open angle glaucoma

Exfoliation Glaucoma

Clinical Characteristics
Ocular Features: 

Whitish flakes resembling dandruff appear on the anterior lens capsule during midlife, often accompanied by pigment.  It is a progressive disorder in all aspects and once established does not regress.  The condition is often asymmetrical and even unilateral, at least in some stages.  This fibrillar material is deposited throughout the anterior chamber including the trabecular meshwork where it blocks the outflow mechanism leading to glaucoma.  The latter is often severe and difficult to control.  It is claimed that the risk of glaucoma is 6 times greater among such patients compared with individuals who do not have exfoliation.  Cataract prevalence is higher among patients with exfoliation and those with cataracts have a higher prevalence of exfoliation.  Dilation is often difficult in such patients and operative complications such as capsular rupture, lens mobility, and vitreous loss are greater.  Posterior synechiae are more frequent in exfoliation patients.  Pupillary block and angle closure glaucoma are additional glaucoma risks.

The majority of evidence suggests that the source of the exfoliation material is the extracellular matrix of ocular structures including the lens epithelium, iris pigment epithelium and the non-pigmented ciliary epithelium.  The exact composition of the material, however, has not been established.

Systemic Features: 

Some consider this to be a systemic disease as well and have associated it with widespread cardiovascular complications, including hypertension, stroke, myocardial infarctions and transient ischemic attacks.  Fibrillar material has been identified in autopsy material among many visceral organs including heart, kidney, liver, and CNS meninges.  Physiologic or etiologic connections, however, have not been established.  The mortality rate among patients with exfoliation syndrome does not appear to be increased and it is currently not recommended that all individuals with ocular pseudoexfoliation undergo general systemic evaluations.

Genetics

This disorder has an ethnic population distribution, an important indication of its genetic basis.  It occurs with high frequency in Scandinavians, Amerindians, Greeks and selective black populations in Africa.  It is not seen in Eskimos. 

There is evidence that mutations in LOXL1 (15q22) confer susceptibility to exfoliation syndrome.  However, a specific mutational basis and transmission pattern has yet to be determined.  Available evidence is most suggestive of autosomal dominant inheritance but a multifactorial or susceptibility mechanism cannot be ruled out.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the exfoliation is available.  Cataract extraction may result in reduction of diffused extracellular material and it has been reported that the intraocular pressure is easier to control.  The risk of intraoperative complications is high, however, and surgical caution must be exercised.

References
Article Title: 

Mechanisms of Glaucoma in Exfoliation Syndrome

Ozaki M. Mechanisms of Glaucoma in Exfoliation Syndrome. J Glaucoma. 2018 Feb 9. doi: 10.1097/IJG.0000000000000906. [Epub ahead of print] PubMed PMID: 29432334.

PubMed ID: 
29432334

Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma

Thorleifsson G, Magnusson KP, Sulem P, Walters GB, Gudbjartsson DF, Stefansson H, Jonsson T, Jonasdottir A, Jonasdottir A, Stefansdottir G, Masson G, Hardarson GA, Petursson H, Arnarsson A, Motallebipour M, Wallerman O, Wadelius C, Gulcher JR, Thorsteinsdottir U, Kong A, Jonasson F, Stefansson K. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007 Sep 7;317(5843):1397-400.

PubMed ID: 
17690259

Exfoliation syndrome

Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001 Jan-Feb;45(4):265-315. Review.

PubMed ID: 
11166342

Glaucoma, Open Angle, Primary

Clinical Characteristics
Ocular Features: 

It has long been known from both clinical and genetic criteria that the disease called glaucoma is a heterogeneous condition. The common denominator is considered to be an optic neuropathy for which the primary risk factor is an elevation of intraocular pressure. However, the well-known clinical profile of glaucomatous retinal and optic nerve damage can also be found among patients without increased IOP and for these the cause remains elusive.  Ultimately, damage to retinal neurons and their axons result in loss of visual field and optic nerve volume with eventual blindness if untreated.

Systemic Features: 

No systemic abnormalities are consistently associated with primary open angle glaucoma.  However, glaucoma occurs in a large number of ocular and systemic disorders as well as chromosomal aberrations and in many such conditions there are anatomic abnormalities in the anterior chamber angle.  A variety of mainly anecdotal risk factors such as obesity, smoking, diabetes, migraines, stress and cardiovascular disease have been reported but their causative relationships have not been established.

