dyschromatopsia

Spinocerebellar Ataxia 7

Clinical Characteristics
Ocular Features: 

Pigmentary changes in the retina are somewhat variable but often begin with a granular appearance in the macula and spread into the periphery.  The macula often becomes atrophic and dyschromatopsia is common.   Retinal thinning is evident, especially in the macula.  Decreased visual acuity and loss of color vision are early symptoms and the ERG shows abnormalities of both rod and cone function.  External ophthalmoplegia without ptosis is a frequent sign.  Most adults and some children eventually are blind. 

Systemic Features: 

Symptoms of developmental delay and failure to thrive may appear in the first year of life followed by loss of motor milestones.  Dysarthria and ataxia are nearly universal features while pyramidal and extrapyramidal signs are more variable.  This can be a rapidly progressive disease and children who develop symptoms by 14 months are often deceased before two years of age.  However, adults with mild disease can survive into the 5th and 6th decades.  Peripheral neuropathy with sensory loss and motor deficits are usually present to some degree but the range of clinical disease is wide.  Cognitive decline and some degree of dementia occur sometimes. 

Genetics

Spinocerebellar ataxia 7 is caused by expanded trinucleotide repeats (CAG) in the ATXN7 gene (3p21.1-p12) and inherited in an autosomal dominant pattern.  The number of repeats is variable and correlated with severity of disease.  Most patients with 36 or more repeats have significant disease. This disorder is sometimes classified as a progressive cone-rod dystrophy.  It is sometimes referred to as olivopontocerebellar atrophy type III or OPCA3.

This disorder exhibits genetic anticipation especially with paternal transmission as succeeding generations often have earlier onset with more severe and more rapidly progressive disease. This is explained by the fact that younger generations tend to have a larger number of repeats and sometimes the diagnosis is made in children before the disease appears in parents or grandparents.

Spinocerebellar ataxia 1 (164400) is a similar autosomal dominant disorder with many of the same clinical and genetic features.  It is caused by excess CAG repeats on the ATXN1 gene on chromosome 6. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known for the disease.  Low vision aids and mobility training may be useful in early stages. 

References
Article Title: 

Stargardt Disease

Clinical Characteristics
Ocular Features: 

Stargardt disease or fundus flavimaculatus is a progressive form of juvenile macular degeneration with considerable clinical and genetic heterogeneity.  It may be considered a syndromal cone-rod dystrophy because of overlapping clinical features such as loss of color vision and photophobia in some patients.  Adding to the confusion is the fact that mutations in at least 4 genes are responsible for similar clinical characteristics.  Due to the lack of diagnostic distinctions and the wide range of nonspecific clinical manifestations, Stargardt disease and fundus flavimaculatus are discussed here as a single entity.

Onset of vision loss is often noted late in the first decade of life usually with rapid progression.  However, some patients are asymptomatic until much later, even into the fifth decade.  There is evidence that patients with an early onset have a worse prognosis compared to those with a later onset.  Nevertheless, large series of patients contain at least 23% with 20/40 or better acuity, about 20% with 20/50 -20/100, 55% have 20/200-20/400, and a small number have vision less than 20/400. 

Some color discrimination is lost and photophobia may be a complaint.  Dark adaptation is prolonged but nightblindness does not usually occur and peripheral visual fields are normal.  The posterior pole characteristically has yellowish pisciform, round, and linear subretinal lipofuscin deposits which often extend to the equator.  These may be present before clinical symptoms are present.  Histopathology reveals accumulations of this material in RPE cells.  Atrophy of the RPE in the same region is often visible as well but these changes may be subtle initially.  Some patients have peripheral pigment clumping which may resemble the bone spicule configuration seen in retinitis pigmentosa.  However, retinal vessel caliber is normal in Stargardt disease.  Extensive macular disease can be associated with temporal pallor of the optic nerve.  The ERG shows reduced photopic responses with normal or near normal scotopic tracings.  Fluorescein angiography often reveals more extensive disease than seen on fundoscopy.  Window defects are common in the macula where the RPE is atrophied.  The flecks may be hypo- or hyperfluorescent.  Over 50% of patients have patches of angiographically dark choroid in the posterior pole which is thought to be secondary to transmission blockage by lipofuscin accumulations in the RPE. 

Systemic Features: 

None.

Genetics

This group of disorders may be caused by mutations in at least 4 genes.  These are: STGD1 (248200) caused by mutations in the ABCA4 gene located at 1p22.1, or in CNGB3 (262300) (8q21-q22) which also is mutant in achromatopsia 3 (ACHM3), STGD3 (605512) caused by mutations in the ELOVL4 gene at 6q14, and STGD4 (603786) caused by a mutation in PROM1 on chromosome 4p.  STGD4 and STGD3 disease have been found in pedigrees consistent with autosomal dominant inheritance but STGD1 disease seems to be inherited in an autosomal recessive pattern.

