autosomal dominant

Cataracts, Congenital, Volkmann Type

Clinical Characteristics
Ocular Features: 

The nature of lens opacities is highly variable, ranging from dense opacification to barely detectable opacities.  The opacities may be located in the embryonic, fetal and juvenile nuclei as well as around the Y sutures.  They are congenital in origin and progressive.   Minimal opacities can be asymptomatic early but all eventually require removal, usually by the first or second decades of life.  Most cases have been reported from Denmark. 

Systemic Features: 

No systemic disease is present. 

Genetics

This type of cataract is inherited in an autosomal dominant pattern.  The causative mutation is unknown but a presumed locus has been identified at 1pter-p36.13.  This type of cataract may be allelic to congenital posterior polar cataract (116600).

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Coppock-like (604307), and lamellar (116800), cataracts. Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant cataracts may require removal. 

References
Article Title: 

Fibrosis of Extraocular Muscles, CFEOM1

Clinical Characteristics
Ocular Features: 

Hereditary CFEOM is a congenital, nonprogressive condition.  The eyes are usually fixed in the infraducted position about 20-30 degrees below the primary position.  Horizontal movement is absent or severely restricted.  Blepharoptosis is almost always present and patients exhibit a marked chin-up position of gaze.  Binocularity is usually absent.  Some patients have large amounts of astigmatism.  Amblyopia has been reported to occur on a refractive or strabismic basis.  However, careful examination of the optic nerve may reveal anomalies such as increased cupping, asymmetric cupping and hypoplasia and could be responsible for the reduced vision in some patients.

Neuropathologic studies in rare patients have shown defects in brainstem neural development including in one case absence of the superior division of the oculomotor nerve.  Fibrosis of extraocular muscles and Tenon's capsule as well as adhesions to the globe and between muscles have been described.   Anomalous insertions of EOMs may also occur.  An MRI can reveal atrophy of the levator palpebrae and the superior rectus muscles as well as absence or hypoplasia of the oculomotor and sometimes abducens nerves.  It is now considered that CFEOM disorders result from primary neuronal disease resulting in secondary myopathy. 

Systemic Features: 

Late onset gait abnormalities associated with MRI documented vermis atrophy have been reported in a single autosomal dominant pedigree.  The diagnosis of CFEOM1 was confirmed with molecular studies but only two older individuals aged 79 and 53 years had the cerebellar atrophy while a 33 year old in the same family had only CFEOM with no gait difficulties and no neuroimaging abnormalities.

Genetics

CFEOM1 is an autosomal dominant disorder caused by mutations in the KIF21A gene located at 12q12.  This is considered the classic form of congenital, restrictive strabismus but other types such as CFEOM2 (602078) and CFEOM3 (600638, 609384) have also been reported.  CFEOM3 is a clinically heterogeneous autosomal dominant condition and the label is usually applied to individuals who do not meet the criteria for the other two types.  A rare subtype (CFEOM3B) is also due to mutations in the KIF21A gene.  CFEOM3A (600638) is caused by mutations in the TUBB3 gene (16q24) while CFEOM3C (609384) maps to 13q.

The CFEOM2 (602078) phenotype is due to mutations in the PHOX2A (ARIX) gene and inherited in an autosomal recessive pattern.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM3C (609384), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normal ocular movements cannot be restored but large recessions of the inferior recti followed by frontalis suspension of the upper eyelids can improve severe ptosis and the compensatory chin-up gaze. Corneal lubrication must be maintained.  Refractive errors and amblyopia should be corrected.  

References
Article Title: 

Blepharoptosis, Myopia, Ectopia Lentis

Clinical Characteristics
Ocular Features: 

A mother and 2 daughters with ectopia lentis, myopia, and blepharoptosis have been reported.  The axial length of the globes was increased in the mother and one of the daughters while the myopia in the other daughter with ectopia lentis was presumably lens-induced as the equator bisected the visual axis (axial length approximately 25mm).  The upper lid creases were considered to be abnormally high but levator function was good, consistent with levator aponeurosis disinsertion.  Extraocular movements were normal.  

Systemic Features: 

No systemic abnormalities were present.  More specifically, there was no evidence of Ehlers-Danlos (225400) or Marfan syndrome (154700).

Genetics

The presence of similar findings in a mother and 2 daughters suggests autosomal dominant inheritance but no locus has been identified. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Displaced lenses may need to be removed. 

