Ординатура / Офтальмология / Английские материалы / Clinical Medicine in Optometric Practice_Muchnick_2007

The retina may demonstrate vasculitis, macular edema, and exudative retinal detachments. Both optic nerves may swell, causing papilledema secondary to Lyme meningitis. Pseudotumor cerebri (PTC), optic neuritis, and ION have all been associated with Lyme disease. Ultimately optic atrophy may result from Lyme disease involving the CNS.

Lyme disease may be diagnosed early by the formation of a skin rash in a patient with typical symptoms who is living in an endemic area. Nonetheless, the early diagnosis can be problematic, since the patient rarely realizes that a tick bit her, and the rash is seen in

only one third to two thirds of cases. Laboratory testing includes enzyme-linked immunosorbent assay (ELISA) testing and a confirmatory Western blot test, but is often unreliable and insensitive.

Treatment is often started on a patient who either was bitten by a tick and demonstrates a typical postbite, silver dollar–sized red rash, or who has no rash or bite history but has typical symptoms and lives in an endemic area. Oral doxycycline, amoxicillin, or azithromycin has been found to be effective in stage one of the disease. In the more advanced stages of Lyme disease, intravenous antibiotics are often required.

Fungal Infections

Histoplasmosis

Inhalation of the yeast fungus Histoplasma capsulatum causes initial infection of the lungs. The fungus can then travel to all organ systems of the body. The fungus most often is found in soil near bird and bat droppings and the most common patients infected live along the Mississippi valley from Ohio to Alabama and Texas.

Histoplasmosis (POHS) causes a classic triad of retinal findings: macular subretinal neovascularization (SRNVM), peripapillary atrophy, and peripheral choroidal “punched-out” atrophic lesions. This triad results in a disciform macular scar with possible metamorphopsia or central scotoma, and a possible retinal detachment. Ultimately, optic disc edema may occur.

The fundus findings indicate the diagnosis, and laboratory tests are usually not needed. Bilateral fluorescein angiography (FA) should be performed to detect and evaluate subretinal neovascularization. Treatment includes verteporfin photodynamic therapy of the SRNVMs.

Mucormycosis

A rare fungal infection that most often occurs in the elderly or the immunocompromised, mucormycosis is most commonly seen in patients in ketoacidosis from diabetes. It is a devastating disease with a morbidity rate as high as 90%. It has been seen in young, diabetic drugabusers who inhale cocaine, thus introducing the fungus into their nasal mucosa. The fungal infection quickly enters the bloodstream and travels to the brain, causing a cavernous sinus syndrome (CSS). In cases of CSS secondary to mucor infection, the patient may experience diplopia, orbital pain, photophobia, and ptosis. The pupil on the involved side can become dilated, and the conjunctiva becomes engorged. The retina vessels exhibit “box-carring,” or segmentation of the column of blood in the lumen caused by venous stasis.

Treatment includes the antifungal agent amphotericin B with surgical debridement of the necrotic tissue, but the prognosis for survival remains very poor.

Viral Infections

Herpes Simplex Virus I

A DNA virus, herpes simplex virus 1 (HSV-1) is transmitted by direct contact in children and adults. HSV-1 rarely causes genital lesions, and the primary infection may be mild and go unnoticed. The virus then remains dormant in the nerve ganglia until stress, trauma, or sunburn causes a reactivation of the virus. The virus then travels to the dermatome of the involved nerve and causes a cold sore or an associated proliferation of skin vesicles.

The diagnosis of HSV-1 is usually made on the basis of the patient’s signs, symptoms, and history. The Tzanck cell test of skin scrapings can confirm the diagnosis

Posterior ocular involvement includes endophthalmitis and chorioretinitis. HSV-1 infection may lead to an acute retinal necrosis composed of vasculitis, retinal hemorrhages, and retinal necrosis. In addition, HSV-1-associated encephalitis, although uncommon, may cause retinal hemorrhages, retinitis, vasculitis, and exudative retinal detachment. The treatment of the posterior involvement of HSV-1 is aimed at improving the prognosis of the associated encephalitis. Adenosine arabinoside (ARA-A) and acyclovir decrease the mortality rate associated with HSV-1-associated encephalitis. The treatment of the acute retinal necrosis remains problematic, however.

