autosomal dominant

Myopia 2, Autosomal Dominant, Nonsyndromal

Clinical Characteristics
Ocular Features: 

Nonsyndromal, high myopia (over 6 D) has been found in multiple multigenerational families.  Most individuals have no other ocular problems but a small percentage develop degenerative changes in the retina, particularly in the macula (Fuchs spot).  A few individuals have posterior staphylomas with significant vitreoretinal changes conferring higher risks of retinal detachments and macular holes.  Vitreous traction is often present.  The macula in such cases is may be thickened and microcystic with areas of frank retinoschisis.  Of course, vitreous degeneration and retinal detachments are well known sequelae of high myopia. 

Systemic Features: 

There are no systemic features by definition. 

Genetics

Refractive errors are continuous traits with a wide range in most populations.  This suggests that many developmental and heritable (and perhaps environmental) components are responsible.  No specific mutation has been identified but a number of 'susceptibility' loci have been mapped.

Myopia 2 has been linked to a susceptibility locus at 18q11.31.

Evidence of heritability in both syndromal and isolated myopia comes from several sources.  For example, high myopia is a common feature in familial collagenopathies such as Marfan syndrome (154700), Kniest dysplasia (156550), and Stickler syndrome (108300). Multigenerational families with isolated myopia have been reported as well and mutations in multiple genes (at least 18) have been associated with these.  Heredibility studies using twin pairs have identified additional mutations (609256).  Further, the prevalence of myopia among children increases in the presence of parental myopia.

The transmission pattern in most families to which susceptibility loci have been linked is autosomal dominant.  However, a susceptibility locus has been mapped to 14q22.1-q24.2 in several families with good evidence for autosomal recessive inheritance (255500).  In addition, two loci on the X chromosome have been linked to presumed X-linked myopia (MYP1 [310460] at Xq28 and MYP13 [300613] at Xq23-q25).  A patient with high myopia has been reported with a mutation in the NYX gene on the X-chromosome.  This patient did not have congenital stationary night blindness of the type CSNB1A (310500) in which NYX is usually mutated.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Correction of the refractive error is primary.  High myopes require periodic evaluation throughout life and prompt surgical intervention for retinal detachments.  In extreme myopia it may be especially prudent for individuals to avoid impact sports. 

References
Article Title: 

Vitreoretinochoroidopathy

Clinical Characteristics
Ocular Features: 

Clinical features are variable in this ocular disorder. Small corneas and shallow anterior chambers have been described in some patients.  Chronic narrow angle glaucoma or frank angle closure glaucoma attacks may occur.  Microphthalmia has been reported but nanophthalmos has not been documented.  Presenile cataracts, nystagmus, and strabismus are sometimes present.  Some patients have normal vision but others have a severe reduction in acuity, even blindness.

The vitreous is often liquefied and some patients have a fibrillary vitreous with pleocytosis.  Preretinal white dots and neovascularization are often seen, even in children.  Peripapillary atrophy may extend to the macula which may have cystic edema.  Peripherally in annular fashion there is often a pigmentary retinopathy extending to an equatorial demarcation line at the posterior border.  The ERG is usually moderately abnormal with evidence of rod and cone dystrophy generally in older patients in which some degree of dyschromatopsia is often present.  Some patients demonstrate a concentric reduction in visual field that progresses with age.  A reduced light/dark ratio has also been documented in several families.  Retinal detachment is a risk.  A posterior staphylomas has been noted in a few patients. 

Systemic Features: 

No systemic abnormalities have been reported. 

Genetics

This is an autosomal dominant disorder resulting from mutations in BEST1 (11q13), which is also responsible for Best vitelliform macular dystrophy (153700). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No prophylactic treatment has been reported but patients need lifelong monitoring to detect and treat glaucoma, retinal neovascularization, and detachments. 