References
Article Title: 

Neuronal Ceroid Lipofuscinoses

Clinical Characteristics
Ocular Features: 

At least 13 genotypically distinct forms of neuronal ceroid lipofuscinosis have been described.  The ocular features are highly similar in all forms with blindness the end result in all types (although not all cases with an adult onset suffer vision loss).  The onset of visual signs and symptoms is highly variable.  Optic atrophy is the most common finding which may occur as early as two years of age in the infantile form.  Night blindness is a symptom in those with a later onset but panretinal degeneration with unrecordable ERGs eventually occurs.  Pigmentary changes throughout the retina are often seen and sometimes occur in a bull’s-eye pattern.  Retinal blood vessels may be attenuated and lens opacities of various types are common. 

Systemic Features: 

The neuronal ceroid lipofuscinosis are a group of inherited neurodegenerative lysosomal-storage disorders characterized by the intracellular accumulation of autofluorescent lipopigment causing damage predominantly in the central nervous system.  The result is a progressive encephalopathy with cognitive and motor decline, eventual blindness, and seizures with early death.  While early descriptions distinguished several types based primarily on age of onset, genotyping has now identified responsible mutations in at least 10 genes and time of onset is no longer considered a reliable indicator of the NCL type. 

Genetics

The NCLs are usually inherited in autosomal recessive patterns with the exception of some adult onset cases in which an autosomal dominant pattern is sometimes seen.

The various forms of NCL are often divided according to ages of onset but overlap is common.  Thus the congenital form (CLN10; 610127), caused by a mutation in the CTSD gene at 11p15.5, can have an onset of symptoms at or around birth but also is responsible for an adult form (Vida infra).  The CLN1 infantile form (256730), caused by a mutation in the PPT1 gene at 1p32, has an onset between 6 and 24 months  There are several mutations causing late infantile disease (CLN2, 204500) involving the TPP1 gene (11p15.5) leading to symptoms between 2-4 years, the CLN5 gene (256731) at 13q21.1-q32 with onset between 4 and 7 years, the CLN6 gene (601780) at 15q21-q23 showing symptoms between 18 months and 8 years, and the CLN8 gene (610003) at 8p23 with symptoms beginning between 3 and 7 years.  Another early juvenile form (CLN7; 610951) is caused by mutations in MFSD8 (4q228.1-q28.2).

A juvenile form (sometimes called Batten disease or Spielmeyer-Vogt with onset between 4 and 10 years results from mutations in CLN3 (204200) as well as in TPP1, PPT1, and CLN9 (609055).  An adult form known as ANCL or Kuf’s disease results from mutations in CTSD, PPT, CLN3, CLN5, and CLN4 (204300) and has its onset generally between the ages of 15 and 50 years. 

Homozygous mutations in the ATP13A2 gene (1p36.13), known to cause Kufor-Rakeb type parkinsonism (606693), have also been found in NCL.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Treatment is primarily symptomatic for sleep disorders, seizures, psychoses, malnutrition, dystonia and spasticity.  However, there is recent progress in the application of enzyme-replacement therapies in the soluble lysosomal forms of CNL.  Gene therapies and the use of stem cells also hold promise. 

References
Article Title: 

Oculopharyngodistal Myopathy

Clinical Characteristics
Ocular Features: 

Progressive ptosis, which may be asymmetric, is an early sign.  Extraocular palsy occurs as well. 

Systemic Features: 

The mean age of onset of this progressive disease is 22 years.  Pharyngeal and distal limb muscles seem to be primarily involved.  Weakness in masseter, facial, and bulbar muscles have been observed but no muscle group seems to be spared.  Atrophy of facial muscles is common and may be pronounced.  There is considerable variability in expression, particularly in the degree of limb weakness which often appears by the fifth decade.  Swallowing difficulties can be severe.  Respiratory weakness may be evident relatively early, even while patients are still ambulatory.  Loss of ambulation most commonly occurs by the third or fourth decade after the onset of first symptoms.  Serum creatine kinase levels are mildly elevated and histologic changes show chronic myopathic changes with rimmed vacuole formation.  No changes have been found in the central or peripheral nervous system. 

Genetics

The causative mutation has not been identified but mutations causing other forms of hereditary myopathy have been ruled out.  Most families are consistent with autosomal dominant inheritance but the pattern in at least one family has suggested a recessive pattern indicating genetic heterogeneity. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Supportive treatment such as physical and respiratory therapies may be helpful but no specific treatment is available for the muscle disease.

References
Article Title: 

Oculopharyngodistal myopathy

Satoyoshi E, Kinoshita M. Oculopharyngodistal myopathy. Arch Neurol. 1977 Feb;34(2):89-92.

