Features: 

Symptoms of night blindness and tunnel vision (restricted peripheral fields) are present in the first decade of life.  The fundus appearance is typical for retinitis pigmentosa.  Attenuated retinal vessels with a bone spicule pattern of pigment clumping are present.  Evidence of optic atrophy with waxy pallor of the disc is usually visible.   High myopia (>6 diopters) is frequently present.

Systemic Features: 

No systemic disease has been associated with this disorder.

Genetics

This condition generally follows an autosomal recessive inheritance pattern as the result of homozygous mutations in the AGBL5 gene (2p23).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies

Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif H, Khan AO, Sunker A, Al-Mohsen S, Abboud EB, Nowilaty SR, Alowain M, Al-Zaidan H, Al-Saud B, Alasmari A, Abdel-Salam GM, Abouelhoda M, Abdulwahab FM, Ibrahim N, Naim E, Al-Younes B, E AlMostafa A, AlIssa A, Hashem M, Buzovetsky O, Xiong Y, Monies D, Altassan N, Shaheen R, Al-Hazzaa SA, Alkuraya FS. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. Genet Med. 2016 Jun;18(6):554-62.

PubMed ID: 
26355662

Short-Rib Thoracic Dysplasia 9

Clinical Characteristics
Ocular Features: 

A pigmentary retinopathy resembling retinitis pigmentosa is present in the majority of individuals.  Reduced acuity is likely responsible for the associated nystagmus and occasional strabismus.  Night blindness is a feature although the age of onset is unknown.  Visual acuity is decreased in the first decade but at least one patient at age 40 years still had vision of 20/40-20/50.  The ERG shows decreased scotopic and photopic responses as early as 12 years of age.  The retinopathy has been described as an atypical nonpigmented retinal degeneration in the peripheral retina. However, bone-spicule pigmentary deposits have been noted.  The retinal disease is progressive. 

Systemic Features: 

The LFT140 mutation has widespread effects, impacting the kidney, liver and skeletal systems.  The thorax is shortened, while the ribs are abnormally short and may result in respiratory difficulties, recurrent infections, and an early demise.  The middle phalanges of the hands and feet often have cone-shaped epiphyses, especially notable in childhood and leading to brachydactyly.  The long bones are often shortened as well.  The femoral neck can be short while the femoral epiphyses are often flattened.  Microcephaly has been reported in several individuals.

The liver may be enlarged and become fibrotic.  The kidneys often are cystic and histologically may have sclerosing glomerulonephropathy.  Kidney disease has an onset in the first decade and its progression often defines the survival prognosis.  Renal transplantation can be lifesaving when nephronophthisis develops.  Psychomotor delays have been reported but are uncommon. 

Genetics

Homozygous or compound heterozygous mutations in the LFT140 gene (16p13.3) have been identified.  However, there is some genetic heterogeneity since several patients having the typical phenotype have been reported with only heterozygous mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the general disease.  Renal and pulmonary function needs to be monitored with intervention as needed.  Some patients have benefitted from renal transplantation.

References
Article Title: 

Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease

Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA, Antony D, Rix S, Decker C, Bachmann N, Bald M, Vinke T, Toenshoff B, Di Donato N, Neuhann T, Hartley JL, Maher ER, Bogdanovic R, Peco-Antic A, Mache C, Hurles ME, Joksic I, Guc-Scekic M, Dobricic J, Brankovic-Magic M, Bolz HJ, Pazour GJ, Beales PL, Scambler PJ, Saunier S, Mitchison HM, Bergmann C. Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease. Hum Mutat. 2013 May;34(5):714-24.

PubMed ID: 
23418020

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Perrault I, Saunier S, Hanein S, Filhol E, Bizet AA, Collins F, Salih MA, Gerber S, Delphin N, Bigot K, Orssaud C, Silva E, Baudouin V, Oud MM, Shannon N, Le Merrer M, Roche O, Pietrement C, Goumid J, Baumann C, Bole-Feysot C, Nitschke P, Zahrate M, Beales P, Arts HH, Munnich A, Kaplan J, Antignac C, Cormier-Daire V, Rozet JM. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet. 2012 May 4;90(5):864-70.

PubMed ID: 
22503633

Retinitis Pigmentosa 71

Clinical Characteristics
Ocular Features: 

Night blindness is noted in the first or second decades of life.  The fundus picture in this condition resembles classic retinitis pigmentosa with attenuated vessels, RPE anomalies with bone spicule clumping and areas of atrophy, and optic disc pallor.  Several patients had optic nerve drusen.  The retina appears to have microcysts, especially in the macula, and the outer retina is thinned.  

