X-Linked RP

X-Linked RP

Dr. Bhakhri is an assistant professor at the Southern California College of Optometry at Marshall B. Ketchum University.  He graduated from the University of Alberta with a Bachelor of Science degree in Biology. He received his Doctor of Optometry degree from the Pennsylvania College of Optometry at Salus University. Dr. Bhakhri completed a post-graduate residency at the Illinois College of Optometry in low vision and ocular disease. He is currently a member of the American Optometric Association and is a fellow of the American Academy of Optometry.

Case Report

A 22-year-old Hispanic male, presented with chief complaints of reduced peripheral fields and night blindness OU. He reported that these symptoms began at a young age and had been gradually worsening. He denied any curtain vision or floaters.  His ocular history was unremarkable except for wearing glasses for myopia.  His medical history was also unremarkable.  He reported no allergies or medications.  Family ocular history revealed two older brothers who had been diagnosed with retinitis pigmentosa (RP) at a young age.

Best-corrected distance visual acuity through his habitual -3.50 DS OU prescription  was 20/20- OD and 20/20 OS.  Confrontation visual fields showed generalized constriction OU.  Color vision testing with Ishihara plates was normal in both eyes.  His pupils were equally round and reactive to light with no afferent pupillary defect.  Extra-ocular muscle testing showed a full range of motion OU. Slit lamp examination was unremarkable, with Goldmann applanation tonometry revealing intra-ocular pressures of 16mmHg OD and OS at 10:30AM.  (Fundus examination OU showed large amounts of chorio-retinal atrophy extending from the periphery and encroaching upon the posterior pole.  A small area of the central macula including the fovea was preserved OU.  Scattered among the areas of atrophy were patches of pigment OU (Figure 1).

A kinetic visual field was performed to gauge the patient’s remaining visual field.  It revealed severe constriction with a size III4e isopter.  The field was estimated to be roughly 5 degrees OU (Figure 2).  Based on the patient’s signs, symptoms, and testing results, he was tentatively diagnosed with retinitis pigmentosa.  The patient was referred for electrophysiology testing and possible genetic testing due to his family history of RP.  While awaiting the referral, an in office pedigree analysis was performed.  It revealed an X-linked recessive inheritance pattern as only males from the patient’s maternal side manifested the disease.  A pattern of un-affected generations was also noted, which is consistent with an X-linked recessive mode of inheritance.  The condition was traced back four generations with certainty.

ERG testing was performed subsequently and it revealed un-recordable scotopic responses OU.  Photopic responses were minimally recordable.  Genetic testing is still pending.  The patient and his family were informed of all results and genetic counselling was recommended along with low vision rehabilitation and orientation and mobility training.

Discussion:

RP is a group of hereditary retinal disorders characterized by degeneration and death of rod and cone photoreceptors leading to nyctalopia, visual field loss, and visual acuity loss.  The condition is thought to affect 1 in every 5000 people. Mutations in over 60 genes are known to cause RP, with varied modes of inheritance including autosomal recessive, autosomal dominant, X-linked (XLRP), and mitochondrial ^1-3.  XLRP is considered to be the most severe form as it leads to earlier loss of vision and field compared to the other modes of inheritance^2,4,5.   Prevalence numbers have XLRP affecting 10-25% of all patients with RP, with it manifesting within the first to second decade of life^6,7.

An understanding of basic genetics is important in understanding the inheritance pattern of XLRP.  To review, males have only one X chromosome, the other sex chromosome is the Y chromosome; females have two X chromosomes.  In XLRP there is a specific gene mutation on the X chromosome.  As males have only one X chromosome, if they have a gene mutation on their X chromosome they will develop the condition.   If a male were to have a daughter, the defective X chromosome would be passed to her, making her a carrier.  Sons would not be affected as they would receive the normal Y chromosome.⁸

Female carriers will rarely show signs of X-linked recessive conditions as they usually have a second intact copy of the gene on their other X chromosome to compensate for the damaged gene.   If a female were to have a daughter, the daughter has a 1 in 2 (50%) chance of inheriting the gene alteration and therefore also becoming a carrier for the disease.  If a female were to have a son, the son also has a 1 in 2 (50%) chance of receiving the mutation and therefore inheriting the condition^8,9. 