PubMed ID: 
836191

Microphthalmia with Coloboma, AD

Clinical Characteristics
Ocular Features: 

Isolated colobomatous microphthalmia is uncommon compared with the syndromal conditions of which there are more than 100.  The clinical findings are confined to the eye in this condition.  The globe is abnormally small (defined by some as less than 20 mm in length in at least one eye).   Incomplete penetrance and variable expression are typical but often the cornea is small and may be cloudy with anterior synechiae suggesting that anterior chamber dysgenesis may also be a feature in some cases.  One or both eyes may be involved.  Visual acuity depends on the structures involved.

It is not uncommon for other ocular abnormalities to occur in association with the malformed globes, such as cataracts, microcornea, sclerocornea and optic nerve dysplasia. 

Systemic Features: 

None.

Genetics

The majority of isolated microphthalmos with coloboma are inherited in an autosomal dominant pattern [see also microphthalmia with coloboma, X-linked (MCOPCB1; 300345)].  Reports are mostly of single kinships.  At least 5 additional genes are involved: MCOPCB2 (605738) results from mutations in a locus at 15q12-q15, MCOPCB3 (610092) is caused by mutations in the CHX10 (VSX2) gene (14q24), MCOPCB4 (251505) frequently has a cystic malformation as well and is likely an autosomal recessive condition but the mutation and its location remain unknown, MCOPCB5 (611638) is caused by a mutation in SHH (7q36), and MCOPCB6 (613703) results from mutations in the GDF3 gene (12p13.1).

For an X-linked form of non-syndromic microphthalmia with coloboma, see Microphthalmia with Coloboma (300345 ).  For a syndromal form of X-linked microphthalmia, see Microphthalmia, Syndromic 1 (309800 ). 

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic malformation. 

References
Article Title: 

Choroidal Dystrophy, Central Areolar 1

Clinical Characteristics
Ocular Features: 

The primary feature of this form of macular dystrophy is atrophy of the RPE and choriocapillaris centralized to the macula.  In early stages among young patients in the second decade of life, some pigment changes are seen in the parafoveal area.  Later, the central macula develops hypopigmentation followed by atrophy of the choriocapillaris.  The area is usually sharply defined but fluorescein angiography often shows multiple window defects beyond the edges.  The same region often has speckled autofluorescence.  Secondary dysfunction of the photoreceptors in this area leads to some mild degree of vision loss in adults between the ages of 30 and 60 years but this progressive disease may eventually result in legal blindness.  The ERG demonstrates a cone dystrophy. The rate of disease progression is highly variable.  Visual acuity varies considerably as does the appearance of the macula.  Older individuals may be misdiagnosed as having age-related macular degeneration. 

Systemic Features: 

There is no associated systemic disease. 

Genetics

CACD1 is caused by a hterozygous mutations in GUCY2D gene localized to 17p13.  One large three generation Irish family has been reported.

For a somewhat similar disorder see choroidal dystrophy, central areolar 2 (613105).

CACD is a genetically heterogeneous disorder with mutations in several genes responsible.  The majority of patients have one of several mutations in the PRPH2 gene (6p21.1-cen) and the inheritance pattern seems to be autosomal recessive (CACD2).  However, other family trees in which mutations in PRPH2 were excluded suggest autosomal dominant inheritance (CACD3; 613144) suggesting genetic heterogeneity such as the CACD1 condition described here.   

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment of the macular disease.  However, some patients can benefit from low vision aids. 

References
Article Title: 

Central areolar choroidal dystrophy

Boon CJ, Klevering BJ, Cremers FP, Zonneveld-Vrieling MN, Theelen T, Den Hollander AI, Hoyng CB. Central areolar choroidal dystrophy. Ophthalmology. 2009 Apr;116(4):771-82, 782.e1.

PubMed ID: 
19243827

Macular Dystrophy, Patterned 1

Clinical Characteristics
Ocular Features: 

Patterned dystrophies of the macula are clinically heterogeneous.  It is common for different patterns to be seen among multiple members of a single family.  They can also be different in the two eyes of the same individual.  RPE changes can often be seen in the second decade of life but visual disturbances may not be noted until a decade or two later.  The process is progressive and eventually macular function is severely depressed with vision in the range of 20/200.  The pigmentary retinopathy occurs at the level of the RPE with the typical appearance of pigment but sometimes an accumulation of white or yellowish deposits is present.  The pattern of changes may appear in a configuration resembling the wings of a butterfly, hence the name.  However, vitelliform-like lesions have also been reported.  Paracentral tritan color defects have been described.

