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Clinical Findings and Management of Choroideremia Matt Goodman, OD [email protected] Abstract A 12-year-old male presents with bilateral vision loss. The exam reveals bilateral acuity reduction, fundus changes, and constricted visual fields. Genetic testing reveals a deletion on the CHM gene consistent with the diagnosis of choroideremia. 1 I. Case History A 12-year-old Caucasian male was referred to the Bascom Palmer Eye Institute neuroophthalmology service with decreased vision. The mother stated that he frequently bumps into objects, especially at night. The patient and mother denied any redness, photophobia, or discharge. The patient reported only wears spectacles while at school. Personal ocular history was unremarkable. Personal medical history was significant for a hospitalization at the age of 18 months for Kawasaki disease. Family history was remarkable for “retinitis pigmentosa” that inflicted the patient’s maternal grandfather, who had since passed on. He was living with both parents and doing well in school. The patient was not taking any medications, and there were no known drug allergies. Review of systems was unremarkable. II. Pertinent Findings Best corrected visual acuity was 20/40 OD and 20/50 OS with a moderate myopic refraction. Pupils were unremarkable and intraocular pressures were within normal limits OU. Motilities were full, and the patient showed a small flick esotropia at both distance and near. Notably, the patient was unable to count fingers during confrontation visual fields testing, but his fields were full to hand motion. Slit lamp examination was unremarkable for anterior segment findings. Fundus examination with a 90D lens revealed a very blonde appearance to the fundus and prominent choroidal vasculature OU. There appeared to be an island of normally pigmented retina centrally OU. The appearance of the ONH and the retinal vasculature was unremarkable OU. Peripheral retinal examination with the BIO showed mild pigment clumping 360 degrees OU. There were no tears, holes, or breaks anywhere in the retina OU. Fundus examination of the mother was unremarkable. Fundus photos of the posterior pole of the patient are pictured below. Of note, skin and hair pigmentation appeared normal. No obvious limb or neurologic abnormalities were present. Facies appeared normal with no findings to suggest a systemic syndrome was present. 2 Stratus macular OCT, while of low image quality, showed mild sub-retinal fluid present OU. Goldmann visual field testing showed a normal response to a Size-V stimulus, but a severely concentrically constricted field to all other size targets OU. A full-field ERG showed a rod-cone dysfunction with the rod ERG being completely undetectable. Macular OCT and Goldmann visual fields are pictured below. III. Differential Diagnosis Leading diagnoses included X-linked retinitis pigmentosa and choroideremia. Others included on the differential diagnosis list were gyrate atrophy, diffuse choroidal atrophy, albinism, post-inflammatory retinal atrophy, and high myopia. The clinical picture of this patient did not fit the typical presentation of X-linked retinitis pigmentosa. First, there is almost always a marked attenuation of the retinal vasculature and a very significant amount of pigment migration3. Second, carriers of the mutated RP gene often show bone spicules in their peripheral retina, even when no symptoms are present3. All of these findings were absent in this particular patient. IV. Diagnosis and Discussion The presumed clinical diagnosis was choroideremia. This was confirmed with genetic testing that showed hemizygous deletion of exons 9-11 on the CHM gene. Mutation specific carrier testing was recommended to all first degree female relatives. The prevalence of choroideremia is estimated to be 1 in every 50,000 to 75,000 people1. It is thought that roughly 6% of patients initially diagnosed with retinitis pigmentosa actually have choroideremia3. It shows an X-linked recessive inheritance pattern and is characterized by progressive chorioretinal degeneration4. Initial symptoms often include 3 progressive reduction of central acuity, nyctalopia, and constriction of the visual field1. The chorioretinal degeneration begins in the mid-peripheral fundus and spreads towards the posterior pole and the ora serrata4. The typical blonde appearance to the fundus is a result of the atrophy of the RPE and choriocapillaris6. However, the deep choroidal vasculature is usually preserved and very prominent on fundus examination6. The central macular pigment is typically preserved until very late in the disease process4. Acuity reduction early in the disease often occurs secondary to the development of cystoid macular edema7. The development of cystoid macular edema was previously thought to be rare, but a recent study found 10 of 16 choroideremia