Herpes Simplex Virus 2

A DNA virus, herpes simplex virus 2 (HSV-2) is transmitted by direct sexual contact, and genital-ocular transmission can occur. Neonatal infection can occur by the infant’s passage through the birth canal and contact with infected maternal fluids. HSV-2 is characterized by recurrent and painful genital ulcers.

Posterior segment involvement occurs in one fifth of encephalitis cases and includes a retinitis with hemorrhages, CWS, vasculitis, retinal detachment, and optic neuritis.

Treatment of HSV-2 encephalitis-related retinitis by using intravenous acyclovir has been shown to be effective, but a risk of serious side effects exists in neonates.

Herpes Zoster Virus

The primary infection of herpes zoster (HZV) causes chickenpox, a highly contagious disease mostly found in infants and children. After the initial clinical manifestations of a mild, vesicular body-wide rash and a week of mild fever, malaise, and headache, the child usually recovers. Sometimes no other signs or symptoms are present but the rash.

During this infection, the varicella (or chickenpox) virus gains access to the sensory ganglion, where it lies dormant. Reactivation of the virus later in life occurs caused by, among other factors, emotional or physical stress, age, or a compromised immune system. The virus travels along the nerves to the skin and produces painful vesicular eruptions. The area of skin served by the infected nerve or nerves first begins to tingle, and the patient may have a fever and headache. Next, the eruption of vesicles that follows this prodrome can be exquisitely painful and is known as shingles. The blisters eventually scab and complete resolution occurs in approximately 4 to 6 weeks. The patient may be left with postherpetic neuralgia (PHN), a persistent, intense, boring pain around the involved eye.

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Very rarely acute retinal necrosis (ARN) occurs, and, in addition, vascular occlusive diseases, optic neuritis, and multifocal choroiditis.

Oral antiviral agents, including acyclovir, famciclovir, or valacyclovir, are mandatory in the treatment of HZO patients within 2 to 3 days of the onset of rash, and should be continued for 7 days. This treatment has been shown to reduce the risk of PHN and it can be effective against ARN secondary to HSV. In patients 40 years or younger, any case of HZO should inspire a diligent search for immunosuppression caused by HIV infection.

Rubeola

This RNA virus causes measles with a mild fever and rash. Rubeola is highly contagious and usually occurs in childhood. In rare cases, rubeola may cause severe bilateral neuroretinitis. This condition occurs a week after the rash appears, and causes dramatic vision loss. Funduscopy reveals diffuse optic disc and macular edema, venous dilation and subsequent optic atrophy. Visual fields will be constricted and permanent visual acuity loss occurs. No treatment exists for the retinopathy.

Rubella

Rubella is the virus that causes German measles, and is common and very contagious. Rubella causes a mild infection in children and adults. The virus is spread by direct contact, and symptoms are a mild fever, lymphadenopathy, and a rash.

Immunization programs in the United States have made congenital rubella rare, but 20% of U.S. women are still susceptible to infection. If rubella occurs in the first trimester of pregnancy, the results can be devastating to the fetus. Of children infected in the first trimester, 80% will develop one of the signs of congenital rubella, either at birth or later in life.

The most common manifestation of congenital rubella is hearing loss, and heart disease develops in two thirds of patients. Other stigmata include mental retardation, microcephaly, vascular effects, and ocular disease.

Almost half of all children with evidence of congenital rubella have the ocular complications of corneal clouding, cataract, glaucoma, strabismus, nystagmus, microphthalmos, or posterior segment disorders. The retinopathy of congenital rubella consists of a salt-and-pepper fundus and a loss of the foveal reflex. The pigmentary changes are stippled and are at a uniform depth under the retinal vessels. Interestingly, the visual acuity is rarely affected and the visual field is typically normal when only the retina is involved. Visual acuity can be significantly reduced, however, by the presence of a choroidal neovascular membrane.

No treatment exists for the retinopathy, and the choroidal neovascular membrane appears later in life and involves the center of the foveal zone. Thus, it is usually not amenable to laser therapy.

Epstein-Barr Virus

A ubiquitous virus that has infected most adults and is the cause of mononucleosis, Epstein-Barr virus (EBV) is confirmed by serological testing in patients with the typical symptom of extreme lethargy.