References
Article Title: 

Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC)

Yardley J, Leroy BP, Hart-Holden N, Lafaut BA, Loeys B, Messiaen LM, Perveen R, Reddy MA, Bhattacharya SS, Traboulsi E, Baralle D, De Laey JJ, Puech B, Kestelyn P, Moore AT, Manson FD, Black GC. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3683-9.

PubMed ID: 
15452077

Optic Nerve Hypoplasia, Bilateral

Clinical Characteristics
Ocular Features: 

The hallmark of this syndrome is bilateral optic nerve dysplasia including aplasia and hypoplasia. It may occur in isolation or as part of other syndromes, especially in those having abnormalities of the central nervous system.  All components of the nerve head are abnormally small including the entire disc area, the cup, and the neuroretinal rim. It has been reported that retinal vein tortuosity is predictive of patients with endocrinopathies.  Retinal arteries often appear straight and narrow but this may not be seen in all cases.  Visual acuity ranges from 20/50 to NLP but usually 20/200 or better.  Many patients have nystagmus and strabismus.

This disorder shares many characteristics with septooptic dysplasia (182230) but the optic nerve anomalies are usually unilateral in the latter disorder and the disc rim often has a double margin.  Mutations in different genes are responsible for the two disorders. 

Systemic Features: 

Pituitary dysfunction and endocrinopathy may lead to life-threatening illness caused by adrenal crisis or hypoglycemia.  An absent or abnormal septum pellucidum is present in 49% of patients and 64% have a hypothalamic-pituitary axis abnormality.  Among those with an abnormal septum pellucidum, 56% have some kind of endocrinopathy. Other midline brain defects and cerebral anomalies have also been reported.

 

Genetics

Bilateral optic nerve hypoplasia is inherited in an autosomal dominant pattern based on the few families reported.  Mutations in the PAX6 (11q13) gene are responsible.

A somewhat similar disease with extensive CNS and endocrinological abnormalities is septooptic dysplasia (182230) caused by mutations in the HESX1 gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the optic nerve hypoplasia but individuals need to be monitored for endocrinopathy and treated appropriately.  Low vision aids and sometimes mobility training can be helpful for some patients. 

References
Article Title: 

Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging

Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003 Nov;88(11):5281-6.

PubMed ID: 
14602752

Foveal Hypoplasia 1

Clinical Characteristics
Ocular Features: 

This is a poorly defined syndrome with features overlapping aniridia, hereditary keratitis, ocular albinism, and iris anomalies as in Peters anomaly.  However, presenile cataracts seem to be unique to this disorder.  The foveal hypoplasia may occur without other anomalies although the fundus is usually lightly pigmented.  As expected, acuity is subnormal from birth, in the range of 20/50, and dyschromatopsia may be present.  Some patients have nystagmus.  Weak iris transillumination has been reported and a small limbal pannus may be present. Lens opacities may become visually significant in the third to fourth decade of life.  OCT has shown abnormal foveal thickness with multiple inner retinal layers somewhat similar to the situation in oculocutaneous albinism (203100) and it has been suggested that 'foveal dysplasia' is a better description than 'foveal hypoplasia'. 

Systemic Features: 

No systemic disease is present. 

Genetics

This disorder is associated with mutations in the PAX6 gene (11p13) and inherited as an autosomal dominant.

The protein product of the PAX6 gene is a transcription factor that attaches to DNA and regulates the expression of other genes.  PAX6 plays a major role primarily in development of the eye and central nervous system but evidence suggests it is also active postnatally.  Hundreds of mutations have been found in disorders such as hereditary keratitis, aniridia, Peters anomaly, hypoplasia and colobomas of the optic nerve.  This database contains 8 conditions in which mutations in PAX6 seem to be responsible, including syndromal conditions such as Stromme and Gillespie syndromes in which there may be cognitive disabilities. 