Subfoveal choroidal neovascularization can occur.

While the ERG may show some diffuse photoreceptor dysfunction in the presence of normal vision, there is little to suggest a primary rod or cone abnormality. Dark adaptation is normal.  Visual fields can reveal a small central scotoma and fluorescein angiography often shows window defects in the posterior pole. 

Systemic Features: 

Simple patterned macular dystrophy is not associated with systemic disease. 

Genetics

Pattern macular dystrophies are usually inherited as autosomal dominant conditions.  Several mutations in separate genes have been linked to these disorders suggesting that this group is genetically as well as clinically heterogeneous. 

Some families have mutations in the photoreceptor peripherin gene (PRPH2) at 6p21.1-cen (169150) whose gene product is active in the retina. It is important to the integrity and stability of the structures that contain light-sensitive pigments (e.g., photoreceptors). More than 100 mutations have been identified. The resultant phenotype can be highly variable, even within members of the same family but most affected individuals have some degree of pigmentary retinopathy within the macula or throughout the posterior pole.  The altered gene product coded by mutations in PRPH2 often leads to symptoms beginning in midlife as a result of the slow degeneration of photoreceptors. This database contains at least 11 disorders in which PRPH2 mutations have been found.

A locus at 5q21.2-q33.2 containing heterozygous CTNNA1 mutations has been linked to a pattern dystrophy (Macular Dystrophy, Patterned 2) (608970). 

As many as 25% of patients with myotonic dystrophy 1 (160900) and myotonic dystrophy 2 (602668) have a patterned pigmentary maculopathy.

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the macular disease but low vision aids should be considered for appropriate individuals. 

Surveillance is useful for the detection of choroidal neovascularization and prompt treatment with ranibizumab injections can be useful in the elimination of this complication.

References
Article Title: 

Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections

Vaclavik V, Tran HV, Gaillard MC, Schorderet DF, Munier FL. Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections. Retina. 2012 Oct;32(9):1942-9.

PubMed ID: 
22466463

Cone Dystrophy 3

Clinical Characteristics
Ocular Features: 

The evidence for the existence of pure cone dystrophies is inconclusive.  Certainly some patients at least early in the disease seem to have pure cone dysfunction but eventually rod involvement becomes apparent.  Loss of central acuity and color vision occurs in young adults between the ages of 20 and 40 years.   Symptoms usually worsen with age and most patients eventually are legally blind.  Photophobia is common.  Pigmentary mottling in the retina may be evident before symptoms appear.  Thinning of the retina, especially the macula, is seen late in the disease.  Peripheral visual fields and rod function are often normal for many years although scotopic responses on the ERG eventually become attenuated. 

Systemic Features: 

No systemic disease is associated with cone dystrophies. 

Genetics

There is considerable genetic and clinical heterogeneity in photoreceptor disease.  Heterozygous mutations in the GUCA1A (GCAP1) gene located at 6p21.1 seem to be responsible for this form of cone dystrophy, and inheritance therefore follows an autosomal dominant pattern.  However, mutations in the same gene are also associated with macular dystrophy.  The same region contains the RDS (PRPH2) gene which is also known to cause retinitis pigmentosa (608133) and fundus albipunctatus (136880).  RDS (PRPH2) mutations have also been reported in some cases of so-called adult-onset vitelliform macular dystrophy (AVMD)(608161).

Another autosomal dominant cone dystrophy, RCD1, has been linked to a locus at 6q25-q26 but the gene has not yet been identified (180020).  There is also a cone dystrophy with primarily peripheral involvement (609021). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the disease is available but low vision aids can be helpful in selected patients.  Red tinted lenses may provide comfort in bright light. 

References
Article Title: 

Cataracts, Congenital, Autosomal Dominant

Clinical Characteristics
Ocular Features: 

Most cataracts arise as part of the aging process.  However, early onset lens opacities may be familial, often transmitted in an autosomal dominant pattern.  These have a highly variable appearance and may be unilateral or bilateral.  There can be considerable interocular asymmetry in morphology, density, location, and rate of progression.  This is also true of intrafamilial characteristics.  Age of onset is variable. 

Systemic Features: 

There are no associated systemic abnormalities. 

Genetics

At least 25 loci scattered among multiple chromosome have been identified to cause simple autosomal dominant cataracts (See 604219).  It is not yet possible to make phenotypic - genotypic correlations due to the large variation in clinical characteristics. 

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens extraction is indicated when the opacities become visually significant. 

References
Article Title: 

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