EBV has been implicated as the cause of a multifocal choroiditis with panuveitis. In this case patients may experience a visual acuity drop to light perception and the funduscopic evaluation reveals yellowgray RPE lesions with shallow serous detachment over the active lesions. A relative afferent pupillary defect (RAPD) may be present and associated with a mild papillitis.

The treatment for EBV includes acyclovir and laser therapy for choroidal neovascularization. All children and adults with mononucleosis should have a dilated fundus evaluation to monitor for active retinal lesions and neovascularization.

Cytomegalovirus

Although cytomegalovirus (CMV) may affect the brain, lungs, GI tract, liver, and spleen, the most frequent manifestation is in the eyes. This DNA virus is a member of the herpes family of viruses and is transmitted by contact with bodily secretions. CMV retinopathy may occur when the immune system is compromised, as in AIDS, and when the CD4 count, which monitors the status of the immune system, is less than 50 cells/mm3.

CMV retinopathy is usually asymptomatic and is discovered on routine eye examination. If the posterior pole is involved, however, the visual acuity may be affected and scotomata may develop. CMV retinopathy consists of retinal hemorrhages and CWS with exudates that take on the classic appearance of a “cheese and ketchup” fundus (Figure 22-5). An associated necrotizing retinitis (Figure 22-6), and vascular sheathing with rhegmatogenous retinal detachment may be present. Cystoid macular edema, papillitis, and cataract development may be present.

CMV retinitis is the leading cause of blindness in the AIDS population. Therapy for CMV retinitis consists of intravenous antiviral agents (ganciclovir, foscarnet, and cidofovir), intraocular injection of ganciclovir (Vitrasert), and intravitreal injection of antiviral agents.

Regression of CMV retinopathy usually occurs in less than a month, but antiviral therapy must be maintained for the life of the patient. Therapy for CMV retinopathy may be discontinued, however, if the pa-

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tient’s cluster of differentiation 4 (CD4) count remains above 100 to 150 cells/mm3 for 3 to 6 months while on therapy.

If a CWS is found on funduscopy in an asymptomatic patient with no significant medical history, then a CD4 count and serological testing is warranted to confirm the presence of an HIV infection.

CMV retinopathy must be differentiated from noninfectious HIV retinopathy, which typically reveals nonprogressive CWS. No treatment is needed in cases of HIV retinopathy. Differentiation is determined by progression: if the CWS worsen and become associated with hemorrhages, then CMV retinopathy is most likely the etiology. A nonprogressive CWS in an HIV patient is most likely caused by noninfectious HIV retinopathy.

Parasitic Infections

Toxoplasmosis

Caused by the intracellular protozoan parasite Toxoplasma gondii, toxoplasmosis is spread by the eating of uncooked meat. These cases may be reactivations of congenitally transmitted toxoplasmosis from the mother to the fetus. Toxoplasmosis typically affects the retina and nervous system. It causes a yellow-white lesion of the posterior pole, and in active cases an overlying vitritis will be present. An associated disc edema, vitritis (Figures 22-7 and 22-8), subretinal fibrosis and lipids (Figure 22-9), vascular-occlusive disease, and lymphadenopathy may be present.

One in every 3000 births in the United States results in a case of congenital toxoplasmosis, with half of these babies born healthy and exhibiting no clinical signs of the disease. Laboratory tests include a serum antitoxoplasma antibody titer and an anergy panel.

Large, exudative retinal lesions near the macula require treatment with sulfadiazine with clindamycin and prednisone. Pyrimethamine (Daraprim), a folate

FIGURE 22-7 ■ A juxtapapillary retinitis with severe overlying vitritis in an 8-year-old boy who is seropositive for Toxoplasma gondii.

FIGURE 22-8 ■ Reactivation of Toxoplasma retinochoroiditis. Active retinitis can be appreciated as a fluffy white area that is contiguous with a pigmented, previously active chorioretinitic lesion. Inflammatory cells are evident in the vitritis overlying the area of active inflammation.

antagonist, has also been prescribed for toxoplasmosis in conjunction with folinic acid (to reverse a low platelet count).

Toxocariasis

An infection caused by larvae of the Toxocara canis roundworm, toxocariasis is found typically in young children who ingest animal feces (mostly from puppies) that contain the worm eggs. The eggs hatch in the intestines and the worm larvae enter the systemic circulation, spreading to the vital organs and eyes.