Genotyping is necessary for accurate diagnostic determinations.  In particular, a few patients clinically found to have typical areolar macular dystrophy, retinitis pigmentosa, juvenile macular degeneration, and cone dystrophies have been reported in association with several of these mutations and reports have also associated Stargardt disease with mutations in RDS.

A single family with a brother and sister with Stargardt disease and neurological malformations has been reported (612948).  Both had developmental delays associated with absence or hypoplasia of the corpus callosum, upslanted lid fissures, 'flared eyebrows', a broad nasal tip, a broad face with a pointed chin, and sensorineural hearing loss along with mild digital malformations.  Evidence of macular degeneration was seen at age 7 years and vision in both individuals was in the 20/100-20/200 range. No associated locus or mutation has been identified.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this disorder but low vision aids can be helpful especially in the early stages of the disease.

Isotretinoin has been shown to slow the accumulation of lipofuscin pigments in mice but its role in human Stargardt disease has not been reported.  Trials using stem cells are underway with encouraging early results.

References
Article Title: 

Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R. Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions. Genet Med. 2014 Dec 4.  [Epub ahead of print].

PubMed ID: 
25474345

Optic Atrophy 5

Clinical Characteristics
Ocular Features: 

The phenotype in OPA5 has some similarities to that of OPA1 (125250, 165500).  Onset occurs as early as the first decade of life in some families but may not be evident until the third decade in other families.  Visual acuity decreases slowly and color vision is impaired, more so in older patients.  Temporal pallor of the optic nerve is usually present and central scotomas with narrowing of the visual fields can be plotted.  The nerve fiber layer is reduced in thickness.  VEP defects likewise are variable and generally more severe in later stages.  No ERG abnormalities have been reported.  This is a bilateral disease with nearly 100% penetrance.

Systemic Features: 

No systemic abnormalities are present.

Genetics

Heterozygous mutations in the DNM1L gene (12p11.21) are found in patients with OPA5.  Morphologic changes found in mitochondria have been interpreted as consistent with an impairment in fission.  Two families who had been previously reported to have mutations at the 22q12.1 locus were found to have the DNM1L mutation.

Like several other forms of heritable optic atrophy, OPA1 (125250, 165500) and OPA4 (605293), this is an autosomal dominant disorder.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment of the optic atrophy is available but low vision aids can be helpful to utilize remaining vision.

References
Article Title: 

Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission

Gerber S, Charif M, Chevrollier A, Chaumette T, Angebault C, Kane MS, Paris A, Alban J, Quiles M, Delettre C, Bonneau D, Procaccio V, Amati-Bonneau P, Reynier P, Leruez S, Calmon R, Boddaert N, Funalot B, Rio M, Bouccara D, Meunier I, Sesaki H, Kaplan J, Hamel CP, Rozet JM, Lenaers G. Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. Brain. 2017 Oct 1;140(10):2586-2596.

PubMed ID: 
28969390

Optic Atrophy 6

Clinical Characteristics
Ocular Features: 

Visual impairment is often noted under the age of 6 years.  The disease is bilateral and loss of vision procedes slowly, eventually reaching 20/100 to 20/200.  Moderate photophobia and dyschromatopsia are present but nystagmus is absent.  The impact on the visual field seems to be minimal and limited to decreased sensitivity in the central areas.

Systemic Features: 

No systemic abnormalities are associated.

Genetics

Evidence for this presumed autosomal recessive type of optic atrophy is based on a single large, consanguineous French Canadian family.  A locus in the 8q21-q22 region presumably containing the mutant gene, designated OPA6, was found.  Linkage analysis excluded genes linked to autosomal dominant optic atrophy.

Another autosomal recessive optic atrophy disorder (OPA7; 612989) has also been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond low vision aids is helpful.

References
Article Title: 

Optic Atrophy 4

Clinical Characteristics
Ocular Features: 

This form of optic atrophy is clinically heterogeneous similar to others.  It is less common than OPA1 (165500).  Visual acuity ranges from normal to 6/200.  Individuals that carry the mutation usually have some degree of bilateral optic disc pallor and dyschromatopsia even in the presence of 20/20 acuity.  This profile is present in the first decade of life in some patients with most experiencing acute or subacute loss of vision between the ages of 18 and 35 years.  Vision loss is progressive in the majority of patients but unpredictable with some experiencing rapid decline whereas others have only a slow decline.  Age and visual acuity are not strongly correlated but in general older individuals have worse acuity.

Systemic Features: 

There are no systemic findings in OPA4.