In terms of specific mutations, genetic studies have located defects in six loci in XLRP.  The RP2 gene accounts for 10-20% of all XLRP cases, while RP3 {retinitis pigmentosa GTPase regulator (RPGR)} accounts for 70-90%^1,10.  The pathogenesis of how defects in these genes result in XLRP is still under investigation but study results have been promising.

Multiple studies have shown that RP2 is used to regulate membrane traffic of proteins, especially transducin ^11,12. This could lead to potential photoreceptor cell death.  However, another study by Li et al revealed that mutations in RP2 resulted in decreased maintenance of photoreceptor function.  They attributed this finding to cone opsin mis-localization and reduced rhodopsin content in photoreceptor outer segments.  Interestingly, they did not find any defects in cellular trafficking like the previously mentioned studies.  They concluded that additional studies are needed to explain the mechanism behind how RP2 controls protein movement in photoreceptors¹³.

RP3 or RPGR is a cilia associated protein and it is thought that gene mutations disrupt the normal function (cellular trafficking, cellular signaling) of these cilia in photoreceptor cells leading to photoreceptor death. The exact mechanism is still being investigated.  However, it is known that there is great phenotypic variability among these mutations secondary to the abstract function of RP3^14,15.  Studies have shown some patients with RPGR mutations may also exhibit respiratory tract infections, hearing loss, and primary cilia dyskinesia in addition to their ocular manifestations.¹⁶

Regardless of the mutation, clinical findings are consistent with other types of RP.  Findings include bone spicules/pigment clumping, chorioretinal atrophy, vessel attenuation, and optic nerve pallor.  Other findings can include the formation of posterior sub-capsular cataracts at a young age, a myopic refractive error, and macular edema.²

Electrophysiology findings will reveal reduced ERG amplitudes (rod involvement initially, with subsequent cone involvement) at a young age, with reductions to non-detectable levels as the patient ages. Visual field testing can show constriction of the visual field, ring scotomas, and islands of vision, which will also progress to non-detectable levels as the condition progresses.

Overall, the visual outcome of patients with XLRP is guarded.  Fishman et al reported in their study that patients are likely to have 20/200 or worse acuity by the fifth decade of life². Jay and Bird noted that patients would progress to 20/200 or worse by the third decade of life.¹⁷  A more recent study, however, found an even more aggressive vision loss in a Puerto Rican  family lineage.  They noted profound visual loss by the second decade of life with progression to near no light perception by age 60.¹⁸

Women who are carriers of the abnormal gene also can show signs of XLRP, but to a much lesser degree. Studies have shown that carriers usually have normal or near normal visual acuity with mild fundus changes.  These changes can include pigment in the retinal periphery and a tapetal like reflex in the posterior pole.  The tapetal reflex has also been described as a metallic sheen or hyper reflective pattern^4,6,7.  The origin of the reflex is unknown at this time, but theories have suggested it originates from reflective particles in the cone inner segments, deposits and degenerations in Bruch’s membrane, or degeneration of the RPE/photoreceptor complex⁴.

Relating to the tapetal reflection, Grover et al, noted that those women with only tapetal changes had a better prognosis in terms of visual function than those women with peripheral bone spiculing.¹⁹  Ancillary test findings can include thinning of the outer retina with spectral domain optical coherence tomography, visual field constriction, and normal or slightly subnormal ERG Findings^6,20.

Treatment

At this time, there is no cure for any type of RP;however, research studies with genetics and stem cells will most likely present the best hope for a cure.  One such study was performed in canines that model RP3 X-linked forms of retinitis pigmentosa.  Using an adeno virus containing a normal copy of the human RP3 gene, the canines showed reversal of opsin mis-localization in treated areas, reversal of bipolar cell dendrite retraction, and retention of outer plexiform layer thickness as compared to untreated areas as determined by OCT²¹.