In infected children an associated fever, cough, skin rash, abdominal pain, and visual impairment may be present. In the eyes, toxocariasis can cause a peripheral chorioretinal granuloma (Figure 22-10), a posterior pole chorioretinal granuloma near the macula (Figure 22-11), or endophthalmitis.

No proven treatment exists for toxocariasis, and the disease tends to be self-limiting. Various antihelminthic medications have been recommended, but these are still of unknown benefit.

HEMATOLOGICAL MANIFESTATIONS Platelet Abnormalities

Because platelets allow for hemostasis by forming vascular plugs at sites of vessel disruptions, coagulative disorders may result in significant fundus abnormalities.

Thrombocytopenia

Accelerated platelet destruction in idiopathic thrombocytopenic purpura (ITP) or drug exposure can both cause a reduction in the total number of platelets, a condition known as thrombocytopenia. The retinal

FIGURE 22-10 ■ Peripheral Toxocara inflammatory lesion with extensive transvitreal fibrosis communicating with the optic nerve. The optic disc and macula have been dragged toward the superonasal quadrant. Linear retinal breaks are evident adjacent to and below the fibrous vitreal membrane.

findings in this condition include vitreous and retinal hemorrhages with bilateral serous retinal detachments and disc edema.

Thrombotic thrombocytopenic purpura (TTP), a disease associated with anemia, fever, CNS dysfunction,

FIGURE 22-11 ■ A focal toxocaral granuloma with fibrous traction band extending into the optic nerve head.

and renal disease, can result in papilledema with retinal hemorrhages and serous detachments secondary to retinal pigmentary epithelial (RPE) damage and focal occlusions of the choriocapillaris.

Drug-induced thrombocytopenia can also significantly affect the retina. For example, the use of aspirin in a patient with age-related macular degeneration may predispose a choroidal neovascular membrane to

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bleed. This can result in massive subretinal and vitreous hemorrhaging and lead to vision loss. Interestingly, studies have shown that aspirin does not affect the progression of diabetic retinopathy.

White Blood Cell Abnormalities

Leukemia

An elevation in the white blood cell count (WBC) can lead to leukemic infiltration of the choroid, retina, or vitreous. Funduscopic evaluation reveals multifocal retinal pigment epithelial defects and serous detachments of the RPE and retina. Leukemic retinopathy consists of vitreous and posterior pole retinal hemorrhages with CWS. Venous occlusion and retinal neovascularization may occur caused by the hyperviscosity caused by leukemia. The retinopathy is treated indirectly by appropriately treating the underlying hematological disorder.

RETINAL/CHOROIDAL TOXICITY Talc Retinopathy

This toxic retinopathy occurs in patients who are substance abusers and inject drugs such as methylphenidate (Ritalin) that are diluted, or “cut,” with talcum powder. The talc particles deposit in the retinal capillaries outside the foveal avascular zone or inner retinal tissues of the macula. The talc particles appear as glistening white shining dots within a retinal vessel. They can simulate carotid emboli, but in the case of talc retinopathy dozens of particles are usually present in both fundi, whereas carotid are typically (but not always) few in number and unilateral. No treatment is needed because these particles are typically benign and cause no symptoms, but CWS and exudates have been known to occur caused by vascular occlusion. Proliferative disease secondary to talc retinopathy is very rare and is amenable to laser photocoagulation therapy.

Red Blood Cell Abnormalities

Anemia

A reduced red blood cell count (RBC) may lead to anemic retinopathy consisting of retinal hemorrhages, edema, exudates and disc edema.

Polycythemia

An elevation of the RBC above six million may produce marked dilation and tortuosity of the retinal vessels that leads to venous stasis retinopathy. Characteristically, superficial and deep intraretinal hemorrhages and disc edema are present.