patients to have cystic edema present on OCT examination7. For this reason, macular OCT is a useful tool to help in identifying the cause of reduced acuity in this patient population8. The CHM gene is the only gene isolated thus far for choroideremia2. The gene encodes for the REP-1 protein, which is involved in intracellular protein trafficking2. A mutation in the gene leads to disabled protein movement and apoptosis3. The REP-2 protein provides redundancy in other bodily tissues, but is absent from the retinal cells2. Large deletions can lead to a host of associated findings systemically, including sensorineural hearing loss, cognitive deficits, absence of the corpus callosum, and cleft palate1. Diagnosis of choroideremia is primarily a clinical one. Common clinical findings include poor dark adaptation, the characteristic fundus appearance described above, a ring scotoma or generally constricted visual field, and reduced or absent rod-cone response on full-field ERG1. Genetic testing is now commonly done to confirm the diagnosis3. It is also possible to assess for reduced levels of the REP-1 protein in peripheral lymphocytes, but this is not commonly done3. Interestingly, female carries may show similar chorioretinal degeneration on fundus exam, but are completely asymptomatic5. The chorioretinal degeneration found in carriers is not visible until much later in life, typically the 3rd-4th decade5. If tested with ERG, carriers may show occasional abnormalities, but ERG is not a reliable indicator for identifying carries of the mutated CHM gene5. V. Treatment There is no cure for choroideremia9. Management typically includes genetic counseling and genetic testing for all female relatives, including prenatal genetic testing9. Low vision support is often utilized, especially late in the disease process9. Progression of the disease is generally monitored with Goldmann visual fields and clinical examination9. Several interventions to help slow the progression of the disease have been proposed, with limited efficacy. They include UV protection, lutein supplementation, increasing leafy vegetable intake, and supplementation of Omega-3 fatty acids through diet9. A current therapeutic study that shows promise is the ciliary neutrophic factor (CNTF) capsular implant. The implant is filled with cells genetically modified to produce CNTF and is clipped to a suture on the ciliary body. The release of the CNTF into the vitreous has shown promise for rescuing dying retinal cells and has potential to improve vision in choroideremia patients9. 4 Several recent studies have shown that topical carbonic anhydrase inhibitors, such as dorzolamide, are more effective at decreasing cystoid macular edema in choroideremia patients compared to standard topical anti-inflammatory drops7. Long-term prognosis for choroideremia patients is poor7. A recent study looked at 115 males choroideremia confirmed via genetic testing and found a trend of slow central acuity loss until the 5th-7th decade of life1. In general, patients under 60 years of age maintained fairly good acuity, with 84% having acuity of 20/40 or better1. However, patients over the age of 60 did not fare as well, with 35% having acuity of 20/200 or worse1. VI. Conclusion Choroideremia is an X-linked recessive disorder characterized by chorioretinal degeneration that begins in mid-peripheral fundus early in life1. Genetic testing is confirmatory, but clinical suspicion is required. Various mutations in only the CHM gene have been identified in choroideremia2. Currently, there is no cure for choroideremia, and long-term visual prognosis remains poor9. Bibliography 1. Roberts MF et al. Choroideremia (CHM) is characterized by progressive chorioretinal 2. 3. 4. 5. 6. 7. 8. 9. degeneration in affected males and milder signs in carrier females. BJO 2002 Jun;86(6):658-62. Van den Hurk JA et al. Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene. Hum Mutat 1997;9(2):110-7. MacDonald IM et al. Choroideremia gene testing. Expert Rev Mol Diagnostics 2004 Jul;4(4):478-84. Katz BJ et al. Fundus appearance of choroideremia using optical coherence tomography. Adv Exp Med Biol 2006;572:57-61. Thobani A et al. Microperimetry and OCT findings in female carriers of choroideremia. Ophthalmic Genetics 2010 Dec;31(4):235-9. Zweifel SA et al. A novel optical coherence tomography finding. Archives of Ophthalmology 2009 Dec;127(12): 1596-1602. Genead MA and Fishman GA. Cystic macular edema on spectral-domain optical coherence tomography in choroideremia patients without cystic changes on fundus examination. Eye 2011 Jan;25(1):84-90. Genead MA et al. Retinal nerve fiber thickness measurements in choroideremia patients with spectral-domain optical coherence tomography. Ophthalmic Genetics 2011 Jun;32(2):101-6. Duncan JL et al. Macular pigment and lutein supplementation in choroideremia. Exp Eye Res 2002 Mar;74(3):371-81. 5