True isolated foveal hypoplasia without lens or corneal disease does exist as well but this condition (FVH2) is not well defined.  Homozygous mutations in SLC38A8 have been found to cosegregate with this form of foveal hypoplasia among families of Jewish Indian ancestry.  Hypopigmentation is not a feature of isolated foveal hypoplasia secondary to such mutations but misrouting of optic nerve axons may be present.  Nystagmus and reduced vision but no anterior segment abnormalities were present.

With the widespread utilization of OCT measurements, we have learned that underdevelopment of the fovea can be a feature of numerous ocular disorders (more than 20 in this database).  In most conditions, the foveal dysplasia is part of a disease complex as in foveal hypoplasia with anterior segment dysgenesis (609218).

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated when lens opacities become visually significant. 

References
Article Title: 

Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism

Poulter JA, Al-Araimi M, Conte I, van Genderen MM, Sheridan E, Carr IM, Parry DA, Shires M, Carrella S, Bradbury J, Khan K, Lakeman P, Sergouniotis PI, Webster AR, Moore AT, Pal B, Mohamed MD, Venkataramana A, Ramprasad V, Shetty R, Saktivel M, Kumaramanickavel G, Tan A, Mackey DA, Hewitt AW, Banfi S, Ali M, Inglehearn CF, Toomes C. Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism. Am J Hum Genet. 2013 Dec 5;93(6):1143-50.

PubMed ID: 
24290379

Keratitis, Hereditary

Clinical Characteristics
Ocular Features: 

The disorder begins in the first year of life with a band of vascularized opacification inside the limbus.  Evidence of inflammation is seen in the anterior stroma and the Bowman membrane becomes replaced by fibrovascular tissue.  The disease is recurrent and progressive and there is usually asymmetry between the two eyes.  Non-penetrance and considerable variation in expression have been reported.  Acute episodes are characterized by photophobia, tearing, mucous discharge, and punctate keratitis.  The limbal opacification may progress centrally and eventually leads to a reduction in vision.  Deficits in visual acuity may lead to deprivation amblyopia and secondary esotropia.

In a 4 generation family, foveal hypoplasia, iris stromal defects, and ectropion uveae were seen in several of the fifteen affected individuals.  It has been suggested that this may be a variant of aniridia. 

Systemic Features: 

No systemic disease has been found. 

Genetics

This is an autosomal dominant disorder reported in several multigeneration families.  Mutations in the PAX6 gene (11p13) seem to be responsible.  The same gene is mutant in Gillespie syndrome (206700), aniridia (106210) and Peters anomaly (604229). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no effective treatment.  Penetrating keratoplasty in several individuals has been followed by similar disease in the donor tissue. 

References
Article Title: 

Dominantly inherited keratitis

Kivlin JD, Apple DJ, Olson RJ, Manthey R. Dominantly inherited keratitis. Arch Ophthalmol. 1986 Nov;104(11):1621-3.

PubMed ID: 
3778274

Cone-Rod Dystrophies, AD and AR

Clinical Characteristics
Ocular Features: 

Cone-rod dystrophies (CRD) are a group of pigmentary retinopathies that have early and important changes in the macula.  Cone dysfunction occurs first and is often followed by rod photoreceptor degeneration.

Common initial symptoms are decreased visual acuity, dyschromatopsia, and photophobia which are often noted in the first decade of life.  Night blindness occurs later as the disease progresses.  A fine nystagmus is also common. Visual field defects include an initial central scotoma with patchy peripheral defects followed by larger defects in later stages.  The fundus exam can be normal initially, but is followed by pigmentary bone spicule changes, attenuation of retinal vessels, waxy pallor of the optic disc and retinal atrophy.  A ring maculopathy surrounding the fovea is usually evident.  The ERG first reveals photopic defects and later scotopic changes.  Fluorescein angiography and fundus autofluorescence generally reveal atrophic retinopathy.  Many patients eventually become legally blind as the disease progresses and some end up with no light perception.