Sickle Cell Anemia

This hemoglobinopathy produces the worst retinal abnormalities in patients who inherit the sickle cell hemoglobin SC (double heterozygous genotype) gene. In this disease, the red blood cell exhibits resistance to malaria. The sickle-type hemoglobin causes deformation of the erythrocyte under conditions of decreased oxygen tension, however. The abnormally shaped red blood cells become trapped in capillaries, causing occlusions. This produces hypoxic conditions to the organs with low-pressure hemodynamics, including the lungs, GI tract, spleen, and bone. In the eye, sickle cell anemia (SCA) may produce nonproliferative retinal lesions (vascular tortuosity, retinal hemorrhages, and black sunburst lesions), or proliferative changes. Proliferative SCA evolves through five stages, beginning with peripheral arteriolar occlusions (stage I) and leading to peripheral arteriovenous (AV) anastomoses (stage II), “sea-fan” neovascularization (stage III), vitreous hemorrhage (stage IV), and, finally, retinal detachment (stage V). Laser photocoagulation can be applied in a panretinal photocoagulation (PRP)–like pattern for treatment of the neovascular tissue.

Phenothiazine Retinopathy

Thioridazine (Mellaril) and chlorpromazine (Thorazine) are the phenothiazines that most commonly cause pigmentary retinopathy. Patients who take any phenothiazine medication should be evaluated for retinopathy at least once yearly with visual acuities, color testing, funduscopic evaluation, and visual fields to ensure that retinal pigmentary changes are not occurring. The prescribing physician should be made aware when pigmentary retinopathy is discovered. By changing the medication, the physician will be able to avoid further toxic effects while continuing to appropriately manage the mental health of the patient.

Chloroquine Retinopathy

These medications are used in the treatment of RA and SLE, and can cause a “bull’s-eye” maculopathy. This condition is caused by a mottling of the RPE in the fovea and parafoveal areas. Hydroxychloroquine is less likely to cause a retinopathy than chloroquine. It is suggested that patients on these medications be tested twice yearly with red stimulus visual field testing, Amsler grid testing, visual acuities, fundus evaluation, and photographs. Any macular granularity or loss of the foveal reflex while taking either of these medications should warrant concern of a potential retinal toxic reaction.

Tamoxifen Retinopathy

Some forms of breast cancer are stimulated to proliferate by the attachment of estrogen molecules to estrogen receptors in the cytoplasm of cells. Tamoxifen is an antiestrogen medication that attaches to these receptor sites, thus competing with estrogen. By competing

with estrogen, tamoxifen has been shown to reduce the rate or reoccurrence of breast cancer. The medication has been shown to be toxic to the retina, even in small doses. The retinopathy is usually discovered on routine examination, although there may be a blurring of vision that motivates the patient to seek an eye examination. Multiple refractile particles are deposited in the macula, with the superficial deposits being white and the deeper lesions yellow. Cystoid macular edema (CME) can result in reduced visual acuities. Titration of the medication may be necessary to reduce the retinopathy and prevent maculopathy, but the risk of recurrent metastatic breast cancer must be weighed against the benefit of stabilization or reversal of the retinopathy.

BIBLIOGRAPHY

Bartlett JD, Jaanus SD: Clinical ocular pharmacology, ed 4, Boston, 2001, Butterworth Heinemann.

Batisse D, et al: Acute retinal necrosis in the course of AIDS. Study of 26 cases, AIDS 10:55-60, 1996.

Fisher JF, et al:The acute-retinal necrosis syndrome. Part I: clinical manifestations, Ophthalmology 89:1309-1316, 1982.

Locke LC: Ocular manifestations of hypertension, Optom Clin 2:47-76, 1992.

Mandell GL, Bennett JE, Dolin R: Principles and practice of infectious diseases, ed 5, New York, 2000, Churchill Livingstone.

Onofrey BE, Skorin L Jr, Holdeman NR: Ocular therapeutics handbook, ed 2, Philadelphia, 2005, Lippincott, Williams & Wilkins.

Silverstein BE, et al: CMV-associated acute retinal necrosis syndrome, Am J Ophthalmol 123:257-258, 1997.

Singerman LJ, Jampol LM: Retinal and choroidal manifestations of systemic disease, Baltimore. 1991,Williams & Wilkins.

Despite the recent and dramatic proliferation of new insights into the genetic basis of disease, the integration of genetics into optometric practice remains a daunting task. To this end, Charles M. Wormington, Ph.D., O.D., has promoted the concept of “molecular optometry,” whereby eye care practitioners are sensitized to the genetic basis of oculosystemic disease. This approach involves an understanding of the basics of genetics, an appreciation for the new discoveries in the field of genomics, and a practical means for implementing the “new genetic” thinking into the

practice of optometry.