Genetics

Primary open angle glaucoma likely consists of a collection of disorders resulting from an optic neuropathy.  Based on family data and ethnic distribution there can be little doubt that genes influence susceptibility to this disease.  In fact, 13 types have been described based on the unique chromosomal locations of mutations that have been associated with each.   Mutations in MYOC (1q23-q24) are responsible for a substantial proportion of POAG cases known as GLC1A through as yet unknown mechanisms.  Others types labeled GLC1B through GLC1O may result from specific mutations located on 10 different chromosomes.  In the absence of pedigrees with typical Mendelian inheritance patterns, it is reasonable to consider that the genes reported to be associated with POAG so far simply confer susceptibility to the optic neuropathy characteristic of clinical glaucoma (for further discussion see 137760).  Unidentified environmental factors in combination with other genes in individual genomes likely determine the degree of susceptibility in each person. 

Treatment
Treatment Options: 

Lowering of intraocular pressure remains the only clinical treatment available to lower the risk of POAG.  Unfortunately, this is not always effective, especially when the intraocular pressure is not significantly elevated.  There are no infallible guidelines for optimum pressure control and the therapy regimen must be tailored by follow-up monitoring of visual field and optic cup changes.  Once established, it is a lifelong disorder that requires active management.

Early detection is important in the management of glaucoma.  It is largely a 'silent' disease and the eye care professional cannot assume that absence of symptoms correlates with absence of disease.  A family history of glaucoma, especially in first degree relatives, as well as African American, Native American, and Hispanic ethnicity, and increased age are associated with an elevated risk of open angle glaucoma.  Patients belonging to such high risk groups should be monitored with regular examinations.

References
Article Title: 

Variants in the PRPF8 Gene are Associated with Glaucoma

Micheal S, Hogewind BF, Khan MI, Siddiqui SN, Zafar SN, Akhtar F, Qamar R, Hoyng CB, den Hollander AI. Variants in the PRPF8 Gene are Associated with Glaucoma. Mol Neurobiol. 2017 Jul 13. doi: 10.1007/s12035-017-0673-5. [Epub ahead of print].

PubMed ID: 
28707069

Open-angle glaucoma

Quigley HA. Open-angle glaucoma. N Engl J Med. 1993 Apr 15;328(15):1097-106. Review.

PubMed ID: 
8455668

Glaucoma, Pigment Dispersion Syndrome

Clinical Characteristics
Ocular Features: 

This is a form of open angle glaucoma with early onset (usually before the age of 40 years).  Marked pigment deposition in the trabecular meshwork, on the lens, zonules, and the corneal endothelium can often be seen prior to elevation of the intraocular pressure. It can be present asymmetrically, even unilaterally, but primarily in early stages.  The pigment source in humans seems to be the iris in which hypopigmentation leads to radial transillumination defects and mouse models corroborate this.  The iris configuration is sometimes described as flat or even concave.  The pattern of pigment deposition on the posterior surface of the cornea is known as a Krukenberg spindle and considered diagnostic.  Untreated, the characteristic optic nerve damage and visual field changes of glaucoma eventually occur.  Early-onset and rapidly progressive nuclear cataracts have been reported in some patients.

In one longitudinal study of 113 patients diagnosed with pigment dispersion and followed for 24 years, 23 had glaucoma initially and 9 more eventually required treatment for elevated pressure. The mean age at diagnosis was 42 years and myopic males were the most commonly affected.

The syndromic nature of PDS is suggested by the association of lattice degeneration, retinal tears, and detachments in a significant number of individuals.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal dominant form of glaucoma-related optic neuropathy that shares some features with open angle juvenile glaucoma (137750), such as myopia and early onset.  The pigment dispersion syndrome described here, however, maps to a different locus (7q35-q36).  Another candidate locus is located at 18q11-q21 but the causative mutations remain elusive.

A four generation family with an apparent autosomal recessive pattern has been reported.

The autosomal dominant pattern is not always apparent from history alone and examination of relatives is necessary to document the familial nature of this disease. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual glaucoma therapies are indicated.  Some have advised limiting vigorous impact sports to reduce the amount of pigment released.  All individuals with pigment dispersion must be followed vigilantly for development of glaucoma as the risk is high.  It has been estimated to be 10% within 5 years and 15% in 15 years, regardless of age and family history.  Further, the pigment dispersion is progressive along with the risk of elevated pressure as eventually 30 -50% of patients develop glaucoma.  However, regression of pigment deposition, decrease of iris transillumination and even stabilization of pressure has also been noted in some, mostly younger, patients.