Cone-rod dystrophies are a group of disorders separate from rod-cone dystrophies where the primary defect is in the rod photoreceptors with typical pigmentary changes in the peripheral retina. The progression of vision loss is generally slower in rod-cone dystrophies. Cone dystrophies comprise another group of disorders with exclusive cone involvement in which the macula often has a normal appearance in association with loss of central acuity.

Systemic Features: 

No systemic disease is associated with simple cone-rod dystrophies.  See below for syndromal disorders with cone-rod dystrophy. 

Genetics

Non-syndromic cone-rod dystrophies can be either autosomal dominant, autosomal recessive or X-linked and are caused by defects in at least 17 different genes.  This database entry discusses only the autosomal disorders.  See X-linked cone-rod dystrophies in a separate entry.

Cone-rod dystrophies inherited in an autosomal dominant pattern include:

CORD2 (120970) is caused by mutations in CRX at 19q13.3, a homeobox gene responsible for the development of photoreceptor cells.  These are responsible for 5-10% of autosomal dominant cone-rod dystrophy cases (602225) and can also cause one type (LCA7) of Leber congenital amaurosis (602225) and a late-onset retinitis pigmentosa phenotype.

CORD5 (600977) is caused by mutations in the PITPNM3 gene at 17p13.1. 

CORD6 (601777) is caused by a mutation in GUCY2D in a similar location on chromosome 17. 

CORD7 (603649) is caused by mutations in RIMS1 at 6q12-q13.

Mutations in AIPL1 (604392), located in the same region, usually causes a form of Leber congenital amaurosis (LCA4) as well as retinitis pigmentosa (604393) but has also been reported in a cone-rod pigmentary retinopathy.

CORD11 (610381) is caused by mutations in RAXL1 (19p13.3).

CORD12 (612657) results from mutations in the PROM1 gene (4p15.3).

Mutations in the gene GUCA1A on chromosome 6p21.1 causes CORD14 (602093).

An as yet unclassified autosomal dominant type of cone-rod dystrophy has recently been localized to 10q26.

Cone-rod dystrophies inherited in an autosomal recessive pattern include:

Mutations in ABCA4 at 1p21-p13 is responsible for 30-60% of cases of autosomal recessive CRD (CORD3; 604116) .  ABCA4 is also known to cause autosomal recessive Stargardt disease.

CORD8 (605549) has been found in a single consanguineous family and the mutation localized to 1q12-q24.

ADAM9 (602713) at 8p11 and 8p11.23 contains mutations that have been shown to cause autosomal recessive CORD9 in several consanguineous families.

Mutations in RPGRIP1 (14q11) are responsible for CORD13 (608194).

The CDHR1 gene (10q23.1) contains mutations that cause CORD15 (613660).

Other autosomal CRD disorders are CORD1 (600624) described in a single individual and possibly those due to mutations in HRG4 at 17q11.2 (604011).

Syndromal cone-rod dystrophies:

Cone-rod dystrophy may also be associated with other syndromes, such as Bardet-Biedl syndrome (209900), or spinocerebellar ataxia Type 7 (164500), autosomal recessive amelogenesis imperfecta with cone-rod dystrophy or Jalili syndrome (217080), neurofibromatosis type I (162200), and hypotrichosis with juvenile macular dystrophy and alopecia (601553).  Metabolic disorders associated with cone-rod dystrophy include Refsum disease with phytanic acid abnormality (266500) and Alport syndrome (301050). 

Cone-Rod Dystrophy 19 (615860) has been associated with male infertility as the result of mutations in TTLL5 affecting both photoreceptors and sperm.

Pedigree: 
Autosomal dominant
Autosomal recessive
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: 

A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q

Kamenarova K, Cherninkova S, Romero Dur?degn M, Prescott D, Vald?(c)s S?degnchez ML, Mitev V, Kremensky I, Kaneva R, Bhattacharya SS, Tournev I, Chakarova C. A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q. Eur J Hum Genet. 2012 Aug 29. doi: 10.1038/ejhg.2012.158. [Epub ahead of print]

PubMed ID: 
22929024

Cone rod dystrophies

Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007 Feb 1;2:7. Review.