BASIC GENETICS The Human Genome

All the information necessary for the production and maintenance of human life is found stored in the human genome. The human genome is made up of 23 different chromosomes.

Genes

Approximately 50,000 genes are contained in these 23 chromosomes. A single gene is a code for a certain product, and genes are a way to pass traits from one generation to the next.

DNA

Each gene is composed of deoxyribonucleic acid (DNA). DNA is a double-stranded helix composed of four bases: adenine (A), guanine (G), thymidine (T), and cytosine (C). A is always paired to T, and G is always paired to C. DNA is responsible for the transmission of genetic information and is particularly stable, can be faithfully replicated, and has fantastic diversity because of pairing of its bases. For example, in areas of the gene that code for proteins, DNA bases are arranged in triplets, called codons, in which a single codon specifies a certain amino acid.

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Base Pairs

Three billion base pairs compose the DNA found in a single genome. All cells within a single human body contain the same 3 billion base pairs. All genes are made of DNA, but only approximately 10% of the DNA in a genome encodes genes. The remaining DNA is repetitive and its function is not well understood.

RNA

Information that is encoded in the DNA mostly concerns the production of specific proteins, although it may also consist of ribonucleic acid (RNA). Information is transmitted from DNA to RNA for the eventual production of a protein. A special type of RNA, messenger RNA (mRNA), is encoded by a certain “sense strand” of the DNA double helix and is translated into proteins.

Transcription

mRNA is created by genes through a process called transcription. mRNA is then used to express the information encoded in the DNA, usually for the production of a specific protein.

occurring in the sperm or egg (the germline) produces changes that are transmitted to the progeny.

Chromosomal Disorders

The presence of more or less than the 22 pairs of autosomal chromosomes and one pair of sex chromosomes has dramatic and deleterious effects on the human organism. The results are known as chromosomal disorders and they are the most common cause of fetal loss and the presence of birth defects in surviving progeny.

Mitochondrial Defects

Defects in the mitochondria produce metabolic and neurodegenerative disease. The eye is particularly vulnerable to mitochondrial disorders. Chronic external ophthalmoplegia (CPEO) is caused by single deletions in mitochondrial DNA and is characterized by ptosis, ophthalmoplegia, and myopathy of the limbs.

Leber’s hereditary optic neuropathy (LHON) is a chronic, painless, bilateral vision loss that usually occurs in males in their late teens and early 20s. The vision loss is caused by mDNA mutations and tobacco and alcohol use.

Translation

The mRNA produced by transcription is then used to produce the desired protein in a process called translation. The protein consists of a specific amino acid sequence. Only approximately 2% of the human genome is used to produce proteins, and some of the rest controls the expression of genetic information and the coding of some RNA molecules. The majority of the human genome has an unknown function, however.

FUNCTIONAL GENOMICS

Although the study of the patterns of inheritance of specific traits is well known as “genetics,” the study of the function of genes and genomes is known as “genomics.” According to Jameson and Kopp, understanding gene regulation and function can provide a better insight into the pathophysiology of disease. In addition, genomics encompasses the use of genetic study to develop newer therapeutic interventional strategies.

The Human Genome Project

The human genome project (HGP) began in the mid 1980s and succeeded in characterizing the entire human genome. The result is the sequencing of the entire DNA of the human being. The genetic map produced revealed that all human disease has a genetic component. Practically all biomedical research is now centered on genetics and the study of complex genetic disease.

Disease Classification

Functional genomics shifts the classification of diseases from a clinical description, or phenotype, to a genetic description. This new genetic classification system helps to explain variations in course, treatment, and presentation as the result of differences in patterns of inheritance and gene expression.

Mutations

When a change in the primary nucleotide sequence of DNA occurs, the result is called a mutation. Mutations represent a fundamental change in the product produced by the affected gene, and so may be lethal, deleterious, or advantageous to the organism. A mutation

Disease Testing

New diagnostic tests have been developed thanks to the HGP. In these testing strategies, DNA, RNA, chromosomes, and proteins are analyzed with the intention of detecting inheritable disease and identifying mutations to aid in diagnosis and improve prognostication. Genetic screening tests are now commercially