Laser iridotomy has been suggested as therapeutically useful in the reduction of the IOP but there is no statistical confirmation of this.

References
Article Title: 

Glaucoma, Open Angle, Juvenile

Clinical Characteristics
Ocular Features: 

Primary open angle glaucoma is a genetically and clinically heterogeneous condition.  The type described here often has its onset in juveniles, much earlier than the usual type, and is much more rare.  Onset is often in the second or third decade with an average age of onset of 18 years.  It is rare for this form of POAG to be diagnosed after 40 years of age.  IOP is commonly as high as 50 mmHg and the pressure is difficult to control.  Glaucomatous changes in the optic nerve progress rapidly. The usual pharmacologic agents can be helpful early but surgical control is often required.  Myopia is common (87%) but no anterior chamber anomalies are present.  Juvenile POAG is more common in African Americans.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Juvenile onset open angle glaucoma, GLAC1A, is inherited in an autosomal dominant pattern with high penetrance.  It is caused by a mutation in MYOC located at 1q21-q31.  The usual adult onset glaucoma is caused by different mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual pharmacologic treatment may be effective in some, especially early, but some form of glaucoma filtration surgery is eventually required in over 80% of patients.

References
Article Title: 

Marfan Syndrome

Clinical Characteristics
Ocular Features: 

Marfan syndrome typically has skeletal, ocular and cardiovascular abnormalities.  The globe is elongated creating an axial myopia and increasing the risk of rhegmatogenous retinal detachments.  Ectopia lentis is, of course, the classical ocular feature and is often if not always congenital with some progression.  The lenses most frequently dislocate superiorly and temporally and dilating the pupils often reveals broken and retracted lens zonules.  Phacodenesis and iridodenesis are commonly present even in the absence of evident lens dislocations. Cataracts develop several decades earlier than in unaffected individuals. The cornea is generally several diopters flatter than normal and there is an increased risk of open angle glaucoma.  There is considerable clinical variation among patients.

Systemic Features: 

Patients with the Marfan phenotype are usually tall with disproportionately long limbs (dolichostenomelia) and digits (arachnodactyly).   Patients frequently have scoliosis or kyphoscoliosis.  The joints are lax and hyperflexible although contractures can also occur.  The sternum is often deformed, either as a pectus excavatum, or sometimes pectus carinatum.  The hard palate is high and narrow resulting in crowding of the teeth and maloccclusion.  The defect in fibrillin is responsible for the weakness in connective tissue that leads to frequent cardiac valve malfunction, especially insufficiency of the aortic valve resulting from aortic dilatation, tear, and rupture.  The latter is often life-threatening as aortic dissection can be fatal.  Mitral valve prolapse is seen as well.  Cardiovascular disease is primarily responsible for the shortened life expectancy in this disease, more pronounced among males.

Genetics

As many as 25% of cases are caused by new mutations, but familial cases usually follow an autosomal dominant pattern of inheritance.  Autosomal recessive inheritance is claimed for several individuals in a consanguineous Turkish family.  Mutations in the fibrillin-1 gene (FBN1) on chromosome 15 (15q21.1) are considered responsible for the typical phenotype.  The exact nature of the fibrillin defect is unknown but the result is a generalized weakness in connective tissue.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani syndrome (608328) which is allelic to the Marfan syndrome.

Mutations in FBN1 have also been found in cases with isolated autosomal dominant ectopia lentis (129600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Isometric exercises such as weight lifting should be avoided as should contact sports in which blunt trauma to the chest may occur because of the weakened aortic wall due to cystic changes that predispose the athlete to aortic dissection.  A dislocated and/or cataractous lens may need to be removed from the visual axis, and, of course, periodic retinal examinations for retinal holes and retinal detachments should be made.   Beta-adrenergic blockade reduces the risk of aortic dilatation and improves survival.

Pravastatin has been reported to reduce aortic dilation in marfan mice.

References
Article Title: 

Pravastatin reduces marfan aortic dilation

McLoughlin D, McGuinness J, Byrne J, Terzo E, Huuskonen V, McAllister H, Black A, Kearney S, Kay E, Hill AD, Dietz HC, Redmond JM. Pravastatin reduces marfan aortic dilation. Circulation. 2011 Sep 13;124(11 Suppl):S168-73.

PubMed ID: 
21911808
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