Stem cell research on humans with RP has also begun at the University of California-Irvine; however, the primary objective of the trial is to determine the safety of a single injection of retinal progenitor cells into the eyes of patients with advanced RP.  No results are available at this time. However, if the treatment is proven to be safe, this could lead to further research assessing the effect of the treatment on ocular function.

The topic of vitamin supplementation in RP patients is a topic of particular interest. Previous studies have reported beneficial effects of vitamin A and/or fish oil (DHA) supplementation in slowing the progression of RP as measured by ERG testing.^22-25  Conversely, a recent Cochrane Review was performed studying the validity and strength of these studies.   Overall, the review studied three randomized control trials that evaluated the effectiveness of vitamin A, fish oils (DHA) or both in patients with RP.  The results revealed no clear evidence for benefit of treatment with vitamin A and/or DHA for people with RP, in terms of the mean change in visual field and ERG amplitudes at one year and the mean change in visual acuity at the five year follow-up.²⁶

One option that does exist for some patients is a retinal prosthesis called the Argus 2.  The device consists of three pieces: a camera mounted on glasses, a video processing unit, and the retinal prosthesis. The system works by direct stimulation of the relatively preserved inner retina via retinal microelectrodes, thereby replacing the function of the impaired photoreceptors. Specifically, visual data from the glasses-mounted video camera is transformed to a basic image by the video processing unit, before being transmitted to the retinal electrode array over the macula. Retinal responses are then sent via the optic nerve to the visual cortex for interpretation.^27,28  This device is not an option for all patients as only patients 25 years and older with RP that have advanced to the point of having bare light or no light perception in both eyes are eligible for the device.  Improvement of function in terms of orientation and mobility, target localization, shape and object recognition and reading of letters and short unrehearsed words have also been shown.  However, there remains a wide-ranging variability in the functional outcomes among the patients.  At this time, the factors that contribute to these differences are unknown.  Software and hardware updates, such as the ability to see color are being investigated for future models.²⁷  It should be mentioned that this device is a visual aid and not a cure for RP.

Although current research options are encouraging, standard treatment at this time should consist of referrals for genetic testing as the condition is X-linked.   Families, especially female carriers should be counselled on the potential of passing on the affected X gene to their children.

Patients should also be referred for low vision rehabilitation as they will need to learn how to adapt to their vision loss.  Traditional options can include hand magnifiers, stand magnifiers, and telescopes.  However, success with these devices depends on the amount of acuity and field loss the patient has.  Low vision technology including CCTVs, adaptive software, and optical character recognition devices should also be introduced depending on the stage of the XLRP.  Lastly, all patients should be referred for orientation and mobility training.

Conclusion:

XLRP is a devastating ocular disease with a complex pathophysiology.  Clinicians should be cognizant of the strong genetic component of the condition and provide or refer for appropriate genetic testing and counselling.  Although potential cures and treatment options are being investigated, all patients should be introduced to low vision rehabilitation.

References

1.            Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F. Retinitis pigmentosa: genes and disease mechanisms. Current genomics. Jun 2011;12(4):238-249.

2.            Fishman GA, Farber MD, Derlacki DJ. X-linked retinitis pigmentosa. Profile of clinical findings. Archives of ophthalmology. Mar 1988;106(3):369-375.

3.            Anasagasti A, Irigoyen C, Barandika O, Lopez de Munain A, Ruiz-Ederra J. Current mutation discovery approaches in Retinitis Pigmentosa. Vision research. Dec 15 2012;75:117-129.

4.            Genead MA, Fishman GA, Lindeman M. Structural and functional characteristics in carriers of X-linked retinitis pigmentosa with a tapetal-like reflex. Retina. Nov-Dec 2010;30(10):1726-1733.

5.            Berson EL, Sandberg MA, Rosner B, Birch DG, Hanson AH. Natural course of retinitis pigmentosa over a three-year interval. American journal of ophthalmology. Mar 15 1985;99(3):240-251.

6.            Acton JH, Greenberg JP, Greenstein VC, et al. Evaluation of multimodal imaging in carriers of X-linked retinitis pigmentosa. Experimental eye research. Aug 2013;113:41-48.