Systemic Features: 

Only a few patients have been reported with this form of RP and the full phenotype is unknown.  Some individuals are obese and one patient in addition had postaxial polydactyly and hypercholesterolemia suggestive of a Bardet-Biedl-like phenotype.  No reported patients have had rib dysplasia.

Genetics

Homozygous or compound heterozygous mutations in the IFT172 gene (2p23.3) have been identified in this condition.

The same gene is mutated in the recessive short-rib thoracic dysplasia 10 syndrome with or without polydactyly (615630).  Individuals with the short-rib syndrome may have night blindness and fundus changes resembling retinitis pigmentosa.

Because of the phenotypic overlap with other conditions such as Bardet-Biedl syndrome, the short-rib thoracic 10 syndrome (615630), Majewski syndrome (263520), Jeune syndrome (208520), short-rib thoracic dysplasia 9 (266920), and certain types of polycystic diseases of the kidney with abnormalities of the cilia, it has been suggested that RP71 should be classified as a syndromic ciliopathy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Said S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet. 2015 Jan 1;24(1):230-42.

PubMed ID: 
25168386

Retinitis Pigmentosa 72

Clinical Characteristics
Ocular Features: 

The history and fundus findings are typical for classic retinitis pigmentosa with onset of symptoms in the 4th and 5th decades or earlier. Salt and pepper pigmentation may also be present. These consist of night blindness, decreased visual acuity, and constriction of visual fields.  The fields are constricted to 10-30 degrees, and vision ranges from 20/25 to 20/40.  Optic pallor is often present, the retinal vessels are narrowed and bone-spicule pigmentation has been described.  Vitreous 'condensation' sufficient to obscure fundus details may be present.  ERG responses are absent or substantially reduced.  Heterozygotes have no symptoms or fundus abnormalities.

Systemic Features: 

No systemic features have been described.

Genetics

Homozygous mutations in the ZNF408 gene (11p11.2) are responsible for this condition.  The product of this gene is a transcription factor highly expressed in fetal and adult retina and plays a role in vasculogenesis.

Heterozygous mutations in the same gene cause familial exudative vitreoretinopathy (FEVR6) (616468) described in one family with significant vitreal and retinal vascular disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic disease.  Tinted lenses may provide some benefit.

References
Article Title: 

Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations

Avila-Fernandez A, Perez-Carro R, Corton M, Lopez-Molina MI, Campello L, Garanto A, Fernandez-Sanchez L, Duijkers L, Lopez-Martinez MA, Riveiro-Alvarez R, Da Silva LR, Sanchez-Alcudia R, Martin-Garrido E, Reyes N, Garcia-Garcia F, Dopazo J, Garcia-Sandoval B, Collin RW, Cuenca N, Ayuso C. Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations. Hum Mol Genet. 2015 Jul 15;24(14):4037-48.

PubMed ID: 
25882705

Retinal Dystrophy, Newfoundland Type

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity, mostly age-dependent.  Night blindness can occur in early childhood but usually later even though scotopic responses can be undetectable in the first decade of life while photopic responses are reduced on the ERG at all ages.  Both rod and cone responses may be extinguished in later life.  Visual acuity can be decreased beginning in early childhood and legal blindness usually occurs by the second or third decade of life.  However, the loss of vision continues to progress and severe vision loss to finger-counting may be present in older individuals.  A scallop-bordered lacunar atrophy may be seen in the midperiphery.  The macula is only mildly involved by clinical examination although central retinal thinning is seen in all cases.  Dyschromatopsia is mild early and usually becomes more severe.  The visual fields are moderately to severely constricted although in younger individuals a typical ring scotoma is present.  The peripheral retina contains ‘white dots’ and often resembles the retinal changes seen in retinitis punctate albescens.

Systemic Features: 

None reported.

Genetics

Homozygous mutations in the RLBP1 gene (15q26.1) are responsible for this disorder.  Homozygous mutations in RLBP1 have also been found among patients with fundus albipunctatus (136880), retinitis punctata albescens, and in Bothnia type retinal dystrophy (607475),

NFRCD clinically resembles Bothnia type retinal dystrophy (607475) which likewise results from mutations in the RLBP1 gene but the maculae appear normal or have only a mild ‘beaten-bronze’ atrophy.

See Flecked Retina entry for somewhat similar conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

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