Genetics

This is an autosomal dominant disorder secondary to mutations in the OPA4 gene at 18q12.2-q12.3.

Other autosomal dominant optic atrophy disorders include OPA1 (125250, 165500) and OPA5 (610708).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for hereditary optic atrophy but low vision aids can be helpful for visual assistance.

References
Article Title: 

Night Blindness, Congenital Stationary, CSNB1A

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.  The photopic ERG is usually 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. 

CSNB1A, or type 1A, is associated with myopia which ranges from mild to severe.  Rod function is completely absent.  Nystagmus and strabismus are inconsistent findings.   Visual acuity ranges from 20/30 to 20/200.  Retinal pigmentation is usually normal in the X-linked forms.  Night blindness is more severe in this form than in another X-linked CSNB, type 2A (300071). 

Systemic Features: 

No systemic disease is associated with congenital stationary night blindness.

Genetics

Congenital stationary night blindness type 1A is an X-linked disorder caused by a mutation in the NYX gene located at Xp11.4.  Only males are affected and carrier females do not have clinical disease (although homozygous females with typical findings have been described).

Approximately 45% of X-linked CSNB are of this type while about 55% have another X-linked form known as CSNB2A, or type 2A (300071) resulting from a mutation at Xp11.23.  A single patient with high myopia absent night blindness with a mutation in the NYX gene has been reported.

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: 

Goldmann-Favre Syndrome/ESCS

Clinical Characteristics
Ocular Features: 

Enhanced S-cone syndrome, sometimes called Goldman-Favre syndrome, is a retinal disorder characterized by increased sensitivity to blue light, night blindness from an early age, and decreased vision.  Additional features include an optically empty liquefied vitreous, progressive foveal or peripheral retinoschisis, macular cysts, chorioretinal atrophy and pigmentary retinopathy as well as posterior subcapsular cataract formation.  Hyperopia is a feature, at least in childhood.   Enhanced S-cone syndrome is the only retinal disorder that has a gain of a subtype of photoreceptors, in this case the S-cones (short wave length) that detect blue light. Rod photoreceptors and red and green cone receptors are degenerated to a variable degree. Electroretinography shows an extinct rod photoreceptor response and hypersensitivity to shorter wavelengths.

There is considerable variation in the clinical features of NR2E3 mutations which has led to some confusion in the nosology.  Some cases are called juvenile retinoschisis, others are called retinitis pigmentosa, or clumped pigment retinopathy.  Central acuity ranges from near normal (20/40) in young people to 20/200 or worse especially in older adults.  Visual field constriction likewise varies from patient to patient.  Retinal pigmentary changes and the amount of cystic changes in the macula are somewhat age dependent.

Systemic Features: 

No general systemic manifestations are associated with enhanced S-cone syndrome and Goldman-Favre syndrome.

Genetics

This is an autosomal recessive retinal disorder caused by mutations in NR2E3, also known as PNR, located on chromosome 15q23.  It is a part of a transcription factor complex necessary for the development of photoreceptors.  Mutations in NR2E3 cause degeneration of rod photoreceptors and an increased number of S-cone photoreceptors resulting in an increased ratio of blue to red-green cone photoreceptors. Mutations in the NR2E3 gene can also cause a clinical picture resembling simple autosomal recessive retinitis pigmentosa.

Two brothers with an enhanced S-cone phenotype and normal rod function have been reported.  Scotopic b-wave ERG amplitudes were normal but OCT showed flattening of the macular area and thinning of the photoreceptor layer.  This may be the result of a different mutation in this family but no molecular defect was found.

Several Moroccan families have been reported with homozygous or compound heterozygous mutations in the NRL gene (162080).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is presently no effective treatment for the disorder, but visual function can be improved with low vision aids. Cataract surgery may be beneficial.

Improvement in vision has been reported with the use of topical carbonic anhydrase inhibitors.

References
Article Title: 

Expanded Clinical Spectrum of Enhanced S-Cone Syndrome

Yzer S, Barbazetto I, Allikmets R, van Schooneveld MJ, Bergen A, Tsang SH, Jacobson SG, Yannuzzi LA. Expanded Clinical Spectrum of Enhanced S-Cone Syndrome. JAMA Ophthalmol. 2013 Aug 29.  [Epub ahead of print] PubMed PMID: 23989059.

PubMed ID: 
23989059

Phenotypic variation in enhanced S-cone syndrome

Audo I, Michaelides M, Robson AG, Hawlina M, Vaclavik V, Sandbach JM, Neveu MM, Hogg CR, Hunt DM, Moore AT, Bird AC, Webster AR, Holder GE. Phenotypic variation in enhanced S-cone syndrome. Invest Ophthalmol Vis Sci. 2008 May;49(5):2082-93.

PubMed ID: 
18436841

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