PubMed ID: 
17270046

Gillespie Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral aniridia, partial or complete, is the ocular characteristic of Gillespie syndrome.  The iris may be relatively intact but immobile leading to the description in some patients of "dilated and fixed pupils", or congenital mydriasis.  The pupillary margin may be scalloped with iris strands to the lens.  The pupillary sphincter is sometimes absent and the mesodermal surface missing.  The fovea sometimes appears hypoplastic and some patients have decreased visual acuity.  Strabismus and ptosis are often present.  There may also be retinal hypopigmentation.  Cataract, glaucoma, and corneal opacities are not present. 

Systemic Features: 

Most patients have some degree of developmental delay ranging from difficulties with fine motor tasks to frank mental retardation.  Many have a hand tremor, some degree of hypotonia, and learning difficulties.  MRI imaging often shows cerebellar and sometimes cerebral hypoplasia. 

Genetics

This is an autosomal dominant disorder usually due to a heterozygous mutation in the PAX6 gene (11p13).  However, some patients with typical features do not have a mutation in this gene suggesting that there is genetic heterogeneity.  Some patients without point mutations nevertheless have defects in adjacent DNA suggesting a positional effect.  The possibility of autosomal recessive inheritance in some families with parental consanguinity cannot be ruled out.  The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Mutations in the ITPR1 gene have also been identified in Gillespie syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Retinitis Pigmentosa, AD

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa is a large group of disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The later may have a 'bone corpuscle' appearance with a perivascular distribution.  A ring scotoma is sometimes evident.  Age of onset and rate of progression is highly variable, even within families.  The rods are impacted early but cone deterioration with loss of central vision usually follows.  Some patients complain of dyschromatopsia and photophobia.  The ERG generally documents this progression but the mfERG shows wide variations in central cone functioning.  Legal blindness is common by the 5thdecade of life or later.  The course of clinical and ERG changes is more aggressive in the X-linked form than in the autosomal dominant RHO disease.  The final common denominator for all types is first rod and then cone photoreceptor loss through apoptosis.

As many as 50% of patients develop posterior subcapsular cataracts.  The vitreous often contains cells and particulate debris.   Retinal arterioles are often attenuated and the optic nerve may have a waxy pallor, especially late in the disease.  Occasional patients have cysts in the macula.  Some patients experience continuous photopsia.  

Systemic Features: 

The 'simple' or nonsyndromal type of RP described here has no systemic features.  However, the retinopathy is seen in a number of syndromes and, of course, in trauma and in some infectious diseases as well. 

Genetics

A significant proportion of RP cases occur sporadically, i.e., without a family history.  Mutations in more than 25 genes cause autosomal dominant RP disorders and these account for about one-third of all cases of retinitis pigmentosa but there are many more specific mutations.  More than 100 have been identified in the RHO gene (3q21-q24) alone, for example.  Mutations in some genes cause RP in both autosomal recessive and autosomal dominant inhritance patterns.  See OMIM 268000 for a complete listing of mutations.

Many genes associated with retinitis pigmentosa have also been implicated in other pigmentary retinopathies.  In addition numerous phenocopies occur, caused by a variety of drugs, trauma, infections and numerous neurological disorders.  To make diagnosis even more difficult, the fundus findings and ERG responses in nonsyndromic RP in most patients are too nonspecific to be useful for classification. Extensive systemic and ocular evaluations are important and should be combined with genotyping in both familial and nonfamilial cases to determine the diagnosis and prognosis. 

For autosomal dominant retinitis pigmentosa resulting from mutations in RP1, see Retinitis Pigmentosa 1 (180100). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in 8 patients without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  The use of oral and systemic carbonic anhydrase inhibitors can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E. 

References
Article Title: 

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

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