7.            Bird AC. X-linked retinitis pigmentosa. The British journal of ophthalmology. Apr 1975;59(4):177-199.

8.            Rubin R, Strayer DS, Rubin E. Rubin's Pathology: Clinicopathologic Foundations of Medicine. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.

9.            McClatchey KD. Clinical Laboratory Medicine. Lippincott Wiliams & Wilkins; 2002.

10.          Breuer DK, Yashar BM, Filippova E, et al. A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. American journal of human genetics. Jun 2002;70(6):1545-1554.

11.          Schwarz N, Hardcastle AJ, Cheetham ME. Arl3 and RP2 mediated assembly and traffic of membrane associated cilia proteins. Vision research. Dec 15 2012;75:2-4.

12.          Schwarz N, Hardcastle AJ, Cheetham ME. The role of the X-linked retinitis pigmentosa protein RP2 in vesicle traffic and cilia function. Advances in experimental medicine and biology. 2012;723:527-532.

13.          Li L, Khan N, Hurd T, et al. Ablation of the X-linked retinitis pigmentosa 2 (Rp2) gene in mice results in opsin mislocalization and photoreceptor degeneration. Investigative ophthalmology & visual science. Jul 2013;54(7):4503-4511.

14.          Zahid S, Khan N, Branham K, et al. Phenotypic conservation in patients with X-linked retinitis pigmentosa caused by RPGR mutations. JAMA ophthalmology. Aug 2013;131(8):1016-1025.

15.          Hosch J, Lorenz B, Stieger K. RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy. Ophthalmic genetics. Mar 2011;32(1):1-11.

16.          He S, Parapuram SK, Hurd TW, et al. Retinitis Pigmentosa GTPase Regulator (RPGR) protein isoforms in mammalian retina: Insights into X-linked Retinitis Pigmentosa and associated ciliopathies. Vision research. 2// 2008;48(3):366-376.

17.          Jay B, Bird A. X-linked retinitis pigmentosa. Transactions - American Academy of Ophthalmology and Otolaryngology. American Academy of Ophthalmology and Otolaryngology. Sep-Oct 1973;77(5):OP641-651.

18.          Tzu JH, Arguello T, Berrocal AM, et al. Clinical and Electrophysiologic Characteristics of a Large Kindred with X-linked Retinitis Pigmentosa Associated with the RPGR Locus. Ophthalmic genetics. Feb 20 2014.

19.          Grover S, Fishman GA, Anderson RJ, Lindeman M. A longitudinal study of visual function in carriers of X-linked recessive retinitis pigmentosa. Ophthalmology. Feb 2000;107(2):386-396.

20.          Alexander KR, Barnes CS, Fishman GA. ON-pathway dysfunction and timing properties of the flicker ERG in carriers of X-linked retinitis pigmentosa. Investigative ophthalmology & visual science. Sep 2003;44(9):4017-4025.

21.          Beltran WA, Cideciyan AV, Lewin AS, et al. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proceedings of the National Academy of Sciences of the United States of America. Feb 7 2012;109(6):2132-2137.

22.          Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Archives of ophthalmology. Jun 1993;111(6):761-772.

23.          Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Archives of ophthalmology. Sep 2004;122(9):1297-1305.

24.          Berson EL, Rosner B, Sandberg MA, et al. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses. Archives of ophthalmology. Sep 2004;122(9):1306-1314.

25.          Hoffman DR, Locke KG, Wheaton DH, Fish GE, Spencer R, Birch DG. A randomized, placebo-controlled clinical trial of docosahexaenoic acid supplementation for X-linked retinitis pigmentosa. American journal of ophthalmology. Apr 2004;137(4):704-718.

26.          Rayapudi S, Schwartz SG, Wang X, Chavis P. Vitamin A and fish oils for retinitis pigmentosa. The Cochrane database of systematic reviews. 2013;12:CD008428.

27.          Luo YH, da Cruz L. The Argus II Retinal Prosthesis System. Prog Retin Eye Res. Sep 25 2015.

28.          Humayun MS, Dorn JD, da Cruz L, et al. Interim results from the international trial of Second Sight's visual prosthesis. Ophthalmology. Apr 2012;119(4):779-788.